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Please Post Vitamins/Supplements used in with Prescription Stimulants

adderall dextroamphetamine amphetamine stimulant adhd dexedrine vitamin supplement herbs stack

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#31 medievil

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Posted 04 March 2016 - 08:58 PM





Zinc Glycinate


Magnesium lys-bi-glycinate



Chalk it up to personal brain chemistry or synergy but WOW one week in and still going very very strong. And yet i feel and behave as I normally do, just internal Bliss...hope its not psychosis.... :cool:

Errr what benefits are you getting, if you feel like you have eternal power over every human being that may be psychosis, or what do you mean  with internal bliss?

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#32 Mr. Psychillogical

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Posted 12 April 2016 - 02:37 AM

  1. I have:
    -- rhodiola rosea from (works slightly around 300 mg)
    -- caffeine pills (strong rush of anxiety + works for only 1 hour each 200 mg dose)
    -- L theanine (cannot notice anything even at 400 mg)
    -- Piracetam (tried 4 g for 3 days before switching to aniracetam because it may work faster. Didn’t take any choline source in combination and got bad brain fogs.)
    -- alpha gpc 50% (Currently using: as I've mentioned, 350 mg along with aniracetam. Alpha GPC kicked in within 20 minutes, and it seemed to work for me)
    -- pramiracetam (haven't tried yet)
    -- oxiracetam (tried 200 mg once, and it didn't do anything. I think it's too sketchy and understudied to use as a beginner with amphetamine)
    -- aniracetam currently using: 300 mg twice a day along with alpha gpc. Not sure if it is working yet
    -- L tyrosine from (extremely potent for me! 500 mg could make me euphoric for 5 hours! Sadly, its jittery + anxiety + incredulous mood swing + horrendous comedown + migraines are absolutely destructive to such a degree that I locked the bottle in a unused drawer)
    -- Gingko Bilbo, (haven’t tried yet)
    -- phenylethylamine from (In transit, will arrive soon! Ordered 2 days ago! I’ve heard a lot of good things about this as well! In laymen’s terms, this is basically a less stimulating version of l tyrosine that shares similar mechanism of action, right?)
    -- ashwagandha (haven’t tried it)
    -- Acetyl-L-Carnitine (In transit, will arrive soon!)
    -- Omega 3 fish oil (In transit, will be taken with aniracetam for fat solubility)

The reason why I have not used the supplements that are italicized is that I simply fear interactions. Amphetamines + all these additional brain altering stuff = I’ll just stick to one that may work the best for me + most likely replace amphetamine

  1. I am not that afraid of the short term interactions between literally the lowest dosage of aniracetam and dexedrine. I’m using the lowest dosage of aniracetam solely for quitting dexedrine. If x number of cell deaths will occur in this 2 weeks, so be it. It’s better than getting stuck on dexedrine forever.

  2. My plan is:
    -- Find the best supplement or nootropic that can replace amphetamine  find the right dosage that will function for me
    -- Taper off amphetamine as soon as I discover a decent replacement: the definition of decent replacement = something that keeps me sitting down + concentrating longer than 2 hours each dose.
    -- From then on, keep increasing dosage for the replacement herb or nootropic and lowering Dexedrine!
    -- No more restraining BS from Dexedrine!!!!

  3. I’d love to try vitamin B + magnesium calcium after aniracetam = suited in the stack. I prefer adding them one by one just to be extra cautious. Sounds so ironic coming from a desperate nootropic experimenter.

  4. Just an update, the second brainfog + lethargy from aniracetam + alpha gpc went away. This afternoon, I experienced no crash from dexedrine! Moreover, my attention span kept rotating till now. Can’t really tell that much of a difference, but it’s better than piracetam with no choline!

  5. My friend, recently, diet may not be a viable option because I’ve never ever been so appetite suppressed. For the past month of me trying to get off dexedrine, I have lost both appetite + libido + interest in anything. Absolutely nauseous + full for the entire day. I just ate twice today…

  6. I found aerobics to be very difficult recently, and therefore, I’m attempting to return to pushups + damn strength training bring back good memories and lots of endorphins for me personally!

  7. I will form a life style before quitting full on cold turkey. Cold turkeying without any plans/habits/routines is a failure for me. I feel like much more capable of forming them on dexedrine, and this is a beautiful + golden advice!

  8. Side effects when cold turkeying:
    -- Chronic boredom: everything’s just boring! I’d just walk around my house for hours! Painful!
    -- Anxiety: intertwined with boredom. Just very very anxious + a sense of hopelessness when I saw myself struggling so badly!
    -- Complete loss of motivation: like sky has lost its colors. I literally felt like a zombie. Lifeless…
    -- Even with brutal force, max attention timed with my video record (I really did it just to make sure I know if I was legit screwed) = 45 mins. After 45 mins, I nearly cried because I just couldn’t focus.
    -- Cognition below human: I stared a two lines of sentences in my English article (school) for 20 mins along with freakish anxiety + brain fog in a psychedelic level. I have severe ADHD, and this really happened a lot. I’m not sure if you can relate to this.

  9. Timing of cold turkeying: I think it really depends on how long it takes for me to find a good replacement. May last for a relatively long time, but as long as I can stay somewhat functional (8 hours of concentration min), I’m good. Furthermore, I will bring all dem bad supplements + herbs + vitamins on as soon as I get off with this little ****dexedrine. Lol.

  10. Tapering + dosage skipping:
    -- I may cut dexedrine to 7.5 mg for several days, and if I’m good there, I will cold turkey!!

  11. Today’s attention span was impressive: I wrote all these things within 1 hour and 20 mins, and it’s 8 pm already (which, for the most of the time, dexedrine’s effects = long gone), but today, it feels smooth. Maybe just placebo, but still better than nothing.

  12. Fear of withdrawal symptoms: For me, it was actually the opposite. I never knew dexedrine has that bad of an withdrawal until I was off it for 2 weeks. I felt like I was in another dimension for the first week. It was just… I felt detached from reality almost…

You might be interested in this article, which describes how to reduce the risks of amphetamine neurotoxicity: http://www.brainprotips.com/adde...

The gist is as follows: 
1. Supplement with vit. D3
2. Stay cool (don't overheat)
3. Take baby aspirin or another NSAID
4. Supplement with magnesium
5. Melatonin in the evening (XR is preferable) 
6. Use extremely low doses before moderate or high doses of amphetamine, because pre-treatment is neuroprotective
7. Avoid concurrent alcohol use
8. Supplement with NAC and selenium
9. Drink green tea
10. If you're hardcore about neuroprotection, get some minocycline

You might be interested in this article, which describes how to reduce the risks of amphetamine neurotoxicity: http://www.brainprotips.com/adde...

The gist is as follows: 
1. Supplement with vit. D3
2. Stay cool (don't overheat)
3. Take baby aspirin or another NSAID
4. Supplement with magnesium
5. Melatonin in the evening (XR is preferable) 
6. Use extremely low doses before moderate or high doses of amphetamine, because pre-treatment is neuroprotective
7. Avoid concurrent alcohol use
8. Supplement with NAC and selenium
9. Drink green tea
10. If you're hardcore about neuroprotection, get some minocycline

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Click HERE to rent this advertising spot for BRAIN HEALTH to support LongeCity (this will replace the google ad above).

#33 Mr. Psychillogical

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Posted 12 April 2016 - 01:34 PM

Possible stack/combo:


- Amphetamine


-Agmatine w/Grape seed extract

- Vit d3


-Tyrosine(low dose)








-zinc glycinate



#34 aftermeritword123

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Posted 14 April 2016 - 05:42 PM

Thanks for the great work :) Might help you in researching.

How often do you do amph? Is it pure, dextro? What's the dosage?

Edited by aftermeritword123, 14 April 2016 - 06:34 PM.

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#35 Mr. Psychillogical

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Posted 15 April 2016 - 03:34 AM


Thanks for the compliment,

That's a pretty personal question but i'll field it...

With my

Well researched supplement regime,


proper diet, 

has allowed me to take my prescribed 40 mg dextroamphetamine instant release successfully,

5- 6 days a week for about two years now.

Edited by Mr. Psychillogical, 15 April 2016 - 03:35 AM.

#36 Mr. Psychillogical

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Posted 21 April 2016 - 04:33 AM

Psychostimulants affect dopamine transmission through both dopamine transporter-dependent and independent mechanisms.

The precise mechanisms by which cocaine and amphetamine-like psychostimulants exert their reinforcing effects are not yet fully defined. It is widely believed, however, that these drugs produce their effects by enhancing dopamine neurotransmission in the brain, especially in limbic areas such as the nucleus accumbens, by inducing dopamine transporter-mediated reverse transport and/or blocking dopamine reuptake though the dopamine transporter. Here, we present the evidence that aside from dopamine transporter, non-dopamine transporter-mediated mechanisms also participate in psychostimulant-induced dopamine release and contribute to the behavioral effects of these drugs, such as locomotor activation and reward. Accordingly, psychostimulants could increase norepinephrine release in the prefrontal cortex, the latter then alters the firing pattern of dopamine neurons resulting in changes in action potential-dependent dopamine release. These alterations would further affect the temporal pattern of dopamine release in the nucleus accumbens, thereby modifying information processing in that area. Hence, a synaptic input to a nucleus accumbens neuron may be enhanced or inhibited by dopamine depending on its temporal relationship to dopamine release. Specific temporal patterns of dopamine release may also be required for certain forms of synaptic plasticity in the nucleus accumbens. Together, these effects induced by psychostimulants, mediated through a non-dopamine transporter-mediated mechanism involving norepinephrine and the prefrontal cortex, may also contribute importantly to the reinforcing properties of these drugs.


Effect of dopamine uptake inhibition on brain catecholamine levels and locomotion in catechol-O-methyltransferase-disrupted mice.

Two different uptake processes terminate the synaptic action of released catecholamines in brain: the high-affinity uptake to presynaptic nerve terminals (uptake(1), followed by oxidation by monoamine oxidase, MAO) or glial cells uptake (uptake(2), followed by O-methylation by catechol-O-methyltransferase, COMT, and/or oxidation by MAO). For dopaminergic neurons, uptake by the high-affinity dopamine transporter (DAT) is the most effective mechanism, and the contribution of glial COMT remains secondary under normal conditions. In the present study we have characterized the role of COMT using COMT-deficient mice in conditions where DAT is inhibited by 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)-piperazine (GBR 12909) or cocaine. In mice lacking COMT, GBR 12909 results in total brain tissue dopamine levels generally higher than in wild-type mice but no such potentiation was ever seen in striatal extracellular fluid. Dopamine accumulation in nerve endings is more evident in striatum and hypothalamus than in cortex. Both GBR 12909 and cocaine induced hyperlocomotion in mice lacking COMT. Unexpectedly, hyperactivity induced by 20 mg/kg GBR 12909 was attenuated only in male COMT knockout mice, i.e., they had an inability to sustain the hyperactivity induced by DAT inhibition. Furthermore, attenuation of hyperlocomotion was observed also after cocaine treatment in both C57BL/6 (at 5 and 15 mg/kg) and 129/Sv (at 30 mg/kg) genetic background COMT-deficient male mice. Despite the possible interaction between DAT and extraneuronal uptake (and subsequently COMT), the role of COMT in dopamine elimination is still minimal in conditions when DAT is inhibited.


Regulation of dopamine transporter function and plasma membrane expression by dopamine, amphetamine, and cocaine.

Pharmacological alterations in dopamine transporter (DAT) function not only modulate dopamine reuptake, but they can induce rapid changes in the plasmalemmal expression of the transporter. By modifying transporter membrane expression, drugs may alter the maximum rate of neurotransmitter clearance, shifting cellular transport capacity and disrupting normal receptor stimulation. DAT-interacting drugs include the illicit and highly abused psychostimulants amphetamine and cocaine. Regulation of transporter activity and plasma membrane expression by these drugs has been implicated in the long-term processes of reward and addiction. This review summarizes the regulation of DAT by transporter substrates and blockers with particular emphasis on the modulation of DAT cell surface expression by acute exposure to amphetamine and cocaine.


The effect of N-acetylcysteine on amphetamine-mediated dopamine release in rat brain striatal slices by ion-pair reversed-phase high performance liquid chromatography.

The amphetamine (AMPH)-induced alteration in rat brain dopamine levels modified by N-acetylcysteine (NAC) administration has been examined using isocratic ion-pair reversed-phase high-performance liquid chromatography with electrochemical detection. The aim of the development of a novel validated evaluation scheme implying a double AMPH challenge was to enhance the efficiency of AMPH-triggered dopamine release measurements in rat brain striatal slices by improving the reproducibility of the results. The proposed experimental protocol was tested in vivo and proved to be capable of fast and reliable drug screening for tracing the effect of NAC as a model compound in AMPH-mediated dopaminergic response. The subcellular localization of the dopamine mobilizing effect of NAC has been established indirectly by the use of an irreversible dopamine vesicular depletor, reserpine. The antioxidant NAC at 10 mM plays an important role in the complete suppression of acute AMPH-elicited dopamine release. The possible role of this quenching effect is discussed.


#37 Mr. Psychillogical

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Posted 21 April 2016 - 05:08 AM

Magnesium treatment palliates noise-induced behavioral deficits by normalizing DAergic and 5-HTergic metabolism in adult male rats.

Magnesium (Mg) is the fourth most abundant biological mineral essential for good health. Neuroprotective, anxiolytic and antidepressant effects of magnesium following stress and brain injuries are well established. In present study, we analyzed the protective effects of magnesium in rats exposed to sub-chronic noise stress. Magnesium Chloride (MgCl2, 100 mg/kg) was administered intraperitoneally once daily for 15 days prior exposure to noise stress. Rats were exposed to noise stress for 4 h after administration of magnesium for 15 days. At the end of treatment behavioral alterations were assessed. Animals were decapitated following behavioral testing and the brains were dissected out for neurochemical estimations by HPLC-EC. Improvement in noise-induced memory deficits as assessed by novel object recognition (NOR) test and elevated plus maze (EPM) test was found in magnesium treated rats. This improvement in noise-induced behavioral deficits following treatment with magnesium may be attributed to a significant decrease (p < 0.01) in dopamine (DA) and serotonin (5-hydroxytryptamine; 5-HT) turnover as compared to control rats observed in present work. These results suggest that treatment with magnesium can attenuate the noise-induced deficits and may be used as a therapy against noise-induced neurodegeneration. Moreover an adequate amount of magnesium in daily diet may help to develop the ability to resist against or cope up with stressful conditions encountered in daily life.

Baicalin may have a therapeutic effect in attention deficit hyperactivity disorder.

Baicalin is a flavonoid purified from Scutellaria baicalensis Georgi. It possesses a variety of pharmacological properties, such as anti-inflammatory, antioxidant, antiapoptotic, and neuro-protective properties, and provides protection against cerebral hemorrhage. However, it is seldom considered a therapeutic in mental disorders. Recent studies showed that baicalin protects cerebral functions against ischemia and has sedative and anxiolytic-like effects. Animal experiments showed that it protects dopaminergic neurons in the striatum, hippocampus and substantia nigra. It also has effects such as anti-depressive and anti-epileptic and offers resistance to Parkinson's.


Oroxylin A improves attention deficit hyperactivity disorder-like behaviors in the spontaneously hypertensive rat and inhibits reuptake of dopamine in vitro.

In previous studies we have demonstrated that the γ-aminobutryic acid-A (GABA-A) receptor antagonist oroxylin A has an awakening effect and it also represses ADHD-like behaviors (hyperactivity, impulsivity and inattention) in the spontaneously hypertensive rat (SHR) model of attention-deficit hyperactivity disorder (ADHD). We hypothesized that the effects of oroxylin A were exerted via the GABA-A receptor given the important role of the GABAergic system in ADHD. However, it is possible that aside from the GABAergic system, oroxylin A may influence other systems especially those implicated in ADHD (e.g. DAergic, etc.). To test this hypothesis, we evaluated the effects of GABA agonist, or dopamine (DA) antagonist in oroxylin A-induced alleviation of ADHD-like behaviors in SHR. SHR showed inattention and impulsivity as measured by the Y-maze and the electro-foot shock aversive water drinking tests, respectively. Oroxylin A significantly improved these behaviors, furthermore, its effect on SHR impulsivity was attenuated by haloperidol, a DA antagonist, but not by baicalein, an agonist of the GABA-A receptor. In vitro studies showed that oroxylin A inhibited DA uptake similar to methylphenidate, a dopamine transporter blocker, but did not influence norepinephrine uptake unlike atomoxetine, a selective NE reuptake inhibitor. Collectively, the present findings suggest that oroxylin A improves ADHD-like behaviors in SHR via enhancement of DA neurotransmission and not modulation of GABA pathway as previously reported. Importantly, the present study indicates the potential therapeutic value of oroxylin A in the treatment of ADHD.


Role of monoaminergic system in the etiology of olive oil induced antidepressant and anxiolytic effects in rats.

Olive oil is the major component of the Mediterranean diet and has rich history of nutritional and medicinal uses. In the present study, the antidepressant and anxiolytic effects and their neurochemical basis following repeated administration of extravirgin olive oil were monitored. Male albino Wistar rats were used during study. Animals of test group were given olive oil orally at the dose of 0.25 mL/kg daily for 4 weeks. Control rats received equal volume of water. Elevated-plus maze (EPM) test and forced swim test (FST) were performed for the assessment of anxiety and depression like symptoms. An increase in time spent in open arm in EPM and increased struggling time in FST following long-term administration of olive oil indicate that olive oil has anxiolytic and antidepressant properties. Neurochemical results showed that repeated administration of olive oil decreased the levels of brain 5-HT (5-hydroxytryptamine), 5-HIAA (5-hydroxyindoleacetic acid), and levels of DA (dopamine); however, levels of DA metabolite HVA (homovalinic acid) were increased. Hence, present findings suggest that olive oil has neuroprotective effects. It reduces behavioral deficits via altering 5-HT and DA metabolism. So it could be used as a therapeutic substance for the treatment of depression and anxiety.


Antidepressant-like effect of Salvia sclarea is explained by modulation of dopamine activities in rats.

The purpose of the present study was to screen aromatic essential oils that have antidepressant effects to identify the regulatory mechanisms of selected essential oils.


The antidepressant effects of essential oils of Anthemis nobilis (chamomile), Salvia sclarea (clary sage; clary), Rosmarinus officinalis (rosemary), and Lavandula angustifolia (lavender) were assessed using a forced swim test (FST) in rats. Rats were treated with essential oils by intraperitoneal injection or inhalation. Serum levels of corticosterone were assessed by enzyme-linked immunosorbent assay (ELISA).


Among the essential oils tested, 5% (v/v) clary oil had the strongest anti-stressor effect in the FST. We further investigated the mechanism of clary oil antidepression by pretreatment with agonists or antagonists to serotonin (5-HT), dopamine (DA), adrenaline, and GABA receptors. The anti-stressor effect of clary oil was significantly blocked by pretreatment with buspirone (a 5-HT(1A) agonist), SCH-23390 (a D(1) receptor antagonist) and haloperidol (a D(2), D(3), and D(4) receptor antagonist).


Our findings indicate that clary oil could be developed as a therapeutic agent for patients with depression and that the antidepressant-like effect of clary oil is closely associated with modulation of the DAnergic pathway.


#38 Mr. Psychillogical

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Posted 01 May 2016 - 06:45 PM

Dextroamphetamine Enhances “Neural Network-Specific” Physiological Signals: A Positron-Emission Tomography rCBF Study
Previous studies in animals and humans suggest that monoamines enhance behavior-evoked neural activity relative to nonspecific background activity (i.e., increase signal-to-noise ratio). We studied the effects of dextroamphetamine, an indirect monoaminergic agonist, on cognitively evoked neural activity in eight healthy subjects using positron-emission tomography and the O15 water intravenous bolus method to measure regional cerebral blood flow (rCBF). Dextroamphetamine (0.25 mg/kg) or placebo was administered in a double-blind, counterbalanced design 2 hr before the rCBF study in sessions separated by 1–2 weeks. rCBF was measured while subjects performed four different tasks: two abstract reasoning tasks—the Wisconsin Card Sorting Task (WCST), a neuropsychological test linked to a cortical network involving dorsolateral prefrontal cortex and other association cortices, and Ravens Progressive Matrices (RPM), a nonverbal intelligence test linked to posterior cortical systems—and two corresponding sensorimotor control tasks. There were no significant drug or task effects on pCO2 or on global blood flow. However, the effect of dextroamphetamine (i.e., dextroamphetamine vs placebo) on task-dependent rCBF activation (i.e., task − control task) showed double dissociations with respect to task and region in the very brain areas that most distinctly differentiate the tasks. In the superior portion of the left inferior frontal gyrus, dextroamphetamine increased rCBF during WCST but decreased it during RPM (ANOVA F (1,7) = 16.72, p < 0.0046). In right hippocampus, blood flow decreased during WCST but increased during RPM (ANOVAF (1,7) = 18.7, p < 0.0035). These findings illustrate that dextroamphetamine tends to “focus” neural activity, to highlight the neural network that is specific for a particular cognitive task. This capacity of dextroamphetamine to induce cognitively specific signal augmentation may provide a neurobiological explanation for improved cognitive efficiency with dextroamphetamine.
Dextroamphetamine rCBF PET monoamines dopamine working memory hippocampus dorsolateral prefrontal cortex
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The modulatory effects of monoaminergic neurotransmitters on neurophysiological function in the cortex have been shown previously in animal and human studies. Early studies of sensory stimulation in monkeys demonstrated that monoamines suppress spontaneous background neural firing while specifically enhancing cortical neural responses to a sensory stimulus (Foote et al., 1975).Segal and Bloom (1976b) demonstrated that norepinephrine exaggerated inhibition of hippocampal response to an unconditioned tone, and then enhanced the excitatory response to that same tone once it became a conditioned stimulus for reward. Norepinephrine also has been shown (Woodard et al., 1979) to enhance signal-to-noise (STN) responses in many other brain areas including the somatosensory cortex, cerebellum, lateral geniculate nucleus, and spinal trigeminal nucleus. Brozoski et al. (1979) reported that depletion of dopamine in prefrontal cortex impaired the ability of monkeys to perform delayed-response tasks, similar to ablation of the dorsolateral prefrontal cortex (DLPFC).Sawaguchi and Goldman-Rakic (1991) found that local pharmacological blockade of D1 receptors in the DLPFC impaired performance on an oculomotor delayed-response task. Weinberger et al. (1988) demonstrated in schizophrenic patients that central dopamine levels, as evidenced by CSF concentration of the dopamine metabolite homovanillic acid, predicted prefrontal regional cerebral blood flow (rCBF) during performance of a prefrontally linked task, the Wisconsin Card Sorting Task (WCST). Recently, an inverted U-type dose–response relationship has been shown between D1 receptor stimulation in the prefrontal cortex and delay-related prefrontal cortex neuronal firing (Williams and Goldman-Rakic, 1995) or delayed-response performance (Murphy et al., 1996). Their report confirms earlier studies by Bauer and Fuster (1978)and Arnsten and Goldman-Rakic (1990) that showed that there appears to be an optimal range of dopamine stimulation in the prefrontal cortex and that either too little or too much dopamine results in diminished prefrontal cortex function.
The STN effects of monoamines on neurophysiological function are further supported by studies using monoamine agonists. Segal and Bloom (1976a) reported that dextroamphetamine could facilitate self-stimulating behavior and reduce spontaneous cell discharges in the hippocampus, actions that are seen with locus ceruleus stimulation and are thought to be mediated by norepinephrine. More recently, in a study on the effects of amphetamine on cognitively related rCBF patterns in schizophrenic patients, Daniel et al. (1991), using xenon −133 dynamic single photon emission computer tomography to measure rCBF while subjects performed the WCST, demonstrated a striking effect of dextroamphetamine on task-dependent activation of rCBF. In contrast to placebo, dextroamphetamine produced specific and selective activation of the DLPFC, and this correlated with improved performance on the task. However, this earlier study was undertaken in an illness-specific population with a limited resolution rCBF technique.
Dextroamphetamine is a nonspecific indirect monoamine agonist (Weiner, 1972). Under certain circumstances, it has been shown to improve cognitive efficiency and measures of attention (Robins and Everitt, 1987). The preliminary rCBF data from studies of patients with schizophrenia (Daniel et al., 1991) suggest that its cognitive effects may be related to its capacity to modulate cognitively related cortical STN. We undertook the present study to explore this possibility further. In particular, we sought to examine the following: (1) Does the effect of dextroamphetamine on enhancing cortical STN extend to normal subjects, to cognitive tasks other than the WCST, and to cortical regions other than the frontal lobes? (2) If so, does the regional pattern of the effect differ according to different regional demands of the task? To date, there is no study of normal subjects that has examined monoamine-related task-specific rCBF changes with these goals.
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Subjects. Eight healthy subjects (four males and four females, mean age 25 years, range 22–32 years) were studied in a double-blind placebo-controlled manner. Each subject signed informed consent to participate in this study, which had the approval of the National Institutes of Mental Health institutional review board and the National Institutes of Health radiation safety committee. The subjects were screened for past and present history of neurological, psychiatric, or substance abuse problems, and had no history of other medical problems or medical treatment relevant to cerebral metabolism and blood flow. Subjects were instructed to refrain from nicotine and caffeine for 4 hr and from over-the-counter medications for 24 hr before the positron-emission tomography (PET) scan.
PET scans. rCBF measurements were made using the O15 water intravenous bolus PET technique. A total of eight measurements, four each on two separate days, were carried out in each subject. For each rCBF measurement, subjects received an intravenous bolus of 37.5 mCi of O15water 1 min after initiation of the cognitive or sensorimotor control task. The PET scans were performed on a Scanditronix PC2048–15B brain tomograph (15 contiguous slices; reconstructed in-plane resolution 6–6.5 mm; axial resolution 6.5 mm). During the scan procedure, the subjects lay supine with their heads immobilized in a thermoplastic mask. The time course of regional cerebral radiation concentration was determined simultaneously for the 15 slices by collecting a total of 16 scans (12 × 10 sec, 4 × 30 sec) during the 4 min after arrival of the tracer in the brain. The slices were obtained parallel to the canthomeatal line, and the lowest slice was collected 16 mm above the canthomeatal line. Transmission scans obtained in the same planes as the PET scans were used to correct for count attenuation by tissue and skull. Scan data were reconstructed with corrections for attenuation, scatter, random coincidences, and deadtime.
An arterial input function was measured via automated arterial blood sampling, with blood withdrawn continuously at a rate of 3.8 ml/min, and coincident events were counted by paired sodium iodide detectors and corrected for random coincidences and dispersion (Daube-Witherspoon et al., 1992). The arterial time–activity curve was fitted with a least-squares method (Koeppe et al., 1985) on a pixel-by-pixel basis to the real time–activity curves to produce quantitative images of rCBF. For regional analyses, rCBF values for each pixel then were expressed as a percentage of the mean rCBF value for the entire brain (i.e., the data were “normalized” to the global mean).
Cognitive tasks. rCBF was measured while subjects performed two cognitive tasks, the Wisconsin Card Sorting Task (WCST) and Ravens Progressive Matrices (RPM), and two matching sensorimotor control tasks, Wisconsin Card Sorting Control (WCSC) and Ravens Progressive Matrices Control (RPMC).
The WCST has for many years been a standard of neuropsychological testing of the prefrontal cortex in man. The WCST increases rCBF in DLPFC in normal subjects (Weinberger et al., 1986; Berman et al., 1995) and is particularly sensitive to dysfunction of DLPFC (Milner, 1963;Milner and Petrides, 1984). For this study, a computerized version of the WCST was used. Subjects viewed a computer screen that displayed five boxes. Subjects were asked to match the contents of the center box to one of the four outside boxes. Subjects were not informed of how to make the match, but had to determine from trial and error whether to match on the basis of color, shape, or number using feedback displayed on the screen after each response. After the subject has made a series of correct responses, the “rule” changes and subjects must determine a new rule for matching. The sensorimotor control task for the WCST was a no-delay, matching-to-sample task designed to be similar to the WCST in visual stimulation and motor response requirements, but without the abstract reasoning and working memory components of the WCST. Subjects simply matched the central target stimulus to one of four unchanging surrounding answer boxes. Stimuli were presented on a computer monitor mounted above the subject. For both tasks, subjects responded to each trial with a minimum of motor activity by pushing one of the four buttons arranged in a cross-shaped array corresponding to the arrangement of answers on the screen. The buttons were mounted on a 2 × 3 × 0.5 inch response box that was held in the right hand. Before the PET scans, subjects were trained in this mode of response until the association between the answer on the screen and the corresponding button became automatic.
RPM was first published in 1938 as a nonverbal “test of a person’s present capacity to form comparisons, reason by analogy, and develop a logical method of thinking, and of innate inductive ability” (Raven, 1938). It is generally accepted as a measure of general intelligence and has been shown to correlate with a number of standardized intelligence tests. Previous studies have shown that posterior cortical regions and hippocampus are especially activated (Berman et al., 1988;Haier et al., 1992; Ostrem et al., 1993) in association with this task. For this test, subjects are shown pictures of matrices (i.e., related patterns), each of which is a figural design with a part removed. The subject must choose the correct missing part from six to eight alternatives shown in the same visual frame. The matrices increase in difficulty as the test continues. The control task was a simple no-delay “match-to-sample” task. Subjects were asked to report verbally their choices for both of the RPM conditions.
Because each subject underwent the study on two separate occasions (drug or placebo), to minimize learning effect, subjects were given instructions on the performance of the tasks and were allowed to practice the tasks before they were taken into the scanning room. For RPM, the matrices on which the subjects practiced were not repeated and a fresh set of matrices were used during each scanning session. Tasks were begun 1 min before the injection of O15water and were continued throughout the ensuing 4 min of the scan period. Performance on the WCST was scored as per Heaton et al. (1993), whereas performance of RPM was analyzed as percent of correct trials.
Test conditions and drug administration. Subjects were studied in a double-blind cross-over design during two PET sessions separated by 1 to 2 weeks. Each session consisted of an initial sham resting procedure performed to acclimatize the subject to the procedure, followed by four separate rCBF measurements made during performance of the two cognitive tasks (WCST and RPM) and their matching sensorimotor control tasks (WCSC and RPMC). The order of the tasks was counterbalanced across subjects, but kept constant for the two visits of each subject. Approximately 120 min before each PET session, subjects received an oral dose of either placebo or dextroamphetamine (0.25 mg/kg). Timing of administration of dextroamphetamine was based on pharmacokinetic data indicating that plasma levels of dextroamphetamine administered orally peak 2–3 hr after administration (Angrist et al., 1987). The order of the drug and placebo administration also was counterbalanced across subjects. A simple mood rating scale (Goldberg et al., 1991) was administered before and 2 hr after administration of the drug. Profile of Mood States (POMS) (McNair et al., 1992) and Speilberger anxiety scales (Speilberger, 1983) also were administered after the PET scans on each test day. Arterial pCO2 levels were determined at the end of each scan. Blood pressure and heart rate were obtained at baseline and every half hour for 2 hr after administration of the drug. Serum drug levels were obtained at the beginning of each PET session and at the end of each rCBF measurement. Serum dextroamphetamine levels were measured using gas chromatography analysis (National Psychopharm Laboratories, Knoxville, TN) with a sensitivity of 5 ng/ml. Because of technical difficulties, only seven of the eight subjects had serum amphetamine levels measured.
Image processing and statistical analysis. Coplanar magnetic resonance image (MRI) scans were obtained for each subject using the same external landmarks as for the PET scan (i.e., the canthomeatal line). As for the PET studies, a set of fifteen 6.5-mm-thick T2-weighted MRI slices were obtained. Each of the PET scans of a given subject were coregistered to his or her MRI scan using ANALYZE (Biomedical Imaging Resource, Mayo Foundation), a three-dimensional contour matching algorithm (Jaing et al., 1992). Individualized regions of interest (ROIs) for each subject were drawn on the MRIs for a variety of cortical and subcortical regions. Cortical ROIs included inferior, middle, and superior frontal gyri and superior temporal, parietal, and occipital cortices. Anterior cingulate, thalamus, caudate, putamen, and hippocampal ROIs also were drawn (Fig.1). These individualized ROI templates then were applied to the coregistered PET rCBF scans of each subject, and the mean normalized rCBF value for each ROI for each of the task conditions was determined. To reduce the number of comparisons, area-weighted averages for like structures were combined across several slices as reported previously (Berman et al., 1995). This ROI approach was chosen because of previous experience with it in the analysis of rCBF data associated with these tasks. For global CBF and each region separately, a 2 × 2 ANOVA with two repeated measures (task and drug) was performed to assess the interaction between drug and task. Post hoc matched-pairt tests between drug and/or task conditions, pCO2, global CBF, and task performance scores also were performed. Because each subject had serum amphetamine levels measured five times at ∼12 min intervals, one-way ANOVA was performed to determine whether there was a significant change in amphetamine levels over time.
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The results of this study show that dextroamphetamine, although having no clear global CBF effects, induced cognitive-specific signal changes in selected cortical areas. During the WCST, there was increased “signal” relative to the control task (i.e., activation) in the superior portion of the left inferior frontal gyrus, a region shown in several other studies to be consistently activated by performance of this task (Berman et al., 1986, 1995; Weinberger et al., 1986, 1988; Rubin et al., 1991; Marenco et al., 1993; Catafau et al., 1994), and relatively decreased activation of the right hippocampus, an area not normally activated (Berman et al., 1995). In contrast, during RPM, amphetamine evoked an opposite pattern of regional changes, i.e., increased right hippocampal “signal” and decreased activation in the left inferior frontal gyrus. We will discuss these findings as they relate to four issues: (1) the regional specificity of the tasks; (2) the effects of monoamines on cortical activity; (3) the regionally specific neuromodulatory effect of monoamines; and (4) the regional and “task-specific” neuromodulatory effect of dextroamphetamine.
Regional specificity of the tasks
Although both WCST and RPM are thought to involve abstract reasoning and problem solving, they differ along a number of important dimensions that may explain the differences in the neural systems most crucial for the performance of each task. RPM, although generally accepted as a good indicator of general intelligence, involves considerably more visuospatial processing and computational problem solving than does the WCST. Additionally, although WCST trial processing occurs over very short periods of time (2–3 sec), RPM trials occur over considerably longer durations, suggesting that RPM might also differ from the WCST by requiring more long-term mnemonic processes. Animal studies suggest that working memory tasks with short delays analogous to the WCST may be mediated by DLPFC (Goldman-Rakic and Rosvold, 1970), whereas tasks with longer delays also may require mediation by the hippocampus (Zola-Morgan and Squire, 1985). Milner (1963, 1964) has shown that the WCST is a sensitive indicator of the integrity of the DLPFC, and patients with frontal lobe pathology do poorly on this task. In contrast, although patients with postrolandic lesions do poorly on the RPM (Basso et al., 1973), there is no evidence that patients with prefrontal lesions have particular difficulty with it.
In a study on normal subjects and patients with schizophrenia, a disease process wherein dysfunction of the prefrontal cortex has been implicated (Weinberger et al., 1986), Berman et al. (1988) demonstrated that normal subjects did not activate DLPFC while performing RPM to the degree that they did during the WCST (Weinberger et al., 1986). In addition, they demonstrated that schizophrenic patients, like normal subjects, had maximal rCBF elevations posteriorly with no significant DLPFC deficit while performing the RPM. Recently, Ostrem et al. (1993), while demonstrating common areas of activation for the two tasks, i.e., the superior portion of the inferior frontal gyrus (Brodman areas 9 and 46), the occipital lobe, and inferior parietal lobule (areas 7 and 40), found that DLPFC activation was greater during the WCST. They also demonstrated differential activation of the hippocampus. Hippocampal activation increased during RPM but showed a relative decrease during WCST. From these studies, it can be inferred that WCST and RPM have different evoked neural patterns and that DLPFC probably is more critical for WCST performance and hippocampus for RPM performance. Our present data suggest that amphetamine exaggerates these specific neurofunctional differences between the tasks by enhancing the neural activation signals in the regions that are differentially most critical for the various cognitive operations involved.
Effects of monoamines on cortical activity
A diverse range of findings have been reported on the effects of administration of amphetamine, a nonspecific monoamine agonist, on cortical activity in animals and humans. Although some animal studies (Nahorski and Rogers, 1973; Carlsson et al., 1975; Berntman et al., 1976, 1978; McCulloch and Harper, 1977; Neuser and Hoffmeister, 1977;Wechsler et al., 1979; Porrino et al., 1983) reveal diffuse increases in cerebral blood flow and glucose metabolism after acute parenteral administration in the resting state, other reports using sensory and/or behavioral activation paradigms suggest that dopamine and norepinephrine suppress spontaneous neural firing while specifically enhancing the capacity of neural systems to increase activity focally in response to a specific stimulus or task (Foote et al., 1975; Johnson et al., 1983; Sawaguchi, 1987). These studies along with other animal studies (Bunney et al., 1987; Robins and Everitt, 1987) suggest that catecholamines modulate the ratio of neurofunctional STN. Our present data are consistent with these observations: during each of the two task paradigms, cortical activity increased in those areas most critical for the task (i.e., increased physiological “signal”), but decreased in areas that may be less critical (i.e., decreased “noise”).
Regionally specific neuromodulatory effects of monoamines
There is evidence supporting the regionally specific neuromodulatory role of the different monoamines. Selective dopaminergic neurotransmission in the DLPFC has been shown to be important in carrying out tasks involving working memory (Sawaguchi and Goldman-Rakic, 1991; Williams and Goldman-Rakic, 1995). In a like manner, there are electrophysiological studies (Glowinski et al., 1984;Mantz et al., 1988; Mogenson and Yim, 1991) and imaging studies that support the neuromodulatory role of dopamine at this site. Daniel et al. (1989) demonstrated that the dopamine receptor agonist apomorphine augmented relative rCBF in schizophrenic patients while they performed the WCST. Friston et al. (1992) reported that in normal subjects during performance of a verbal memory task, apomorphine attenuated rCBF increases in DLPFC and augmented rCBF in the posterior cingulate. Kapur et al. (1994) described similar findings with apomorphine. More recently, Dolan et al. (1995) demonstrated that cognitive task-related activation of the anterior cingulate cortex in schizophrenic patients can be modulated by apomorphine. Despite the focus on dopamine, norepinephrine appears to have as important an influence on prefrontal cortex function. Li and Mei (1994) have shown that infusion of yohimbine, an α2 antagonist, into the DLPFC markedly impairs delayed-response performance in a delay-dependent manner, paralleling the effects seen by Sawaguchi and Goldman-Rakic with dopamine (1991).
Similarly, monoamine agonists have been shown to have neuromodulatory effects in the hippocampal region. Segal and Bloom (1976a) demonstrated the facilitating action of dextroamphetamine in inhibiting spontaneous cellular discharges in the hippocampus, presumably attributable to norepinephrine agonism. Using buspirone, an anxiolytic with predominantly 5-HT1A agonistic effects, Coop and McNaugghton (1991)demonstrated that reduction in hippocampal rhythmical slow activity in rats was mediated by 5-HT1A receptors and not by D2 receptors. Similarly, 5-HT agonists modulate CA1 pyramidal cell firing patterns (Sprouse and Aghajanian, 1988). Likewise, Friston et al. (1992)reported that in normal subjects during performance of a verbal memory task, buspirone attenuated blood flow increases in the retrosplenial region. Monoaminergic neuromodulatory effects thus can be differentiated at two discrete brain areas (DLPFC and hippocampus) that are implicated in the functional anatomy of memory, and also highlighted in the results of this study. Our data are consistent with the interpretation that the effects of dopamine on prefrontal working memory play a major role during the WCST, whereas 5-HT affects hippocampal function during RPM, but we cannot exclude the possibility that both regional findings may result from dopaminergic and/or noradrenergic effects.
Anatomic and “task-specific” neuromodulatory effect of dextroamphetamine
The effect of amphetamine on monoaminergic activity is nonspecific, including release of dopamine, norepinephrine, and 5-HT from storage sites in nerve terminals (Weiner, 1972, 1980; Moore, 1978;Creese, 1983; Kuczenski, 1983, 1989; Glennon et al., 1987). Although the D-isomer of amphetamine, dextroamphetamine, is relatively more selective in enhancing dopaminergic activity, effects on other monoamines such as 5-HT and norepinephrine also have been observed (Bonhomme et al., 1995; West et al., 1995). Thus, the rCBF effects in this study, although likely related primarily to dopaminergic activity, also may involve an interplay of different monoamines.
Our results, although supporting the notion that performance of the two abstract reasoning neuropsychological tasks used in this study is dependent on different neural systems subserving different aspects of memory, also support the notion that dextroamphetamine has the capacity to differentially modulate these neural systems. The hippocampal region has been implicated in tasks requiring spatial memory (Parkinson et al., 1988; Rolls, 1991; O’Keefe, 1993) and working memory that involve long processing times (Goldman-Rakic and Friedman, 1988) and is activated by RPM. Similarly, there is converging evidence supporting the role of DLPFC for the performance of the WCST (Milner, 1963, 1964;Berman et al., 1995). Dextroamphetamine, presumably through its effects on monoaminergic neurotransmission, appears to selectively enhance the signal in the hippocampal region during performance of RPM and in the DLPFC during WCST.
It should be noted that these task-based, regionally specific effects of dextroamphetamine on rCBF were accompanied by a statistically significant improvement in the performance of RPM (increase in percent of correct responses). In contrast, no significant difference was noted in performance of the WCST. This lack of improvement in performance during the WCST may be because (1) the subjects were made to practice the tasks before scanning sessions to preclude any learning effect, and (2) it is likely that there was a ceiling effect on the performance of the WCST, the simpler task. In contrast, for RPM, because separate sets of matrices were used for the practice and scanning sessions, there was no ceiling effect, leaving room for improvement.
Our data suggest that dextroamphetamine, rather than having a fixed pharmacological effect on rCBF patterns, enhances the specific neural systems called on for optimal performance of a certain task. During cognitive tasks that have regionally different activation patterns, dextroamphetamine enhances the distinctiveness of the individual patterns and accentuates their differences. These neurophysiological effects of dextroamphetamine may explain its positive impact on cognitive efficiency.

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Edited by Mr. Psychillogical, 01 May 2016 - 06:50 PM.

#39 Mr. Psychillogical

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Posted 01 May 2016 - 07:23 PM

Chronic inositol increases striatal D(2) receptors but does not modify dexamphetamine-induced motor behavior. Relevance to obsessive-compulsive disorder.

A large body of evidence suggests that the neuropathology of obsessive-compulsive disorder (OCD) lies in the complex neurotransmitter network of the cortico-striatal-thalamo-cortical (CSTC) circuit, where dopamine (DA), serotonin (5HT), glutamate (Glu), and gamma-amino butyric acid (GABA) dysfunction have been implicated in the disorder. Chronic inositol has been found to be effective in specific disorders that respond to selective serotonin reuptake inhibitors (SSRIs), including OCD, panic, and depression. This selective mechanism of action is obscure. Since nigro-striatal DA tracts are subject to 5HT(2) heteroreceptor regulation, one possible mechanism of inositol in OCD may involve its effects on inositol-dependent receptors, especially the 5HT(2) receptor, and a resulting effect on DA pathways in the striatum. In order to investigate this possible interaction, we exposed guinea pigs to oral inositol (1.2 g/kg) for 12 weeks. Subsequently, effects on locomotor behavior (LB) and stereotype behavior (SB), together with possible changes to striatal 5HT(2) and D(2) receptor function, were determined. In addition, the effects of chronic inositol on dexamphetamine (DEX)-induced motor behavior were evaluated. Acute DEX (3 mg/kg, ip) induced a significant increase in both SB and LB, while chronic inositol alone did not modify LA or SB. The behavioral response to DEX was also not modified by chronic inositol pretreatment. However, chronic inositol induced a significant increase in striatal D(2) receptor density (B(max)) with a slight, albeit insignificant, increase in 5HT(2) receptor density. This suggests that D(2) receptor upregulation may play an important role in the behavioral effects of inositol although the role of the 5HT(2) receptor in this response is questionable.





Molecular mechanisms underlying forskolin-mediated up-regulation of human dopamine D2L receptors.

1. Human dopamine (DA) D2long (hD2L) receptors, expressed by Ltk- cells, can be up-regulated by treating the cells with forskolin for 16 hr (Johansson and Westlind-Danielsson, 1994). We have examined some of the molecular mechanisms underlying this forskolin-mediated up-regulation. 2. Forskolin (100 microM, 16 hr), but not 1,9-dideoxyforskolin, a forskolin analogue that is unable to activate adenylyl cyclase and raise intracellular cAMP concentrations, up-regulates the hD2L receptor population by 43%. The implication of a cAMP-dependent increase in the receptor up-regulation was further substantiated by treating the cells with 8-bromo-cAMP or prostaglandin E1 (PGE1). The forskolin-mediated rise in receptor number was blocked by cycloheximide or an antisense phosphorothioate oligodeoxynucleotide (ODN) directed toward the hD2L mRNA. KT5720, a specific protein kinase A (PKA) inhibitor, completely blocked the receptor rise, whereas pertussis toxin (PTX) attenuated the increase considerably. Forskolin also produced an increase in the level of the DA hD2short (hD2S) receptor expressed by Ltk- cells. This increase was 2.5-fold higher than that found for the hD2L receptor. 3. The forskolin-mediated hD2L receptor rise is dependent on de novo protein synthesis, a rise in cAMP levels, PKA activation, and, at least partially, PTX-sensitive G proteins. 4. Long-term increases in intracellular cAMP levels may change the sensitivity of a DA receptor expressing cell to DA by increasing D2 receptor density through enhanced cAMP-dependent transcription.


Dopamine D2 receptor upregulation in rat neostriatum following in vivo infusion of forskolin

INTRACEREBROVENTRICULAR (i.c.v.) forskolin infusion for 5 days resulted in a concentration-dependent increase in rat striatal dopamine (DA) D2 receptors measured with [3Hjraclopride. In animals given 50 nmol/h forskolin, the highest concentration used, raclopride-mediated suppression of spontaneous locomotor activity was attenuated, and (±)-7-hydroxy-dipropyl-amino-tetralin HBr (7-OH-DPAT)-mediated inhibition of striatal DA synthesis, as estimated by the accumulation of DOPA following inhibition of cerebral decarboxylase, was enhanced. These data suggest that the DA D2 receptor increase comprises receptors localized both post- and presynaptically. The density of striatal DA D1 receptors was also changed with the forskolin treatment, in a concentration-dependent fashion, but in the opposite direction to DA D2 receptors. These findings suggest that striatal DA receptor sensitivity can be changed by manipulation at the second messenger level (e.g. independent of direct neurotransmitter-receptor interactions) in vivo.


#40 Mr. Psychillogical

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Posted 22 May 2016 - 04:27 AM

Effects of buspirone on dopamine dependent behaviours in rats.

Buspirone, a partial agonist of 5-hydroxytryptamine autoreceptors, selectively blocks presynaptic nigrostriatal D2 dopamine (DA) autoreceptors. At doses which antagonised action of apomorphine in biochemical presynaptic nigrostriatal D2 DA autoreceptor test systems buspirone neither induced catalepsy nor antagonised apomorphine-induced turning behaviour in rats indicating that at these doses buspirone does not block postsynaptic striatal D2 and D1 DA receptors. This study determines whether at high doses buspirone blocks postsynaptic striatal D2 and D1 DA receptors and provides behavioural evidence for selective blockade of presynaptic nigrostriatal D2 DA autoreceptors by smaller doses of buspirone. We investigated in rats whether buspirone induces catalepsy and effect of its pretreatment on DA agonist induced oral stereotypies and on cataleptic effect of haloperidol and small doses (0.05, 0.1 mg/kg, ip) of apomorphine. Buspirone at 1.25, 2.5, 5 mg/kg, ip neither induced catalepsy nor antagonised apomorphine stereotypy but did potentiate dexamphetamine stereotypy and antagonised cataleptic effect of haloperidol and small doses of apomorphine. Buspirone at 10, 20, 40 mg/kg, ip induced catalepsy and antagonised apomorphine and dexamphetamine stereotypies. Our results indicate that buspirone at 1.25, 2.5, 5 mg/kg blocks only presynaptic nigrostriatal D2 DA autoreceptors while at 10, 20, 40 mg/kg, it blocks postsynaptic striatal D2 and D1 DA receptors. Furthermore, buspirone at 1.25, 2.5, 5 mg/kg by selectively blocking presynaptic nigrostriatal D2 DA autoreceptors, increases synthesis of DA and makes more DA available for release by dexamphetamine and during haloperidol-induced compensatory 'feedback' increase of nigrostriatal DAergic neuronal activity and thus potentiates dexamphetamine stereotypy and antagonizes haloperidol catalepsy.

Buspirone, in the adult population is a safe drug (Neppe, 1999b), but, there is little research in children only case reports (Holttum, Lubetsky, & Eastman, 1994; Zwier & Rao, 1994; Leonard, Topol, Bukstein, Hindmarsh, Allen & Swedo, 1994; Stanislav, Fabre & Crismon, 1994; Ricketts, Goza & Ellis, et al, 1994; Soni & Weintraub, 1992; Realmuto, August & Garfinkel, 1989; Alessi & Bos, 1991; Kranzler, 1988; McCormick, Rizzuto & Knuckles, 1994; Balon, 1990). The anxioselective effects of buspirone take three or four weeks to fully manifest (Neppe, 1990; Neppe, 1999 b). It has early effect on irritability and concentration in the anxious patient. The use of buspirone in ADHD was prompted by its anti-aggressive effects combined with the effects noted on irritability and concentration in other conditions. As an adjunct in children and adolescents who had not responded to psychostimulants it was hypothesized that buspirone would be effective.
The population of patients was children and adults prescribed methylphenidate, pemoline or rarely amphetamines. No adequate literature has appeared in this area. There are two case reports using buspirone in ADHD: One is of a child with ADHD plus aggression exists in an inpatient receiving 45mg buspirone per day when the aggression not the ADHD improved (Quiason, Ward & Kitchen, 1991), the second an adult ADHD patient (Balon, 1990). A small double-blind, placebo controlled, crossover study, gave 5 mg buspirone twice a day on weekdays for two weeks (McCormick, Rizzuto & Knuckles, 1994). There was a response in nine of the subjects studied.
1.  Buspirone adjunct to psychostimulants in ADHD (with or without a second diagnosis) will improve the patient’s condition.
2.  Buspirone alone or as adjunct to other medications will improve the condition of children with anger problems.
3.  Buspirone will prove to be safe.
4.  Buspirone will improve ADHD ratings in addition to target symptoms of irritability, concentration, sleep, hyperactivity, emotionality and somatic features.


Average and median doses of buspirone approximated 30 mg per day in all the groups. The buspirone was almost always prescribed as 10mg TID. Adjunctive buspirone was used with the consequence that all ADHD patients and ADHD-plus group were receiving psychostimulants, predominantly methylphenidate, in doses of 30 mg per day. The non-ADHD group had a majority of patients on no psychotropic medications other than buspirone (22 of 29 originally, or 20 of 27 after dropouts). The target symptoms in the non-ADHD group were predominantly aggression and irritability occurring in 23 of the 27 for analysis, 25 of the 29 initially. The four patients without ADHD receiving buspirone for other reasons had their data separated out.

Several target symptoms in the ADHD group improved: (Table 3):

1.  Focus: concentration/ distractibility / school functioning: Of those who still had concentration disturbance, 24 improved out of 25 in the ADHD groups and 7 of 9 in the non-ADHD group.

2.  Aggression: irritability/ anger/ temper tantrums/ low frustration tolerance: Overall >90% improvement combining both groups (p< 0.00001).

3.  Improved sleep (p<.001).

4.  Improved anxiety or anxiety—depression. (p< 0.01).

These results are also clear when the ADHD group is separated into two. Due to small samples sizes the statistical tests lack power.

5. Hyperactivity improved in all 12 patients who had this as a residual pre-buspirone symptom.

A further population of aggressive non-ADHD children also responded well to buspirone alone in similar doses.


Zinc Enhances Efflux Induced by Amphetamine at hDAT

Because Zn2+ inhibited uptake of [3H]MPP+at the hDAT, a similar blockage was to be anticipated for release if efflux simply reflected reversal of transport. This was not the case. Cells that expressed hDAT were preloaded with [3H]MPP+. Upon challenge with a maximally effective concentration of amphetamine (10 μM), transport reversal was induced and this resulted in release of [3H]MPP+ (Fig.2 A). Surprisingly, this amphetamine-elicited efflux was markedly enhanced, rather than inhibited, by the addition of 10 μM Zn2+ to the superfusion buffer (Fig. 2 Aopen squares). We stress that Zn2+ per se did not affect basal efflux (Fig. 2 A). The modulatory effect of Zn2+was lost upon mutational exchange of all three coordinating residues (hDAT-H193K-H375A-E396Q, n = 3, data not shown). In fact, mutation of a single residue, namely His193 to Lys (the corresponding residue found in hNET), sufficed to abolish the enhancing effect of Zn2+; the extent of amphetamine-elicited release was comparable in hDAT-H193K-expressing cells (cf. closed symbols in Fig. 2Aand B). However, Zn2+did not affect transport reversal to any appreciable extent (open symbols, Fig. 2 B).

Figure 2

Influence of Zn2+ on amphetamine-induced [3H]MPP+ efflux.Cells were preloaded with [3H]MPP+ and superfused upon reaching a stable baseline (basal efflux: mean of the three fractions before drug addition; hDAT wt:panel A, ▪/■, basal efflux: 0.247 ± 0.004%·min−1i.e. 245.6 ± 6.7 dpm·min−1n = 60 observations of randomly chosen experiments performed on different days; hDAT-H193K:panel B; ▴/▵, basal [3H]MPP+efflux: 0.433 ± 0.08%·min−1i.e.181.2 ± 7.1 dpm·min−1n = 47; hNET wt: panel C, ●/○, basal [3H]MPP+ efflux: 0.087 ± 0.004%·min−1i.e.125.9 ± 5.3 dpm·min−1n = 60; hNET-K189H:panel D, ▾/▿, basal [3H]MPP+efflux for hNET-K189H: 0.147 ± 0.006%·min−1,i.e. 185.2 ± 8.2 dpm·min−1,n = 56). The experiment was started with the collection of 4-min fractions. After three fractions (12 min) of basal efflux, cells were exposed to Zn2+ (10 μM), or left at control conditions as indicated. After six fractions (from 24 min and onward), amphetamine (panels A and B: 10 μM,panels C and D: 1 μM) was added to all superfusion channels. After nine fractions (from 36 min and onward), all channels were switched back to control conditions. Data are presented as fractional efflux,i.e. each fraction is expressed as the percentage of radioactivity present in the cells at the beginning of that fraction.Symbols represent means ± S.E. of six to twelve observations (one observation equals one superfusion chamber; all experiments were performed in triplicate).


In contrast to wild type hDAT, release from cells expressing the hNET was not affected by co-application of Zn2+ (Fig.2 C). We have exploited this insensitivity to ask if Zn2+-enhanced outward transport was conferred to hNET upon replacement of Lys189 by the appropriate Zn2+coordinating ligand (i.e. His). In fact, in cells expressing hNET-K189H, Zn2+ promoted efflux that had been induced by amphetamine (open symbols in Fig. 2 D); although the effect was less pronounced than that seen with hDAT wt. Finally, Zn2+ did not affect amphetamine-induced release of [3H]MPP+ via hSERT, and cocaine (100 μM) completely inhibited amphetamine-driven efflux mediated by wild type and mutant transporters irrespective of the presence or absence of Zn2+ (data not shown).

We tested Zn2+ over a wide concentration range; up to 300 μM, Zn2+ did not affect basal release of [3H]MPP+ from preloaded cells that expressed hDAT, hNET, or hSERT (see inset to Fig.3). Because the physiological significance of higher concentrations is questionable, we did not further investigate the discrepancy between basal release through hSERT and hNET-K189H, which was not affected by 1 mMZn2+ (see Fig. 3,inset) and efflux through hDAT wt, hNET wt, and hDAT-H193K, which was stimulated to some extent by 1 mM Zn2+ (see Fig. 3inset).

Figure 3

. Concentration-response relationship of amphetamine and Zn2+ induced [3H]MPP+release. HEK-293 cells expressing hDAT wt (▪; [amphetamine]: 10 μM), hDAT-H193K (▴; [amphetamine]: 10 μM), hNET wt (●; [amphetamine]: 1 μM), hNET-K189H (▾; [amphetamine]: 1 μM), or hSERT wt (♦; [amphetamine]: 10μM; basal [3H]MPP+ efflux: 0.224 ± 0.007%·min−1i.e. 243.8 ± 10.9 dpm·min−1n = 40) were preloaded with [3H]MPP+ and superfused, and 2-min fractions were collected. After three fractions (6 min) of basal efflux, cells were exposed to Zn2+ or left at control conditions. After seven fractions (from 14 min onward), amphetamine was added to all superfusion channels for the following five fractions.V efflux/V efflux 0 values were generated by division of the value (mean of the last 6 min of fraction collection) in the presence of amphetamine and Zn2+ by the value in the absence of Zn2+.Inset, influence of Zn2+ on basal [3H]MPP+ efflux. The fractional rates of Zn2+-related [3H]MPP+efflux were generated by subtraction of the value of basal efflux (mean of the first 6 min of fraction collection under control conditions) from the value of efflux in the presence of Zn2+.Symbolsrepresent means ± S.E. of six to ten observations (one observation equals one superfusion chamber; all experiments were performed in duplicate).


In the presence of amphetamine, the efflux-enhancing effect of Zn2+ at hDAT-expressing cells was concentration-dependent; maximum enhancement was observed at 3 to 30 μM Zn2+; higher concentrations caused inhibition of efflux resulting in a bell-shaped concentration-response curve (squares in Fig. 3). A reasonably similar bell-shaped curve was observed if the effect of Zn2+ was evaluated on amphetamine-induced efflux through hNET-K189H (downward triangles in Fig. 3). In contrast, over a similar concentration range, Zn2+ did not enhance efflux in HEK-293 cells expressing hDAT-H193K, hNET wt, or hSERT wt (upward trianglescircles, anddiamonds, respectively, in Fig. 3).


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#41 chemicalambrosia

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Posted 23 July 2016 - 02:13 PM

Cool study on buspirone. What is your current stack?

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#42 Mr. Psychillogical

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Posted 23 July 2016 - 07:44 PM

Citicoline: Dopamine/Acetylcholine support, cardiovascular, cognitive support etc.
Selenium: Powerful antioxidant, thyroid, immune support, cardiovascular 
Zinc Glycinate: Hormone support, peripheral organ health, cognitive support etc.
D3: Muscular/bone, hormone support, cognitive support, cardiovascular etc.
Magnesium lys-bi-glycinate: Multiple benefits specifically, Drug tolerance prevention, cardiovascular, muscle/bone, digestive etc.
Theanine: Cognitive support, anti-anxiety, antioxidant, dopamine support etc.
Melatonin: Antioxidant, sleep support, cognitive support etc.
Sertraline: Antidepressant, anti-anxiety, cognitive support, sleep, digestive/appetite etc. 
Multi-vitamin: Broad spectrum support, deficiency prevention, balancing/ratio etc.
Occusional: Vitamin C/NAC Zantac/tums, aspirin/nsaid, Taurine

#43 Mr. Psychillogical

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Posted 23 July 2016 - 10:30 PM

Neuroprotective potential of Bacopa monnieri and Bacoside A against dopamine receptor dysfunction in the cerebral cortex of neonatal hypoglycaemic rats.

Neonatal hypoglycaemia initiates a series of events leading to neuronal death, even if glucose and glycogen stores return to normal. Disturbances in the cortical dopaminergic function affect memory and cognition. We recommend Bacopa monnieri extract or Bacoside A to treat neonatal hypoglycaemia. We investigated the alterations in dopaminergic functions by studying the Dopamine D1 and D2 receptor subtypes. Receptor-binding studies revealed a significant decrease (p < 0.001) in dopamine D1 receptor number in the hypoglycaemic condition, suggesting cognitive dysfunction. cAMP content was significantly (p < 0.001) downregulated in hypoglycaemic neonatal rats indicating the reduction in cell signalling of the dopamine D1 receptors. It is attributed to the deficits in spatial learning and memory. Hypoglycaemic neonatal rats treated with Bacopa extract alone and Bacoside A ameliorated the dopaminergic and cAMP imbalance as effectively as the glucose therapy. The upregulated Bax expression in the present study indicates the high cell death in hypoglycaemic neonatal rats. Enzyme assay of SOD confirmed cortical cell death due to free radical accumulation. The gene expression of SOD in the cortex was significantly downregulated (p < 0.001). Bacopa treatment showed a significant reversal in the altered gene expression parameters (p < 0.001) of Bax and SOD. Our results suggest that in the rat experimental model of neonatal hypoglycaemia, Bacopa extract improved alterations in D1, D2 receptor expression, cAMP signalling and cell death resulting from oxidative stress. This is an important area of study given the significant motor and cognitive impairment that may arise from neonatal hypoglycaemia if proper treatment is not implemented.



Protein-oil Combination

A special dopamine boosting, antidepressant and immune boosting combination is to blend essential oils with cottage cheese. Using a stick blender mix a couple of desert spoons (or more) of Flax/ Udo’s choice oil with the cottage cheese. Add a dash of liquid (milk, soya milk or cider vinegar for a savoury flavour) to prevent curdling mixture. Add a little garlic, black /cayenne pepper or fresh herbs for flavour, coriander and a whole de-seeded chilli are my favourites. The end product turns out like an instant healthy mayonnaise. You can make a thick gloopy version for baked potatoes, dipping carrot sticks or mayonnaise on a salad. Alternatively use more liquids and less solids to produce a thinner more runny version for pouring over steamed vegetables like a cauliflower/broccoli cheese dish.

#44 Mr. Psychillogical

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Posted 25 July 2016 - 01:51 AM

Before/During :

  • Magnesium Citrate (100mg/3x) or Magnesium Glycinate (200mg/2x) (Glycinate > Citrate > Oxide) (Lowers Tolerance / Prevents Jaw Clenching or Grinding / Better Sleep / Helps Anxiety / Muscle Relaxer) (Anecdotal : Helps increase euphoria and reduces comedown / Helps Focus on stimulants / Removes stimulant headaches)

  • Memantine (Prescription Only) (Reduces Tolerance / Reduces Anxiety) (Anecdotal : May help neurotoxicity of stimulants)

  • Fish Oil (1200mg/360mg Omega-3 / 1x) (Lowers Heart Rate on Stimulants / Heart support / Brain support) (Anecdotal : Makes stimulants much easier on the body / Less Anxiety / Better memory)

  • Vitamin D (2000UI/1x) (Improves Mood / Helps Cardiovascular System / Reduces Blood Pressure)

  • Vitamin B-Complex (Increases Energy and Mood)

  • ALCAR (500mg/2x) Reduces Neurotoxicity

  • R-ALA (100mg/2x) Reduces Neurotoxicity

  • L-Tyrosine (500mg / 1x) (Dopamine Precursor) (Repletes Dopamine / Mental Health Booster / Increase Mood, Focus and Motivation) (Anecdotal Experience : Took it on vyvanse comedown. Extreme euphoria was felt very similar to peaking euphoria. Lasted 30-40 minutes)

  • L-Phenylalanine (500mg / 1x) (Dopamine Precursor / Breaks down into L-tyrosine) (Repletes Dopamine / Mental Health Booster/ Increases Mood, Focus and Motivation) (Anecdotal Experience : Took in conjunction with L-Tyrosine but no change)

  • L-Theanine (200mg/1-3x) (Found naturally in Green Tea) (Very Useful in Conjunction with Caffeine) (Stimulates Dopamine / Lowers Anxiety / Relaxation) (Anecdotal : Takes edge off of stimulants and caffeine / Removes jitters / May help tolerance)

  • Rhodiola Rosea (400mg/1x) (Increases Wakefulness / Reduces Anxiety) (Anecdotal : May help memory and help caffeine tolerance)

  • Whey Protein (Anecdotal : May increase euphoria and Focus)

  • Choline Source (Will help memory and focus)

After Use Only :

  • Melatonin (10mg) (Helps neurotoxicity / Very useful for sleep after stimulant use) (Anecdotal : Lowers Anxiety)
  • Vitamin C (1000-2000mg) (Lowers neurotoxicity / Will help stimulants get out of your system faster)
  • L-Tyrosine (Stated Above)
  • R-ALA (Stated Above)
  • ALCAR (Stated Above)
  • Magnesium Citrate or Magnesium Glycinate (Stated Above)

Other useful Medications in Conjunction with Stimulants :

  • Benzos (Xanax/Valium/Etizolam) Lower anxiety / Helps comedown / Can put you to sleep / Lower Heart Rate Dangers : Stims + Benzos can lead to blackouts / Withdrawals can be fatal Very Addictive. Use sparingly
  • Benadryl (50mg) Sleep Aid / Lowers Anxiety Dangers : May increase heart rate or blood pressure Tolerance Builds fast and can be mentally addictive. Use sparingly
  • Antipsychotics Will knock you out
  • Tums/Baking Soda Will increase absorption and may extend the duration Danger : Can lead to a worse comedown or too long of a duration Anecdotal Experience : I took some with vyvanse and ended up tweaking out 20hrs. I took everything at 6AM and still could not sleep the whole night
  • Noopept or Piracetam May help focus with stimulants (Medium-High Doses may interact. Start very low if used in combination iwth stimulants)

Healthy Habits :

  • Sleep at least 6 hours a day (8 is better)
  • Force yourself to eat food and drink water or the comedown will be much worse
  • Know that the comedown will not last forever. You will feel better
  • All Nighters will just make the comedown worse and will have negative impacts on your mental health

That is the basics of this. I will try to update this post and there may be a few mistakes. Feel free to post any comments on this or ask any questions below

EDIT 1 : /u/herman_gill brought up some interesting points that have been added. If you have any questions, you can also ask him. They include :

  • Taurine (Takes the edge off of stimulants while still maintaining focus and being safer a lot safer than benzos) (May Promote sleep and relaxation) (May improve mood) (May have anti-oxidant like effects)

  • Magnesium Tauarate (May be a better source of magnesium than others previously mentioned. I stand behind chelated magnesium and magnesium citrate personally.

  • CDP-Choline is said to be a good source of choline although I have no personal experience with it.

  • Although the anti-oxidant effects of 10mg of melatonin can be beneficial, anecdotally, using high dosages daily can cause short-term depression, foggy mind, and also trouble sleeping. YMMV


  • Acetylcysteine or NAC, can be very useful in stimulant harm reduction and also acetaminophen overdose. May help addiction and have multiple benefits in combination with stimulant usage.

Accreadited/Orginal: https://www.reddit.c..._to_stimulants/

#45 Mr. Psychillogical

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Posted 30 July 2016 - 04:05 AM

The Protective Effects of Gingko biloba on Adrenal Gland Function in Met-Amphetamine Receiving Rats



The results of the present study show that there was no significant difference in serum levels of ACTH and cortisol in rats receiving normal saline compared with control animals. However, serum levels of ACTH and cortisol significantly increased in rats receiving met-amphetamine compared to control group (P<0.01, P<0.001, respectively). Serum levels of ACTH and cortisol did not significantly change in rats receiving amphetamine + gingko leaf extract compared to control group.


Our study indicated that serum ACTH and cortisol levels increased in met-amphetamine receiving rats, however, administration of gingko leaf extract withstand against this increase in ACTH and cortisol levels. In line with our findings there are other studies showing that chronically using met-amphetamine may destroy the regulatory function of the HPA axis, especially the feedback regulation of cortisol to ACTH [12]. On the other hand, it has also been shown that the extract of Ginkgo biloba possess significant anti-stress properties [13], by which may possess protective effects on adrenal gland. In recent studies it has also been demonstrated that repeated treatment of rats with the standardized extract of Ginkgo biloba leaves, EGb 761, and its bioactive component ginkgolide B (GKB), specifically reduces the ligand binding, and protein and messenger RNA expression of the adrenal mitochondrial peripheral benzodiazepine receptor (PBR), a key element in the regulation of cholesterol transport, resulting in decreased circulating corticosterone levels [14]. Treatment of rats and adrenocortical cells with ginkgolide B (GKB), a purified component of Ginkgo biloba leaf extracts, leads to decreased corticosteroid synthesis 15].


The findings suggest that gingko extract has protective effects against increased adrenal gland function in met-amphetamine receiving rats .



#46 Mr. Psychillogical

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Posted 01 August 2016 - 09:56 PM

Re: What do you do to ease the crash of Adderall? Please share your remedies
I wrote this short guide to surviving the crash and panic symptoms cause by Adderall as a joke, yet when I read it, I realize that it's not all that funny.

I apologize for the long post, but here goes:

1. Smoke if blood pressure isn't too high. If you're trying to not freak out, smoking does not actually help. Smoking helps to focus your attention. Not focusing on how you're "feeling" is a fundamental principle of a smooth "crash" or "come-down." Smoking can be beneficial in alleviating restlessness due to excessive energy and the general dysphoria commonly experienced during a crash; however, don't smoke too many too fast: smoking cigarettes has been linked to panic attacks.
2. Change into Pajammas
3. Watch Tv OR
4. Play Chess, Mahjong, or Minesweeper on the computer
5. Drink Orange Juice (if nothing else, the psychological awareness of Vitamin C flushing out Amphetamines helps.)
6. Drink Nyquil OR
7. Take Benadryll if Nyquil isn't available. (Nyquil contains two ingredients with sedating properties, as opposed to Benadryll's one, uncomfortably sedating antihistamine.)
8. Listen to soothing music at low volumes. 
9. The internet is certainly an excellent distraction.
10. If possible, study, study, study.
11. Reading is good, but only if it's a soothing topic. Avoid medical texts.
12. If available, a small dose of Melatonin may provoke a welcomed surge of sleepiness, though it may not be enough to effectively facilitate sleep.

Second Part:

1. Cold sensations in the extremities (and rarely other parts of the body) are normal.
2. As mentioned, reading medical texts, specifically those pertaining to overdose or heart attacks. Liberally applying diagnoses to yourself while your sympathetic nervous system is still actively affecting your body is a recipe for a panic attack. 
3. Avoid caffeine, for you are trying to reduce psychostimulation. Caffeine, a stimulant, can intensify certain effects of Amphetamine. Also, avoid any medication with the word "day-time" in the title and any OTC medications containing active ingredients ending in "-ephrine." 
4. Avoid antacids, as well as any strong base (e.g. milk). Antacids increase Adderall absorption, possibly leading to dangerously high serum levels in the blood. However, it should be noted that this effect primarily occurs (i.e. is most noticable) immediately after a dose is ingested.
5. Adderall, or amphetamine, is a powerful stimulant. A fraction of the active ingredients (the levo-amphetamine parts) is theorized to directly affect the neurotransmitter norepinephrine (noradrenaline), so Adderall, especially in high doses, is a powerful sympathomimetic. In other words, Adderall, specifically the levo-amphetamine parts, increases activity of the sympathetic nervous system, which greatly increases the often unpleasant phsyiological effects that lead to a panic attack.
6. Numbness and tingling (especially in the extremities), shortness of breath, chest pains, sweating, palpitations and accelerated heart rate, dizziness, faintness, nasuea, stomachaches, and chills are all symptoms of a panic attack. Do not mistake this for a heart attack or other serious complication.
7. A panic attack, or a marked increase of sympathetic activity, is horrifying but certainly not deadly.
8. A panic attack, or intense anxiety with phsyical symptoms, is much more common and more likely than a heart attack. 
9. It is unfortunate, but should be noted, that panic attacks, as well as the expected physiological effects of Adderall, can mimic other, more serious conditions. These include: heart attacks, ischemia, stroke, and other serious medical problems, usually involving the heart, lungs, or brain.
10. Resting and drinking water is a safe bet in treating a crash with or without high-anxiety or an Adderall-induced panic attack.
11. Avoid strenuous exercise and physically demanding activities. These can increase the heart-rate and breathing, which could possibly be dangerous to an already accelerated heartbeat. Also, the accelerated heart rate is likely to worry you. Anxiously focusing on a rapid heart rate will likely increase anxiety, thus the heart rate increases.
12. Pleasant distractions (see above) are vitally important to a mostly stress-free crash. Any external stimuli that is loud, bright, violent, intense, or otherwise unpleasant can increase anxiety and is not reccommended. 

Note: Though probably difficult while the blood vessels are constricted, masturbation has been recommended by males taking Adderall or other stimulants as a beneficial technique to reduce unwanted energy and encourage sleep. However, masturbation is only recommended if going to sleep is the primary concern. Masturbation, as well as intercourse, can increase heart rate and breathing, so neither masturbation or intercourse is recommended if calming the body's respiratory and cardiovascular reaction to the Levo-amphetamine in Adderall is of great concern. Waiting until your heart rate decreases and breathing becomes normal may reduce the likelihood of cardiovascular and respiratory complications that could arise from masturbation. Also, allowing the cardiovascular effects of Adderall to wear off completely or lessen can reduce vasoconstriction (thinned blood vessels), making it easier to obtain an erection. Masturbation has not been proven to be effective in alleviating any side-effect of Adderall, and its therapeutic use does not guarantee any results.


LOL at the masturbation part.

Sorry so long. I thought it was relevant enough to post.

^*Provided by* ^

→ source (external link)

#47 Mr. Psychillogical

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Posted 03 August 2016 - 02:58 AM

[entry='http://mentalhealthd...ent-it/']MentalHealth Daily[/entry]


Surfing the web I stumbled across this little masterpiece! 


Adderall Tolerance: Causes & How To Prevent It

Nearly all individuals taking Adderall can attest to the fact that its psychostimulatory effect is most potent after an initial “first-time” dosage.  Thereafter, its efficacy is generally maintained for weeks, or perhaps months after the initial dosage with favorable results.  However, eventually Adderall users may notice that its therapeutic psychostimulation seems to have dwindled and/or “worn off,” leaving them to speculate that the drug has simply stopped working.

Typically, Adderall doesn’t simply stop working overnight, it takes a period of months for users to notice a gradual decline in its efficacy.  Long-term users may report that the same 20 mg dose of Adderall is no longer providing the same degree of focus and cognitive enhancement as it was during their first few months of usage.  It doesn’t take a neuroscientist to understand that consistent long-term usage of Adderall (an amphetamine based compound with 75% dextroamphetamine and 25% levoamphetamine) is likely to induce tolerance.

It is the tolerance induction that leads most Adderall users back to their doctors to report that their starting dose is no longer working (or effective).  At this point, the doctor suggests increasing the dosage, perhaps to 40 mg – doubling the amount of psychostimulation.  The only problem with this is that eventually (in forthcoming months) the user may become tolerant to the 40 mg dose.  The cycle continues until an Adderall user is on the highest (or possibly a supratherapeutic) dose to cope with his/her tolerance to lower doses.

Eventually, tolerance will also occur on that highest dosage and the user will have hit a proverbial “brick wall” in dosage.  They cannot increase the dosage anymore because risk of adverse effects (e.g. heart abnormalities) is too substantial.  However, decreasing the dosage may result in significant brain fog as characterized by dopamine dysfunction and receptor depletion.  Perhaps some users would benefit from being cognizant of major pharmacological underpinnings associated with Adderall tolerance, as well as hypothetical mitigation strategies.

What is Adderall tolerance?

Adderall tolerance is defined as a reduction in neurophysiologic response associated with repeated administration of Adderall.  As a result, the user must increase the Adderall concentration (dosage) to attain the desired and/or therapeutic effect.  In nearly all cases, Adderall tolerance is considered reversible, but the duration it takes to reverse is contingent upon the same factors that induce Adderall tolerance.

Factors that influence Adderall tolerance onset

Should you become tolerant to the effects of Adderall, it is necessary to analyze the factors that likely contributed to tolerance development.  It is these factors that explain why one individual may develop tolerance within 6 months of Adderall usage, yet another may take 2 years to become tolerant.  Factors that influence tolerance development include: dosage, frequency of use, time span, co-ingested agents, and individual factors.

  1. Dosage (5 mg to 40 mg)

The greater the daily dosage of Adderall that an individual administers, the quicker he/she can expect to develop tolerance. At high dosages, greater quantities of norepinephrine and dopamine are released within the brain, and endogenous production of these neurotransmitters is outpaced by depletion via the dextroamphetamine/levoamphetamine combo.  The higher the dosage of Adderall administered, the greater the the dopaminergic/noradrenergic release.

At a low dosage, concentrations of dopamine and norepinephrine are increased, but not to the same extent as a high dose.  A 5 mg dose should theoretically yield half (50%) the potency of a 10 mg dose.  Lower doses are essentially depleting or “mining” less of the endogenous dopamine/norepinephrine stores when compared to higher doses.

For this reason, users taking the minimal effective dose of Adderall for as long as possible (to manage ADHD symptoms) won’t rapidly develop tolerance to the highest daily dosages.  An individual taking high doses (e.g. 40 mg) from the start of his/her treatment should be thought to deplete dopamine and norepinephrine much quicker than someone taking just 5 mg.  Jumping to a high starting dose without tolerance will yield potent effects, and faster tolerance to all lower doses than all gradual upward titrations.

  1. Frequency of usage

The number of times that you use Adderall per day can affect how quickly you develop tolerance.  Someone that’s using Adderall “all day” is likely to be ingesting a greater overall daily dose, which was already noted to expedite tolerance development.  Someone administering a single dose of Adderall IR (instant release) will have Adderall in his/her system for a shorter duration than someone taking Adderall XR (extended release).

Adderall XR remains active for 12 hours, whereas the IR version elicits a 4 to 6 hour effect.  The time between Adderall doses is likely an important factor to consider regarding tolerance.  The less time between dosages (as a result of highly-frequent administration), the greater the extent of dopamine/norepinephrine depletion and further an individuals’ physiology shifts away from homeostasis.

If you were to take a single-dose of Adderall IR once per day, tolerance onset would be slower than if you were to take Adderall XR once per day.  This is because you are essentially giving your body 18-20 hours “drug-free” – letting your neurophysiology resume (or at least attempt to resume) homeostatic functioning without Adderall; neurotransmitters may be replenished and/or somewhat restored before your next dose.  If you were to take the XR version or multiple IR doses, your neurophysiology will only have 12 hours (significantly less time) to readjust to functioning without Adderall; resulting in faster tolerance onset.

  1. Time span (Weeks, Months, Years)

The total timespan that you’ve been taking a particular dosage of Adderall consistently, the greater your likelihood of tolerance to that dose.  Someone that’s been taking a 40 mg dose of Adderall XR daily for 20 years likely has developed greater tolerance than someone using it for 2 weeks daily.  However, total timespan may be misleading in regards to tolerance onset among those that have gone on “Adderall holidays” or used the drug on an “as needed basis.”

Someone that uses Adderall daily (without missing a single day) may develop tolerance to a 40 mg dose within 6 months, whereas someone who’s been taking Adderall on an “as needed” basis may take 1 to 2 years to develop tolerance to that same dosage.  Therefore, when contemplating time span in relation to tolerance, always consider whether Adderall was used regularly or with breaks – and if it was used with breaks, the length of the “breaks” between dosages.

  1. Co-ingested agents

Many drugs and/or supplements have potential to either expedite or prolong (possibly prevent) tolerance to Adderall.  If you’re taking a drug or supplement that potentiates the effects of Adderall such as via triggering dopamine release and/or norepinephrine reuptake inhibition – it is plausible that tolerance development may be expedited.   On the other hand, if you’re taking a supplement that enhances endogenous production of dopamine/norepinephrine and/or attenuates depletion of neurotransmitters (as induced by Adderall) – tolerance onset may be prolonged (or prevented).

  1. Individual variables

It is also necessary to consider individual variables that may affect Adderall tolerance onset including: a user’s baseline neurophysiology, genetics, diet, stress, and sleep quality.  Someone with favorable neurophysiologic activity pre-Adderall, genes that rapidly restore homeostatic neurotransmission (e.g. generate lost dopamine), eating a healthy diet, with low stress, and quality sleep – is less likely to experience rapid Adderall tolerance than someone in the opposite scenario.  Individuals eating an unhealthy diet with high stress and poor sleep may use up excess dopamine stores quicker while taking Adderall – leading to quicker tolerance.

What causes Adderall tolerance?

There are likely several multifaceted mechanisms by which Adderall tolerance is induced within a user’s neurophysiology.  Repetitive (daily) ingestion of Adderall (75% dextroamphetamine, 25% levoamphetamine) triggers neurophysiologic changes within the central nervous system (CNS) – some of which are induced by the drug and others which accommodate for the drug.  Examples of some alterations that we’d expect following Adderall administration include: neurotransmission (particularly catecholamine levels), neural connectivity, regional activation, and autonomic nervous system function.

When a user initially takes their first dosage of Adderall, he/she experiences a noticeable change in neurophysiology, shifting away from homeostasis; the higher the dose, the greater the shift.  Adderall in particular alters function within the central nervous system to elicit a psychostimulatory effect.  However, over time (with repeated administration), the body learns to not only accommodate, but expect the psychostimulation from Adderall.

As a result, it adapts to regular Adderall administration at an equipotent dosage via desensitization.  The longer an individual takes Adderall at the same dosage, the more desensitized he/she will become to its effect.  As desensitization sets in, rather than responding significantly to the Adderall, a user may perceive it as having lost its initial psychostimulatory “mojo” (effect).

Perhaps an easier-to-understand example of desensitization would be that of partners in a long-term relationship.  The initial time two long-term partners meet, they were likely on their best behavior – trying to impress the other individual with optimal, attractive behavior.  After awhile though (e.g. 6 months), the two become more relaxed and comfortable around the other, engaging in behavior that they would’ve surely avoided on the first date (e.g. farting).

At this point, the initial honeymoon phase of the relationship, and the partners have become desensitized to the other; essentially “tolerant” to the presence of the other – each knows what to expect.  Though some may argue that the relationship is a poor example of desensitization, others may find it useful for this explanation.  Just know that your CNS adapts to any stimulus to which it is regularly and predictably exposed – resulting in desensitization.

Pharmacologic Mechanisms of Adderall Tolerance (Possibilities)

The exact mechanisms by which Adderall induces tolerance aren’t fully elucidated.  Tolerance to Adderall is speculated to principally involve: alterations in catecholamine transmission, particularly dopamine concentrations and receptor densities, as well as calcium ion influx at NMDA receptor sites.  That said, other aspects that may contribute to tolerance include: autonomic nervous system function, neurotoxicity, oxidative stress, and synaptic reorganization.

  • Autonomic nervous system: Psychostimulatory effects derived from Adderall promote increased activation of the sympathetic pathway within the ANS (autonomic nervous system).  As a result, the parasympathetic pathway (those that facilitate relaxation) becomes underactive and sympathetic is in overdrive.  However, with continued administration, the preliminary increases in blood pressure and sympathetic function decrease as the user becomes sensitized.  Various adaptations in the autonomic nervous system following Adderall administration likely contribute to tolerance onset.
  • Calcium ion influx (Ca2+): Many speculate that the primary cause of Adderall tolerance is related to its propensity to alter influx of calcium ions via NMDA receptors.  Specifically, regular Adderall administration triggers an excess influx of calcium ions through NMDA receptors, which in turn, alters synaptic plasticity, neural connectivity, and may even cause damage.  Over time, changes in NMDA receptor function as a result of excess calcium ions may be a prominent biomarker for tolerance onset.
  • Dopamine depletion: The amphetamine mixed salt combo constituent within Adderall functions via TAAR1 agonism and VMAT2 inhibition.  TAAR1 agonism decreases firing of dopamine receptors and increases protein kinase signaling to phosphorylate the dopamine transporter (DAT).  Upon DAT phosphorylation, the DAT is thought to cease functioning or perhaps transport dopamine to the synapse.  VMAT2 inhibition triggers a release of dopamine from presynaptic vesicles into intracellular fluid.  In any regard, endogenous dopamine stores are being utilized quicker than they can be replenished, resulting in dopamine depletion in the basal ganglia and limbic system – leading to tolerance stemming from low dopamine.
  • Gene expression: Evidence suggests that psychostimulants like Adderall facilitate phosphorylation of CREB (cAMP response element binding protein) in dopamine terminals.  Upon phosphorylation of CREB, it binds to CRE within promoter regions of various genes – inducing their transcription.  Researchers have documented that altered gene expression lingers after amphetamine discontinuation and may be yet another mechanism by which individuals become tolerant to Adderall.
  • Hormone concentrations: Adderall is understood to affect concentrations of various hormones, including corticosteroids.  It is known that the body can adjust and become tolerant to increases and/or decreases in levels of hormones resulting from administration of an exogenous substance (e.g. Adderall).  For this reason, it may be necessary to consider the fact that desensitization to hormonal changes may also contribute to tolerance onset.
  • Monoamine depletion: While Adderall primarily affects catecholamine concentrations (dopamine / norepinephrine), it also affects serotonin.  The triad of these neurotransmitters are considered classified as “monoamines.”  Since Adderall affects dopamine the most, depletion of dopamine is most likely.  However, it also utilizes extra norepinephrine and (to a lesser extent) serotonin – perhaps downregulating levels of all three monoamines over a long-term – leading to tolerance development.  Is understood that vesicular storage of dopamine is disrupted following amphetamine administration, perhaps another mechanism contributing to tolerance.
  • Neurotoxicity: While methamphetamine is understood to be neurotoxic, most research suggests that the amphetamines within Adderall are not neurotoxic, especially when ingested at medically prescribed dosages for the treatment of ADHD.  However, others believe that there’s some evidence to suggest that Adderall may induce neurotoxicity, ultimately killing brain cells.  Should certain neurons die as a result of Adderall administration, the cellular loss may result in faster tolerance to Adderall’s effects.  Neurotoxicity may stem from a loss of DA uptake sites within specific regions (e.g. striatum / accumbens) and/or glutamine stimulation.
  • Oxidative stress: Ongoing ingestion of amphetamines is associated with increases in overall oxidative stress.  Therefore, we can speculate that ongoing ingestion of Adderall (dextro/levo-amphetamines) may redistribute dopamine concentrations from vesicles into cytosol (a part of the cytoplasm), thereby losing protection of vesicles and increasing oxidative stress.  This oxidative stress may have deleterious implications, one of which could be neurotoxicity.  In any regard, the oxidative stress increase may be one small mechanism that facilitates tolerance to Adderall.
  • Receptor downregulation: Studies suggest that neuroreceptors may be subject to downregulation after long-term Adderall administration.  Downregulation may occur in specific regions of the brain and may be subject to certain receptor subtypes.  For example, some studies suggest that decreased D2 (dopamine) receptor density is exhibited in the striatum of non-human primates when administered amphetamines over a long-term.  It is logical to assume that D2-receptor density may downregulate as a result of chronic and/or long-term Adderall administration – leading to feelings of anhedonia, anxiety, and depression.
  • Synaptic reorganization: The full extent to which synapses in the brain are reorganized after Adderall (dextro/levo-amphetamine) administration is unknown.  However, it is understood that Adderall alters the influx of calcium ions at NMDA receptor sites, which in turn affects synaptic plasticity.  It should be speculated that synapses reorganize, shift significantly away from homeostasis, and ultimately contribute to Adderall tolerance.
  • Transporter decreases: Research speculates that dopamine transporters (DATs) are altered and/or depleted with repeated Adderall administration.  Some sources estimate that following chronic amphetamine administration, dopamine transporters are decreased by up to 40%.  Although a 40% depletion is unlikely among those taking medically-approved Adderall dosages, even depletion to a lesser extent may be partially responsible for tolerance onset.

Note: Many of the neurophysiologic changes as induced by Adderall, as well as neurotoxicity risks, make it among the most dangerous psychiatric drugs – especially when administered to those without ADHD and/or at high doses.

How to Prevent Adderall Tolerance: Hypothetical Strategies

There are a multitude of opinions floating around the internet regarding how users can prevent Adderall tolerance.  While certain supplements, medications, dosing strategies, etc. – may prolong tolerance development, they are unlikely to fully prevent it.  Tolerance from Adderall is not solely due to a single mechanism (e.g. Ca2+ influx) – if it were, it may be easier to correct.

That said, certain mechanisms appear to account for a greater percentage of tolerance induction from Adderall than others.  It is likely that excess Ca2+ influx at NMDA receptors accounts for a major percentage of tolerance induction, as well as downregulation of dopamine receptors and endogenous levels.  Oxidative stress may account for a smaller percentage of tolerance onset than Ca2+ influx and dopamine receptor downregulation, but it is still necessary to consider.

  1. NMDA Antagonists

Since excess Ca2+ influx at NMDA receptor sites is thought to account for a majority of Adderall tolerance, many believe that concomitant administration of an NMDA antagonist is a viable tolerance prevention strategy.  There are plenty of options regarding NMDA antagonists including: supplements and pharmaceuticals.  Due to the fact that pharmaceuticals are often associated with a host of adverse effects and long-term safety issues, the most practical NMDA antagonist is a magnesium supplement.

Magnesium: Magnesium is an effective NMDA receptor antagonist, meaning it’ll prevent excess Ca2+ influx if administered along with Adderall.  Since Adderall’s absorption is affected by a user’s pH, and an acidic GI tract is known to decrease absorption – it may be best to supplement with magnesium glycinate or taurate (rather than citrate).  Some experts recommend taking around 200 mg three times per day.  It may take some experimentation (and blood work) to determine the optimal amount of magnesium you should take relative to your Adderall dosage to prevent tolerance.

Zinc: Supplemental zinc is considered an effective supplement for altering NMDA receptor function via modulation of ion influx.  One study found that children taking zinc supplements (up to 30 mg per day) for 8 weeks were able to reduce their Adderall dose by around 37%.  Obviously you may want to assess blood levels of zinc prior to, and after consistent supplementation to avoid toxicity.

Huperzine-A: Though most people know huperzine-A as a reversible acetylcholinesterase inhibitor, may are unaware of its effect as an NMDA receptor antagonist.  Research indicates that administration of huperzine-A may interfere with and/or protect overstimulation associated with elevated calcium levels via the NMDA receptor.  Therefore, some speculate that huperzine-A may effectively prevent the onset of Adderall tolerance.  Despite the fact that huperzine-A is considered a “nootropic” by many, users of huperzine-A should be cognizant of potential adverse effects.

Memantine: Many believe that memantine (brand name “Namenda”) is a highly effective pharmaceutical drug to prevent Adderall tolerance.  It exerts an array of pharmacodynamic functions, but its NMDA antagonism is thought to be superior to that derived from agents such as magnesium.  Some Adderall users have managed to convince their psychiatrists/doctors that Namenda is viable concomitant agent for tolerance prevention.

Since Namenda is considered a cognitive enhancer in its own right, perhaps it is synergistic with Adderall as well for treating ADHD, allowing for dosage reductions.  Realize that tolerance may eventually develop to this agent and/or that you may experience unwanted Namenda side effects that could be tough to deal with.  That said, some individuals attribute lack of Adderall tolerance to regular memantine administration.

DXM (Dextromethorphan): Some individuals skip the aforementioned options (magnesium, zinc, huperzine-A, memantine) and start using DXM (dextromethorphan) to offset Adderall tolerance.  DXM is an antitussive (cough prevention) agent found in many over-the-counter drugs such as Mucinex, NyQuil, and Robotussin.  DXM acts as an NMDA receptor antagonist, which may reduce onset of amphetamine tolerance.

However, as a result of its other pharmacodynamic targets, DXM should be avoided among Adderall users.  It is a very “dirty drug” to take solely for the NMDA receptor antagonism.  Most individuals would be far better off pursuing a cleaner, less problematic NMDA antagonist.

  1. Dopaminergic upregulators

Many individuals attempting to halt and/or prolong Adderall tolerance forget that tolerance isn’t solely a byproduct of excess Ca2+ ion influx.  Another prominent mechanism by which Adderall tolerance is established is via dopaminergic adjustments.  Changes in endogenous levels of dopamine, receptor densities (particularly D2) and dopamine transporter (DAT) activity are associated with amphetamine tolerance.

Specifically, Adderall inhibits neurochemical processes from breaking down dopamine, which leads to abnormally high dopamine concentrations.  The high dopamine concentrations decrease the density of dopamine receptors.  As a result, you may want to administer agents that have demonstrated efficacy in upregulation of dopamine receptors (especially D2).

Inositol: There’s modest evidence suggesting that chronic inositol administration significantly increases D2 receptor density in the striatum.  There’s also evidence to suggest that inositol increases 5-HT2 receptor density (to a lesser extent).  Since the Adderall may have downregulated D2 receptors in the striatum, ongoing concomitant administration of inositol may attenuate this downregulation.

Choline: Studies suggest that exogenous choline administration increases dopamine receptor densities in animals by up to 11% compared to animals that didn’t receive any choline.  Ensuring that you’re consuming sufficient choline may slightly mitigate some dopamine receptor downregulation associated with Adderall.  Eating plenty of eggs (particularly the yolks) is considered a viable modality of attaining choline, but supplementation is also effective.

Sulbutiamine: Though literature is relatively sparse regarding sulbutiamine, one study noted that sulbutiamine administration increases the number of dopamine binding sites within the prefrontal cortex.  Individuals may want to increase dopamine receptor count while simultaneously increasing the number of binding sites for maximal efficacy.

  1. Neuroprotective Agents / Antioxidants

Though calcium ion influx (Ca2+) and dopaminergic downregulation (e.g. D2 receptors) may be principally responsible for Adderall tolerance, they may not cover all pharmacologic bases.  Someone may still become tolerant even if they’re taking magnesium or memantine along with inositol and choline.  Another mechanism to consider that may induce Adderall tolerance is that of neurotoxicity and/or oxidative stress.

Due to the oxidative stress as induced by Adderall (possibly via cytosolic redistribution of dopamine stores from vesicles), it may be necessary to take additional neuroprotective agents and/or antioxidants.  Neuroprotective agents and antioxidants decrease amphetamine-induced brain damage and prevent excessive oxidative stress.  Though it cannot be proven that all of these supplements will reduce Adderall tolerance, some may prolong it.

  • Acetyl-L-Carnitine: A mitochondrial enhancer known as “acetyl-l-carnitine” is a known neuroprotective agent.  Some research shows that concomitant administration of Acetyl-L-Carnitine with amphetamine can prevent neurotoxicity.  It may also bolster cognitive performance as a standalone treatment, serving as a viable adjunct to Adderall.
  • Alpha-Lipoic Acid (ALA): A highly effective agent to mitigate oxidative stress within the brain is alpha-lipoic acid.  Alpha lipoic acid is a potent antioxidant that has demonstrated neuroprotective effects.  If Adderall significantly increases oxidative stress, the increase in oxidative stress may cause damage or dysfunction – leading to tolerance.  To prevent oxidative stress (potentially a mechanism contributing to tolerance), supplementation with ALA may be helpful.
  • CoQ10: Many individuals supplement with CoQ10 or Ubiquinol to optimize overall health and improve neurophysiologic functions.  Deficiencies of CoQ10 have been associated with increases in oxidative stress.  Supplementation with CoQ10 may not only improve cognitive function, but may attenuate certain aspects of Adderall tolerance.
  • Curcumin: There are a host of benefits associated with curcuminoids within turmeric, particularly curcumin.  Although its bioavailability is low, administration of a supplement that’s properly formatted (e.g. with bioperine or BCM-95) may decrease oxidative stress and neuroinflammatory markers.  Furthermore, curcumin is thought to act as a neuroprotective agent that is capable of modulating: dopamine receptors, CREB, and gene expression.  Though not well-researched in regards to concomitant administration with Adderall, some speculate that it may decrease tolerance.
  • Creatine: Supplementation with creatine monohydrate elicits synergistic effects with CoQ10 in regards to neuroprotection.  Creatine monohydrate supplementation may reduce oxidative stress and protect the brain from Adderall-induced dysfunction, some of which may lead to tolerance.  In addition to creatine’s efficacy as a mitochondrial enhancer, (which could bolster cognitive function), creatine could aid in Adderall tolerance prevention.
  • Glutathione: Among the most potent of all antioxidants to consider taking with Adderall (especially if you’re an adult) is glutathione.  Glutathione may prevent Adderall-induced oxidative stress and mitigate neurotoxic effects.  Other therapeutic health implications may be associated with regular glutathione administration among adults.
  • Melatonin: Administration of exogenous melatonin has potential to drastically alter your circadian rhythm, which could be deleterious.  However, if administered at a proper time (e.g. 3 hours before bed) at an acceptable dose, melatonin may mitigate oxidative damage associated with Adderall.  It may also prevent circadian rhythm disruption and exhibit neuroprotective effects against neurotoxicity – all of which may influence tolerance.

Note: Contraindications and safety of the aforementioned agents necessitate evaluation with a medical professional prior to usage.  Don’t simply take everything listed here hoping to offset Adderall tolerance – you may alter your neurophysiology to such an extent that your cognitive function is impaired.

  1. Lifestyle interventions

In addition to the drugs and supplements that may offset Adderall tolerance, you could also consider lifestyle interventions.  Most people want to take the “quick and easy” route for tolerance prevention.  Popping another pill to offset tolerance may create more problems than a user initially suspects.

Using any strategy to mitigate Adderall tolerance should be accompanied with strategic lifestyle interventions.  Examples of such lifestyle interventions include: proper hydration, eating a nutrient-dense diet, getting plenty of quality sleep, reducing stress, and modest exercise.  Failure to implement these lifestyle interventions while taking Adderall may expedite tolerance onset, and possibly aging.

Dietary intake & Hydration: It is extremely necessary that any Adderall user ensures optimal dietary intake of nutrient-dense foods.  Failure to consume adequate food is a problem, but a greater problem is a lack of nutrients within one’s diet.  Eating a bag of chips with a soda simply because “you can” while taking Adderall may contribute to disastrous neurological effects (associated with malnutrition) – and faster tolerance onset.

Consume a spectrum of colorful vegetables, protein (foods that increase dopamine), healthy fats, and select whole grains.  Healthy fats may be especially important for offsetting Adderall’s dopaminergic downregulation as they can increase D2 receptors.  In addition to diet, consider that inadequate hydration detrimentally affects brain function – so stay hydrated.

Sleep: Many Adderall users take the drug to compensate for a poor night’s sleep.  Not only will this exacerbate dopamine dysfunction, but it may lead to faster Adderall tolerance.  Getting at least 8 hours of quality (deep) sleep may be necessary after Adderall to help your brain and body recover from excess stimulation.

A reason many people experience “Adderall crashes” after their final dose of the day is because they simply need more time to recover from the excess energy expenditure from the drug.  Don’t skimp on the sleep just because Adderall gives you a psychostimulatory boost.  Sleep deprivation is associated with a host of toxic long-term neurological effects.

Stress reduction: A great way to burn yourself out, induce neurotoxicity, and expedite brain aging is to maintain high stress.  If you’re feeling stressed, your sympathetic nervous system will kick into overdrive, accentuating the effects of Adderall.  Stress takes a toll on your neurotransmission and may deplete catecholamine levels (e.g. dopamine) quicker than necessary.  Consider meditation, deep breathing, or biofeedback (such as with the emWave2) while taking Adderall.

  1. Adderall Potentiation

A strategy that may be feasible to implement is that of Adderall potentiation.  Potentiating the effects of Adderall via concomitant ingestion of a less potent substance may allow users to reap the same therapeutic benefits at lower-than-average dosages.  Dosage reduction of Adderall may help prolong and/or prevent tolerance onset.

  • Alkalinization: A strategy that some have suggested for potentiating the effects of Adderall is alkalinization.  Increasing alkalinity is considered effective in maximizing absorption of Adderall due to the fact that acidity decreases absorption.  Some believe that administering half of a teaspoon of baking soda in water (prior to taking Adderall) could be helpful.  You’ll want to confirm the safety and credibility of this with your doctor though prior to implementing.
  • Caffeine: Intake of caffeine is reported to increase dopamineconcentrations as well as upregulate D2 and D3 receptors in various regions of the brain.  It is possible that caffeine may help offset some receptor depletion associated with Adderall, while simultaneously potentiating its therapeutic efficacy.  Therefore, some may find that concomitant coffee consumption may result in a reduced need for high-dose Adderall. (Source: http://www.ncbi.nlm....ubmed/25871974)
  • L-Tyrosine: Many find that L-Tyrosine supplement (an amino acid precursor) is an effective Adderall alternative.  Tyrosine is a building block for the neurotransmitter dopamine – without adequate dietary intake of tyrosine, an individual will likely be low in dopamine.  Administration of L-Tyrosine along with Adderall is likely to potentiate its stimulatory effect, meaning you may not need as large of an Adderall dose. (Read: “L-Tyrosine benefits” for more information).
  • Nicotine: There are many benefits of nicotine, one of which is enhanced cognitive function.  Many nicotine users find that they’re able to reduce their Adderall dosage with concomitant nicotine administration.  Administration of nicotine is thought to increase concentrations of D2 receptors in certain parts of the brain, potentially helping to offset D2 receptor downregulation from Adderall.  That said, nicotine is among themost addictive drugs and receptor upregulation is not sustained after discontinuation.
  1. Adderall dosing strategies

To prevent tolerance on Adderall, an individual may want to take it as infrequently as possible.  In other words, rather than using Adderall on a daily basis, an individual may want to use Adderall once weekly and/or solely in times when ADHD is severe.  By using Adderall with lengthy breaks of interdose sobriety, a user may prolong tolerance development – especially when augmented with several aforestated strategies.

  • “As-Needed”: Some users have resorted to taking Adderall on an “as needed” basis.  Rather than taking Adderall daily, users only take the drug when absolutely necessary.  For example, unless one needs maximal cognitive resources for occupational and/or scholarly pursuits – Adderall simply isn’t taken.  And when cognitively demanding tasks necessitate completion, the Adderall is strategically administered only for the exact duration necessary to complete the task.
  • Adderall vacations: Another strategy that can be used with the “as needed” dosing is that of an Adderall vacation.  Just like people take vacations to reduce stress and take a break from work, individuals may want to take an extended break from Adderall.  Some users may simply stop taking Adderall for 6 months to overcome the tolerance that they had developed.
  • Minimal effective dose: When starting Adderall, it may be wise to only use the minimal effective dose necessary for symptom management.  If a minimal dose is taken on an “as-needed” basis, and lengthy Adderall vacations are taken, one may avoid tolerance altogether – especially when adding NMDA antagonists, dopaminergic upregulators, neuroprotective agents, antioxidants, and lifestyle interventions.  Work with your doctor to come up with a dose that isn’t higher than necessary and consider usingAdderall IR as opposed to XR (to avoid extended periods under its influence).
Can everyone prevent Adderall tolerance?

It is farfetched to assume that everyone taking Adderall is capable of mitigating tolerance onset with a simplistic regimen of NMDA receptor antagonists, dopaminergic upregulators, neuroprotectives, and antioxidants.  Even if an individual took the right stack of drugs, supplements, and was leading an optimal lifestyle – does not mean Adderall tolerance can always be avoided.

Some individuals will become tolerant to the effects of Adderall no matter what strategies they implement.  However, using logical strategies as outlined above theoretically could go a long way in prevention and/or prolongation of tolerance development as compared to simply doing nothing.  Since Adderall’s mechanism of action is complex, it is likely impossible to cover all pharmacological bases with tolerance prevention strategies.

There may be some lesser-known mechanism by which Adderall could be inducing tolerance (other than Ca2+ and dopaminergic transmission), making it difficult to prevent.  That said, many anecdotal reports have documented substantial tolerance reduction with adjuvant administration of NMDA antagonists.  Despite these reports, it may be necessary to consider that one could eventually become tolerant to the agents that are working to prevent tolerance.

Furthermore, some of these agents may be intolerable for Adderall users, pose serious pharmacokinetic and/or pharmacodynamic interactions, and/or deleterious long-term implications.  For example, taking an agent such as memantine may offset Adderall tolerance temporarily, but a user may eventually become habituated to the effects of memantine and exhibit major alterations in neurochemical processes without it.  Long-term effects may also be considered detrimental to the neurophysiologic health of the user.

Have you developed Adderall tolerance?

If you’ve developed Adderall tolerance, it is necessary to realize that there’s no biological free lunch – the cognitive enhancement and focus you’re reaping today isn’t being magically generated from thin air.  The Adderall is essentially mining your dopamine and altering Ca2+ ionic influx, leading to future tolerance development.  With repeated administration, regardless of whether you haven’t yet become tolerant to Adderall – the dosage will lose its preliminary efficacy, leading you back to your doctor for an increase.

Increasing the dosage may seem like a logical strategy to cope with Adderall tolerance, but what happens when you reach the highest legally prescribed therapeutic dose?  Assuming you’ve reached the highest possible dosage, not only will the side effects be tougher to cope with, but you’re depleting dopamine stores at an even quicker rate than you were at lower dosages.  Eventually you will become tolerant to even the highest dosage – leading you to a dead end.

Thereafter, you may try related psychostimulants medications only to find that they don’t work and/or you may attempt to discontinue treatment only to experience horrific Adderall withdrawal symptoms (most of which are associated with low dopamine).  For this reason, if you’re going to use Adderall, it is wise to consider and discuss tolerance prevention strategies with a medical professional prior to your first dosage.  If you’ve developed Adderall tolerance and/or have a strategy to prevent it, feel free to share a comment below.

For those that have developed tolerance to Adderall, share some specifics such as: how long it took to develop, the dosage you were taking, and how frequently/regularly you administered Adderall.  No user should be considered immune to Adderall tolerance – it is likely to occur in all regular daily users; even if it may take longer to develop in some compared to others.  Although the efficacy of tolerance mitigation agents remains unclear, it is likely that they provide some degree of benefit.


#48 Mr. Psychillogical

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Posted 21 October 2016 - 12:33 AM

Ultimate Guide To Adderall Use


Blog Of Steve Moore: The Adventures of a Rebellious Nerd





What is Adderall, And What Am I Reading?

 Adderall is a combination of Amphetamine's that are prescribed as a treatment for ADHD and some sleep disorders. This drug is quite powerful but is a well tolerated and well-studied drug that has helped millions of people become more productive. This post is a guide to improving the Adderall experience, and get the most out of this drug with as few side effects as possible. 

Why Do I Need This Guide

You need this guide if...

  • You are worried that you are taking too much Adderall.
  • You think Adderall's side effects are overshadowing the benefit.
  • You have a loved one in the previous two categories.
  • You want to take Adderall, but want to save money by cutting pills in half.  
  • You want to tinker with your own biochemistry in order to become immortal, or at least feel like it...
Deconstruction of Adderall's Effects

Adderall works on multiple mechanisms on the body. We know that it stimulates the central nervous system and the release of dopamine and norepinephrine, and that it binds to the dopamine receptors in the brain. This creates a cascade of psychological and physical effects that can be a life saver and/or a train wreck. 

Generally speaking, Adderall is well tolerated by many people. It takes ALOT of Adderall to overdose. The LD50 (lethal dose for 50% of the general population) is 98mg/kg of bodyweight. To put that in perspective, a full therapeutic dose is 60mg a day (one 30mg pill every 4-6 hours). For me, an 83kg (185lbs) guy would need approximately 8134mg of Adderall to off myself. Now, I do not recommend taking anything more than what your doctor says, which is at most 60mg a day, and if you are being all recreational, stop, but if you don't... 60mg a day TOPS... 

 The Good (and conceivably good)

  • Increases focus
  • Increases inhibitory control
  • Increases working memory
  • increases cognition
  • increases motivation
  • Decreases appetite
  • Increases strength
  • Increases endurance
  • Reduces reaction time

The Bad (and conceivably bad)

  • Erectile wackiness (prolonged, dysfunctional, or frequent)
  • Wacky Blood Pressure (can go up or down)
  • reduced blood flow to extremities
  • Nausea
  • Weight loss
  • Loss of Appetite
  • Dehydration (it makes you pee a lot)
  • mood swings
  • depression
  • irritability
  • teeth grinding
  • anxiety
  • repetitive and obsessive behaviors.
  • insomnia
  • Dopamine Resistance
  • Adrenal fatigue
What is our Goal?

 Our goal is to accentuate the effects on focus, duration of effects, inhibitory control, and euphoria, while minimizing the anxiety, irritability, effects on blood pressure, insomnia, tolerance, the crash, and the other weird side effects that are caused by stimulating the central and peripheral nervous system. 

In short, we want to get super motivated for as long as possible, while staying happy, then turn it off and go to bed. 

Shorthand: Drink Water, Breath Deeply, Take L-Theanine, avoid caffeine, meditate, avoid acidic foods, exercise, take 5-HTP, take magnesium, plan your day in writing.

Amplification of Positive Effects

 So, as we know, we want to elevate and elongate the positive effects on production and focus with the smallest dose. This means that we want to increase the amount of Adderall that is absorbed at a time (thus being able to take less), and elongate the effects (so we do not have to take as many pills).


Adderall can be taken in four different ways (but the directions say to take it orally): Ingestion, Insufflation, Sublingually, and Rectally.

The oral route, or taking the pill like a normal human, results in the lowest bioavailability at between 20-25% (though some sites say up to 75). This can be increased by increasing the pH in your stomach. This means making it LESS ACIDIC. The best way I know of to do this is by taking a 1/4-1/2 teaspoon of baking soda mixed in an ounce of water, and drinking it about 10 minutes prior to taking Adderall. Another method is taking it on an empty stomach since your digestive system is still in a fasting state (no stomach acid has been excreted yet). I personally don't like taking Adderall orally because I want breakfast. Eating food is one of the most important cornerstones of good Adderall experiences. 

Insufflation is the act of inhaling Adderall through the nose. For this, you grind the Adderall into a powder than use a straw (or rolled up Benjamin if you are that kind of person) to inhale the powder into your mucous membranes in the sinus. This will absorb about 75% of the amphetamine content. This way is not recommended due to the fragility of the nasal septum. No one wants to damage their nose... 

My personal favorite is sublingual administration. This allows for higher bioavailability without worrying about stomach acid or what you ate. Just stick an Adderall IR under your tongue and let it melt. It also tastes like sucralose, so it's kind of sweet. 

The most powerful way to take Adderall is anally. Sticking Adderall up your butt seems to have the highest absorption rate at 95-99%, and supposedly hits really fast. The way to try this one is pretty interesting. The first step is to make sure you are clean on the inside, so take an enema or eat a lot of fiber. Once you know you are clean, find yourself an oral feeding syringe (you can get them for free at drug stores), a ground up Adderall pill, and some water. Combine the Adderall in about a teaspoon of water in some small cup, and fill your syringe. Lube that sucker up, take a deep breath and inject it where the sun doth shine. After it's in, do a handstand or some kind of inversion, and don't take a poop for like 30 minutes. So... enjoy!


Elongation of effects are of great importance to us, so we want to stop the breakdown and excretion of Adderall.

Adderall is highly sensitive to PH in both the blood, stomach, and kidneys. The higher the acidity of these parts of the body, the faster the breakdown and excretion of amphetamines. This means that we need to somehow boost alkalinity. Here are the methods...

  • Breathing: 
    this method is one of the most important. Many people (especially in america) do not breath deeply. This means that you are not clearing the CO2 out of our system. More CO2 = Higher Blood PH. Be mindful of your breathing. A neat tip is to not only be mindful of breath, but to also to do a set of 30 hyperventilation type breaths every hour or so. This will clear out C02 and increase blood alkalinity. You can check my video on cold meditation for more information on that.
  • Drinking water. 
    Water should have a PH of 7, and that means that the more you drink, the closer to 7 your blood ph will be. This also has the added benefit of keeping your muscles and bodily functions running smoothly. Best way to do this is by drinking .5 liters an hour (1 typical water bottle). The human body can absorb one liter an hour typically, so if you still feel thirsty, feel free to drink more.
  • Avoid acid-forming foods. 
    Acid forming foods basically lower the ph of your urine. This will help your body clear adderall more quickly. So, avoid acid forming, and eat alkalizing foods. It's that simple, The short list is here.
  • Sugar:
    Anything that that has high levels of sugar should be avoided. Sugar causes lactic acid to build up in the body. This is no bueno. Also, high glycemic index foods (ie sugary crap) cause blood sugar spikes and dips which make the adderall experience suck. I have a feeling, and have observed, that when I avoid blood sugar instablility, I feel 123234345623% better on adderall.


Minimizing Side Effects

The minimization of side effects seem to be where the money's at as it relates to adderall use. Many people crash hard or get some kind of weird mood effect (anxiety, paranoia, irritiblilty, mood swings etc) when taking adderall. This can ruin your day. A small population also gets into a weird period of indecision (or sucked into facebook) caused by the positive effect of speeding up the mind. So, to help us a long, here are the top six tips for avoiding bad side effects of adderall.

  1. Take L-theanine
    L-theanine is an amino acid found primarily in green tea. This has an amazing effect on the anxiety and irritability that some experience taking amphetamines. Take 200mg, twice a day while under the effect of adderall. 
  2. Take Magnesium at the end of your day
    Magnesium is a mineral that most people are deficient in. This important little rock is an ingredient in over 200 enzymes in the body. It is also very important to relaxation, and very important to keeping the dopamine resistance at bay. Trust me, take it. I personally use a nebulizer and magnesium sulphate (Epsom salt), but you can also use 2-4 cups of Epsom salt in a bath every night you use Adderall. This will help you sleep, and help you relax. 
  3. Take 5-HTP
    5-HTP is a serotonin precursor that will help your body produce some feel good hormones. This really helps if you find yourself having anxiety and irritability. Unfortunately, you need to take it for about a week before you see any real changes in your serotonin levels. 
  4. Meditate
    Meditation has many benefits, but the ability to relax is the benefit we seek for this article. Doing a deep muscle relaxation meditation (or mindfulness and vipassana) is a very good way to learn to relax on adderall. Sit comfortably with good posture, and deeply breath, and focus on each part of your body, tense it, relax it, then move on to the next. This will get you into a good state of mind to produce some good work without feeling jittery. This also helps with teeth grinding.
  5. Use the Pomodoro Timer
    Sometimes you can get so focused on your work that you forget to take care of yourself. This is a no-no. You may feel productive, but you end up burning out sometimes 20-30% earlier than if you took breaks to take care of yourself. So, the Pomodoro timer is a great method for working. Its 25-minute work sessions with 5-minute breaks, then a 15-minute break every two hours. 
  6. Exercise a couple times a day in small spurts
    Exercise releases the feel-good endorphins we all love. Keeping your blood moving and endorphins high will allow you to feel bulletproof as you kill your day. Your metabolism will be higher, you will be more creative, and the very cool exercise-induced nootropic factor will be helping you along. You may even accidentally find yourself in the flow state.


Keeping Tolerance Down (And Avoiding A Crash)

One big issue facing adderall users is tolerance. Amphetamines quickly build a tolerance in your system, which means you gotta take more to get the effect you are looking for. Some may say "so what, just take more" but this is a HUGE PROBLEM. The tolerance that builds is because of the rebound effect that using any outside chemical to manipulate hormones is bound to cause. To be more specific, there are two reasons your body builds a tolerance to adderall.

  1. Excess Calcium being sucked through the NMDA receptor.
    This is a little over my head, so if you know how this works, please comment below.
  2. A down-regulation of the dopamine receptors themselves.
    This means that the little nodes in your head need more dopamine to feel the same way. kind of like lifting weights, the more you lift, the more you need to lift to get stronger.

So, to keep tolerance down, do this...

  1. Cycle your use. 
    When taking adderall, always make sure to take breaks. This is VITAL for long term users. This allows your body to repair the damage that adderall causes. The body always goes for homeostasis, meaning that its constantly correcting for our misdeeds. When off adderall, the body will make more dopamine to get back to normal. It just takes time to turn the factory back on.
  2. Increase dopamine sensitivity
    Tolerance to dopamine is caused by adderall use. There are ways to do this, but you can start by taking inositol and vitamin B1 (Sulbutiamine).
  3. Take an NMDA Agonist.
    Simple here, take a daily Epsom Salt bath. 2-4 cups in your tub, really hot water. 
  4. Pre-load catecholamine precursers.
    catecholamines are the awesome neutransmitters of epinephrine, dopamine, and norepninephrine. Basically, these are the neurotransmitters that are made with phenylenaline and tyrosine (two amino acids). Adderall causes depletion the levels of dopamine in the body, so you want to ensure you have the building blocks to rebuild the lost product in the brain. Take supplemental phenylenaline and tyrosine after you stop taking adderall (during your breaks), and continue for a couple of weeks after you discontinue use.

    One of the interesting notes on precursers is where they go after digestion. Some amino acids can easily cross into the brain, some can not. You want brain health, so take N-acetyl L-tyrosine to ensure it gets into the brain.
  5. Ensure you are not causing nutritional deficiency's caused by amphetamine use.
    Take a good multi-vitamin, eat healthy foods, meaning lots of veggies.



I hope this helps your Adderall use. If I left anything out, or if you have questions, let me know in the comments below. Go forth and conquer!













Updates and answers to user questions:

#1. To the user who asked about the increase in body temp. At therapeutic doses, the increase in body temp is negligable. It is just a byproduct stemming from the increase in blood pressure and heart rate. It is like a side effect of the side effect.

#2. Epsom Salt is transdermally bioavailable. It does get into the body through the skin. Check the references below. Some of them state that transdermal Epsom salt is controversial, and I included that as well. Personally, I nebulize Epsom salt. It works about as well as an intravenous Magnesium. 

References based on user comments... 







Edited by Mr. Psychillogical, 21 October 2016 - 01:30 AM.

#49 Mr. Psychillogical

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Posted 21 October 2016 - 12:42 AM

Disclaimer: This is a work of postmodern fiction about two irredeemable junkies named Alice and Bob and their cat Fido.  The views contained herein are not medical or legal advice, they are not my views, and they are not the views of LessWrong.com or any of its members.  In fact they are not views at all: they are trans narrative flows in alterity-space, or that's what my lit prof tells me.  I do not condone any illegal activity whatsoever, except jaywalking.
Rationalists_Guide_to_Psychoactive Drugs: STIMULANTS


Today, says Alice, I'm going to talk to you about drugs.  I'll be covering several nutritional supplements, some stimulants and nootropics, and - as some of you have probably guessed - I'll also be talking briefly about recreational drugs, particularly psychedelics.  Now, I don't have any sense of what the popular perception is of drugs around here, but I presume that at least some of you will be a little put off at the suggestion of recreational drug use.  If that is how you feel, please bear with me.  To partake or not partake of prohibited substances is a choice that must be made individually, and for many the payoffs may not be worth the risks; but I hope to convince you that, at least for some people, responsible drug use is a very reasonable and beneficial activity.
Well, hold on, says Bob - who takes a permissive but detached view of these things - hold on, now.  It may be true (as cursory research will show) that drug use is far less dangerous than it's made out to be, and it may be true that some people get a lot of enjoyment out of them.  But if you value knowledge and reason over hedonic pleasure, it seems better to cut them out entirely.  After all, it's your brain on the line if anything goes wrong!
As a matter of fact, says Alice, drugs are good for more than just hedonism.  First of all, they give you a handle on your own neurochemistry.  It's unlikely that your brain is optimally tuned for the things you want to accomplish, so if you can tweak it the right way, you might be able to improve your functioning.  In extreme cases, you might have chronic imbalances leading to depression, mania, etc., in which case you'll probably want to talk to a doctor about medication; but the ability to use drugs to change yourself goes well beyond this.  For example, judicious use of MDMA can help you retrain your social reflexes and become more outgoing and sociable.  Having this handle also allows you to begin to experimentally correlate your subjective experience with the physical processes to which they correspond, and by carefully observing more unusual states of consciousness, you broaden your understanding of the mind and how it operates.  Lastly, psychedelics can sometimes help you understand things differently or more deeply.  I've often found my mathematical ability improved by moderate doses of LSD, for example.  So, even for someone concerned primarily with rationality and the accumulation and application of knowledge, drugs are at least worth considering.
And what of the risks? says Bob.
I was getting to that, says Alice.  There will always be a risk/benefit tradeoff, but the risks can be minimized through careful and responsible use:
Thoroughly research every new drug before trying it.  Unfortunately, in the case of prohibited substances, very little good clinical research has been done (this has started to change in recent years, but there are still vast swaths of uncharted territory).  Nevertheless, there's good information to be had.  For drugs used recreationally, I usually start at Erowid.org, which provides an overall summary of the effects of a wide variety of drugs; academic citations and sometimes full articles, if there are any; "trip reports" (anecdotal evidence is better than nothing, especially if there's a lot of it); and other useful information.  For nootropics and "smart drugs", I usually just start with a Google search and/or Wikipedia.
Pay particular attention to addictive potential, toxicity and contraindications.  Drugs with high addictive potential require extra caution, and should perhaps be avoided by people with akrasia problems.  Also be mindful of any history of addiction you may have in your family.  Regarding contraindications: beside drug interactions, a lot of this is just common sense.  If you are prone to anxiety, you should probably avoid amphetamines.  As far as toxicity goes, a good number to look at is the therapeutic index, which is the ratio of the LD50 (the dose, per kilogram of body weight, at which 50% of experimental test subjects (usually rodents) die) to the effective dose (per kilogram of body weight).  However, keep in mind also that frequent or heavy drug use can tax the liver, and that otherwise safe chemicals may build up to toxic levels over time.
If you decide to take a drug known to be addictive, take it in moderate quantities over brief periods of time, well-separated from each other.  This is not a hard and fast rule: under a doctor's supervision, for example, you may choose to take prescribed medication every day.  You should recognize, however, that this comes at a cost: antidepressants can be used to pull your life together and overcome depression, but it's going to be nasty coming off them.  Finally, as a rule of thumb, oral ingestion is significantly less addictive than smoking, insufflation or injection, since this gives a gradual and delayed onset of the reward stimulus.  For the same reason, you can further reduce your chances of becoming addicted by taking prodrugs wherever possible (e.g. Vyvanse instead of Dexedrine).
Always take a low dose first, in case you react badly, and do so around other people who know what you are taking.
To the greatest extent possible, maintain an open and honest relationship with your doctor, who is in a position to help you minimize the health risks associated with your drug-taking.
If you decide to seek out prohibited substances, it's important to have a good source of high-quality product.  Street drugs may be cut with cheap substitutes or contaminated with solvents used in extraction/synthesis, or they may simply not be what they are claimed to be.  Go to people you trust who already do drugs on a regular basis, and ask them for help finding a reputable dealer.
With that out of the way, continues Alice, let's start simple: what is a drug?  For our purposes, we'll say a drug is any substance consumed for reasons other than its nutritive value or the sensory experience of consumption.  We'll specifically be focusing on psychoactive drugs, which are consumed for their effects on the mind.  Note that just about anything you eat or drink is potentially a psychoactive drug, and you may not have to turn to outlandish synthetic compounds to alter your neurochemistry.  For example: after three years of vegetarianism, I gradually began to develop chronic anxiety, with occasional panic attacks.  It plateaued at a (barely) manageable level, so I never ended up seeking medical help; it took two years before I thought to try eating meat again.  When I finally did, the anxiety immediately vanished and has not returned.  So, for me, meat is a psychoactive drug.  In fact, let's talk about nutritional supplements first.
Supplements and Neurotransmitters
The first group of drugs we're going to be looking at are neurotransmitters, and their chemical precursors, which can be found at health food stores.  First, there are 5-HTP and tryptophan, which are serotonin precursors.  There is some evidence that these can help treat depression, improve quality of sleep, and improve your mood, but since you need to take it for a few days before you start to notice the effect, it might be hard to tell if this is actually doing anything for you.
Next, consider phenylalanine, an amino acid which serves as a precursor to dopamine, norepinephrine and adrenaline.  Phenylalanine is first metabolized into tyrosine, which is also available as a dietary supplement.  Research seems to suggest that these are mainly effective only for people under conditions of physical, emotional or mental stress, and don't do much for the general population.  I've found that, in fact, L-phenylalanine has a noticeable uplifting effect on my mood within a short time of taking it; but maybe this just says something about how much stress I'm under.
Lastly, there's GABA, a neurotransmitter which has an inhibitory effect on the dopamine system and certain other neurotransmitters.  In short, this will calm you down right quick, which makes it useful for dealing with intense and uncontrollable emotions - anxiety, grief, rage, etc.  I find that, for this purpose, theanine is even better: it promotes GABA production and alpha brainwave activity, and also seems to increase dopamine levels.  Its calming effect is very similar to that of GABA, but I find it much less likely to leave me feeling tired and out of it: if anything, it seems to have a mildly stimulating effect.  As an added bonus, theanine appears to boost the immune system.  Theanine synergizes well with caffeine, which we'll cover shortly.
All of the above - 5-HTP, tryptophan, phenylalanine, tyrosine, theanine and GABA - are not only useful for regulating your mood, but also for learning what your neurochemistry feels like from the inside.  I found it edifying to take fairly large doses of 5-HTP (or phenylalanine, etc.) every day for a couple weeks, stop for a few weeks, go back on for a couple weeks, stop, etc. - all the while noting changes in my mood and perception.  In that respect, melatonin tablets can be added to this list: they're not really going to make you a more effective rationalist, but they will teach you what melatonin does to your cognition.  Melatonin will also be useful if you're taking stimulants, which might otherwise interfere with your sleep patterns.
It is also worth mentioning that vitamin deficiencies (or excesses) can have a significant impact on mood and cognitive functioning.  I recommend taking multivitamins; this need not be a daily regimen if you have a healthy diet, just kind of take them when you remember to.  Women should look for multivitamins with iron, and men should look for those without.
Next, let's talk about stimulants, starting with caffeine - by far the most popular, although by no means the most effective.  Caffeine works by blocking the activity of adenosine, an inhibitory neurotransmitter that plays a role in sleep and drowsiness.  As a result, neural activity goes up, accompanied by a kick to the sympathetic nervous system and an increase in blood sugar levels.  Taken on a fairly regular daily schedule, caffeine seems to improve my attention, motivation and energy level.  In the long term, there appear to be health benefits from drinking coffee in this way: in addition to its stimulating effects, it appears to help prevent heart disease, Alzheimer's disease and Parkinson's disease, among others.  For all-nighters, though, caffeine is an inferior choice: although it suffices to keep you up and running, it doesn't seem to do much to mitigate the cognitive effects of sleep deprivation.  Also, as increasing amounts are consumed, a variety of unpleasant side-effects begin to appear, including tremors, heart palpitations, anxiety, diarrhea, and dehydration.  It should also be noted that caffeine builds tolerance, and the withdrawal is rather unpleasant.  Despite this, it seems to make sense to take coffee every day in moderation, unless you are especially sensitive to its negative effects.
Caffeine can also be had in tea (green tea, in particular, also contains theanine, as we discussed), in chocolate, preferably dark (chocolate also contains a number of other psychoactive alkaloids, including phenylalanine and theobromine), in caffeine pills and in energy drinks.  It is perhaps worth mentioning that I find that the energy drinks and energy shots containing other medicinal ingredients (phenylalanine, taurine, B vitamins, etc.) really do seem to be slightly better, minimizing the unpleasant side effects and smoothing out the crash.  Still, I try to avoid these because of the sugar and/or artificial sweetener content.  It is unclear exactly what effect each of these other medicinal ingredients has individually, if any at all, so you should also be warned that you are probably buying some nonsense along with your actually mind-altering compounds.
Next are amphetamines, which act on the serotonin, norepinephrine and especially dopamine systems, causing increased focus, improved cognitive ability, and elevated energy levels.  They also mitigate some of the effects of sleep deprivation, although your cognitive performance will still suffer.  While amphetamines can greatly improve your productivity if used correctly, they can also easily do the opposite, because it's just as easy to hyperfocus on video games as it is to hyperfocus on neural network algorithms.  Body tics and bad habits can also get strongly reinforced, since your reward systems are getting pummelled by dopamine.  Basically, if you're doing amphetamines, keep your akrasia-fighting systems on high alert (fortunately this, too, will be aided by the amphetamines).  Another downside to amphetamines is that they're quite addictive; take them either in fixed quantities on a regular schedule (if you have a prescription) or else in occasional bursts of no more than a few days, and in moderate quantities.
Beside addiction, a lot of the danger from amphetamines comes from failing to eat and sleep, if you're taking them for more than a day or two.  Amphetamines are strong appetite suppressants, and of course they keep you awake, so you'll need to force yourself to eat three square meals a day and get to sleep at a reasonable hour.  Sleep is especially important because the longer you stay up, the more amphetamines you have to take to stay awake; if your dose gets high enough, and if you're badly enough sleep deprived, you put yourself at risk of amphetamine psychosis, which is about as much fun as it sounds like.
There are a number of prescription amphetamines on the market, and these are generally to be preferred to street speed, due to their purity and lack of adulterants.  It's not terribly hard to get diagnosed with ADD/ADHD, so this can be above-the-board.  Dexedrine is pure dextroamphetamine, while Adderall is a mix of dextroamphetamine and racemic salts (which contain a 50%/50% split between dextro- and levoamphetamine).  The difference between the two stereoisomers is complicated, and your best bet is to experiment to see which works best for you, but a rule of thumb is that Adderall has more "kick" at lower doses, while Dexedrine is stronger at higher doses.  Methamphetamine, you may be surprised to learn, is also prescribed for ADHD, although much more rarely.  Meth is stronger, longer-lasting, and significantly more addictive, than amphetamine.  It is also more neurotoxic.  I would recommend exercising extreme caution around this one, or else avoiding it entirely, unless you actually have severe ADHD and this is the only thing that works for you.  Lastly, there is a prodrug for dextroamphetamine that just came on the market, called Vyvanse (lisdexamphetamine).  This has a much slower onset, since it has to be metabolized into dextroamphetamine, and therefore has significantly less addiction potential.
Ritalin works similarly to amphetamines; apparently it tends to produce less euphoria.  Ephedrine is chemically similar to amphetamines, but works primarily by increasing the activity of noradrenaline; it has the advantage of being legally available without a prescription.  I mention these only in passing because I don't have much experience with them; if you want to contribute some information about them, please comment!
I also want to briefly mention MDPV (methylenedioxypyrovalerone), an experimental stimulant still legally available in the U.S. and in Canada (sold online as a research chemical or, sometimes, as "envigorating bath salts").  This one acts as a dopamine and norepinephrine reuptake inhibitor, producing a state reminiscent of that caused by amphetamines.  It has a quick onset and short lifetime (3-5 hours), which makes it well-suited to accomplishing quick chores.  However, there are a number of nasty side effects reported, and it seems to have some addictive potential.  Looking at the evidence, it appears that most of the people reporting this sort of thing were insufflating larger doses; so taken orally and in moderation, this one can still be reasonably safe.  But there's very little out there that's peer-reviewed, so take a look at some trip reports and proceed with caution.
All of this probably makes it sound like stimulants are, at best, not far off from a zero-sum game: they may benefit cognitive performance, but they come with side effects and addictive potential and a nasty crash when you come off them.  Well, good news: we'll be considering Modafinil next, which some are calling the perfect stimulant.  Modafinil is sold by prescription only, but its prodrug, Adrafinil, can be purchased online.  I've taken the latter on a number of occasions, and have been quite impressed with the results.  Adrafinil promotes a state of wakefulness and energy, but without the "edge" that comes with amphetamine use.  Even under conditions of sleep deprivation it has a significant positive effect on cognitive functioning, memory retention, focus and motivation.  It has no significant crash, produces no tolerance, and seems to have very little addictive potential.  You can even sleep on Adrafinil, if you wish; this is a significant advantage over all of the other stimulants we've discussed, since if you take dexedrine at 9PM and finish your work at 1AM, you're still effectively committed to staying up all night.  Adrafinil also seems to have a positive effect on mood; lastly, there are signs it can be used both to prevent and to treat some of the effects of aging on energy level and cognitive ability.
Modafinil and Adrafinil are not perfectly safe, though.  They put a fairly heavy load on the liver and kidneys if taken daily, and should therefore be taken only occasionally, unless as part of medically-supervised treatment.  There are also occasional side effects to watch out for, most notably skin infections.


As we've seen, says Alice with a smirk, you too can alter your neurochemistry for fun and profit - but this must be done responsibly.  Although I've tried to give a sense of the dangers alongside the benefits, this post is really only meant to serve as a broad introduction.  If you're thinking of actually trying any of the drugs I've mentioned, it's important that you do some in-depth research, and a proper cost-benefit analysis.  But with a little practice, you too can expand your mind.

Edited by Mr. Psychillogical, 21 October 2016 - 01:29 AM.

#50 Mr. Psychillogical

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Posted 21 October 2016 - 01:46 AM

The Science Of Dopamine
Ok. ~lostgurl~ and I decided to tie together all the material we could regarding dopamine, because we all know with out those nifty little things we wouldn't have much fun at all. In addition, this stuff just fascinates me and hopefully we can learn to understand it together. Obviously this isn't done yet, it's quite a project. Contribute! And let's hope I got the formatting correct! I didn't the first time! Again?!

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Join Date: 16-10-2007

27 y/o Male from United States





Edited by Mr. Psychillogical, 21 October 2016 - 01:52 AM.

#51 Mr. Psychillogical

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Posted 21 October 2016 - 01:48 AM












A) What is Dopamine?

Dopamine, also known as DA, is a neurotransmitter which is present in many animals. It can be defined as a phenethylamine, a natural compound synthesized from phenylalanine, or more specifically as catecholamine, a chemical compound which is synthesized from the amino acid tyrosine. As a catecholamine, dopamine is the biosynthetic precursor to norepinephrine and epinephrine, other notable and abundant neurotransmitters. Dopamine's structure as a phenethylamine and catecholamine also becomes important when we consider the vast number of other phenethylamines which can substitute dopamine due to homologous structures. Examples of these so-called substituted phenethylamines include 2C's, MDMA, dextroamphetamine, bupropion, and many many others. It should also be noted that in addition to dopamine's neurotransmission use, dopamine is also a neurohormone which stimulates the pituitary's release of another hormone, prolactin.


B) Biochemistry of Dopamine:

Standard Name: Dopamine
Chemical Formula: C6H3(OH)2-CH2-CH2-NH2
Chemical Name: 4-(2-aminoethyl)benzene-1,2-diol
Abbreviation: DA


C) How is Dopamine Biosynthesized?

For the sake of simplicity explicit detail will not be given here. Essentially the base of dopamine is the amino acid tyrosine. Tyrosine, which is naturally biosynthesized in the body from phenylalanine, can also be acquired by means of supplements. Daily dosage suggestion is usually in the range of 500-1500mg though exceeding 12000mg/day can actually have negative effects and reduced dopamine levels significantly. Various sources identify the site of dopamine biosynthesis as either the ventral tegmental area or the substantia nigra pars compacta, though it is positive that dopamine is highly present in both.

Regardless of synthesis location, tyrosine is converted by means of the enzyme tyrosine hydroxylase into L-dihydroxyphenylalanine (also known as L-DOPA). DOPA is then converted to dopamine by means of a chemical reaction called decarboxylation using an enzyme known as dopa decarboxylase (this name is actually a misnomer of sorts for a lyase enzyme called aromatic L-amino acid decarboxylase which actually is used in 5-HTP to serotonin and tryptophan to tryptamine reactions as well. In some of the neurons this dopamine is then stored in vesicles for use, however, in others the dopamine is synthesized further to norepinephrine.




D) Basics of Synaptic Transmission

A synapse is specialized junction where a slim projection of the presynaptic neuron, known as the axon, arrives at branched projections of the post-synaptic cell, known as dendrites. The gap between the axon and the dendrites is estimated to be about 20nm and it is known as the synaptic cleft. When a nerve impulse, known as the action potential, comes through the pre-synaptic neuron it needs to reach the post-synaptic neuron, however, the action potential cannot cross the synaptic cleft. However, neurotransmitters are available to carry this action potential across the synaptic cleft (the process is sickeningly more difficult than this but such a basic understanding is all that is necessary) to the post-synaptic neuron where a receptor specializing in the traveling neurotransmitter with accept it and the impulse into the post-synaptic neuron. Obviously the transferring of this action potential causes a change in voltage of the post-synaptic neuron. This change is simply known as a post-synaptic potential.

Synapses have one final feature which is rather important when discussing dopaminergic systems. When a neurotransmitter is released into the synapse, there are special proteins, known as neurotransmitter transporters, which exit one of the two synaptic membranes after the receptor reaction to pull it away from the synapse in order to recycle the neurotransmitter. This process is known as reuptake and plays the key role of ensuring receptors do not become desensitized. Receptors are also protected from desensitization by monoamine oxidases (MAOs) and catechol-O-methyl transferase (COMT), both of which are enzymes which serve to inactivate and break down specific neurotransmitters. The primary result of desensitization of receptors is a diminishing of the strength of the synapse. Note that it is also possible for neurotransmitter transporters to "reverse" their job in specific conditions, pulling neurotransmitters into the synapse. Synapses in the brain often have an added bit of difficulty because a neuron will often be forming synapses with several other neurons, not just another one. Though, these denser synapses do not operate any different (except in one case which is not of great importance here).


E) Specifics of Dopaminergic Synapses

-Five types of dopamine receptors are known:-Conversion of ATP to cAMP (as well as the left-over pyrophosphate) is catalyzed by adenylyl cyclase-Examples of biochemical purposes of protein kinases:
**Note that PKA's full name is cyclic adenosine monophosphate-dependent protein kinase meaning the enzyme's activity is dependent on which PKA and how much cAMP is present*


F) Dopaminergic Areas of the Brain

Dopaminergic neurons are primarily concentrated in the ventral tegmental area and the substantia nigra pars compacta. However, this does not mean these are the only parts of the brain involved in dopaminergic processes. All known involved areas will now be briefly detailed:

1) ventral tegmental area -- (VTA) -- involved in reward circuit, incentive/motivation, pleasure, addiction

2) substantia nigra -- unpredictable rewards, learning, addiction mimics reward/learn pattern

3) frontal lobes -- pleasure, long-term memory, planning, drive/motivation

4) nucleus accumbens -- reward, laughter, pleasure, addiction, and fear

5) striatum -- planning, modulation of movement, executive function, reward feeling, motivation

6) arcuate nucleus -- neuroendocrine neurons

7) median eminence -- none; however, no blood brain barrier


G) Dopaminergic Pathways

1) mesocortical pathway -- One of the four major dopamine pathways in the human brain, the mesocortical pathway connects the ventral tegmentum with the frontal lobes of the cortex. In addition to its own purposes to run motivation and emotional response systems, the mescortical pathway is necessary to the proper function of the dorsolateral prefrontal cortex, which is the area most responsible for motor planning, organization, and regulation.

Neg.) Flaws in this pathway are often the cause of the negative aspects of schizophrenia, including avolition (extreme lack of motivation), speech poverty, and flat affect

2) mesolimbic pathway -- Another of the four dopamine pathways in the brain. This major pathway links the ventral tegmentum with the nucleus accumbens, which is part of the striatum. The mesolimbic pathway is supposed to be essential in producing feelings of pleasure, as well as other feelings associated with reward and desire. Even though this pathway is highly connected with drug addiction, research shows it is not the euphoria that causes this here but rather incentive salience.

Neg.) The excess of dopamine associated with psychosis and schizophrenia is linked solely to this region. Since researchers know this quite well, anti-psychotics can be developed to specifically target the dopamine receptors in this specific path. The mesolimbic is also well known for losing many dopamine neurons in the progression of Parkinson's though the lost neurons are relatively asymptomatic and thus is not an issue until a large percentage of neurons have been lost.

3) nigrostriatal pathway -- This is the third of the four dopamine pathways which happens to connect the substantia nigra with the striatum. Its key application is movement.

Neg.) This location is of most worry when it comes to Parkinson's victim's lose of neurons, primarily due to speed rather than effect (like the mesolimbic the neurons lost here are barely noticed). This area seems to be especially sensitive to antipsychotics which cause tardive dyskinesia due to the abundance of movement neurons here. Even some simple antipsychotics meant to reduce psychosis have be known to cause parkinsonian movement issues.

4) tuberoinfundibular pathway -- The fourth dopamine pathway and the least neurotransmitter-based of them all. It seems most of the dopamine here is neuroendocrinal. 

Neg.) It seems abnormal lactation, disrupted menstrual cycles, visual issues, sexual dysfunction, and headache are caused when antipsychotics block dopamine here as a side effect, causing prolactin levels to increase in the blood.



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A) Quick Vocab

-- Ampakine -- new drug class of modified benzamide compounds designed to enhance attention span and alertness

-- Dopamine Reuptake Inhibitors -- drugs which bond to dopamine transports and prevent them from removing the DA from the synapse

-- Dopamine Agonists -- drugs which attach to dopamine receptors and simulate dopamine

-- Dopamine Antagonists -- drugs which attach to dopamine receptors and prevent dopamine from entering

-- GABA (gamma-amoniobutyric acid) -- the primary inhibitory neurotransmitter in the CNS as well as the retina

-- Prodrug -- a drug which is administered inactive and becomes an active compound in vivo

-- Racemate (racemic) -- a mixture which is made of two molecules of identical structure but different chirality; thus, racemic - having equal amounts of left- and right-handed enantiomers

-- RC -- research chemical



C) Over-The-Counter Medications, Grey Market Items, Etc.


-As we understand it, vastly more purposes....they are not fully understood yet
-PKA known to calcium channels linked to muscle contraction
-PKA tied to reward and motivation in nucleus accumbens
-PKA is used in metabolism

1) Phenylalanine

2-Amino-3-phenyl-propanoic acid


2) Tyrosine

(S)-2-Amino-3-(4-hydroxyphenyl)-propanoic acid

3) Theanine

2-Amino-4-(ethylcarbamoyl)butyric acid

Theanine is an amino acid which is believed to be found only in tea plants. The known neurochemical effects of theanine on the body are an increase of alpha brain waves as well as stimulating the production of the neurotransmitter GABA. Interestingly, theanine is actually an analogue of glutamate, the most common excitatory neurotransmitter as well as the precursor for GABA (the two neurotransmitters actually have counterbalancing effects), but despite being analogous to glutamate, it does not have quite the same affinity for glutamate receptors, rather simply stimulating release and/or production of GABA. This is the most likely cause of the relaxation and stress-relieving qualities of theanine. Theanine has shown potential medical uses for ADD/ADHD, PMS, and stress-relief.
PERTAINING TO THEANINE; [Note: As of now, SWIM is going to disregard theanine's potential effects on other neurotransmitters because no studies seem to have been conclusive. SWIM would also like to note that theanine is a chiral compound, just like amphetamine, propanolol, and many others, and thus comes in D/L isomers (respectively this means dextrorotary and levorotary). Despite the minute difference between the isomers, the effects are profound. D-Theanine is not as efficiently absorbed and thus bioavailability is decreased. It is believed that some companies have used racemic D/L blends as L-Theanine to cut costs.]

4) Yohimbine

17α-hydroxy-yohimban-16α-carboxylic acid methyl ester

Yohimbine is the alkaloid which comes from the bark of the West-African evergreen Yohimbe. It is known to be an antagonist of the alpha2-adrenergic receptor causing an increase in epinephrine and norepinephrine. It also antagonizes 4 seperate serotonin receptors and use shows an increase of dopamine (some reports of up to 80%) as well as monoamine oxidase ihibiting properties.

5) Mucuna pruriens

-tropical vine found in Central and South America shown to contain L-Dopa, Serotonin, 5-HTP, Nicotine, N,N-DMT, Bufotenine, and 5-MeO-DMT; despite L-Dopa being an excellent source of dopamine booster: A) too many other alkaloids in the plant and B) L-Dopa, as a dopamine agonist, runs a high risk of desensitization; likely little practice medical usage.

D) Dopamine Reuptake Inhibitors

5) CFT
17) RTI-121


1) Amineptine -- (atypical tricyclic antidepressant)


Due to demonstrating abuse potential while on market it was discontinued in 2005 and is currently off-patent.
*Interactions*- monoamine inhibitors and drugs with monoamine inhibition properties
*Side Effects*- Common: acne; Rare/Very Rare: nervousness, irritability, insomnia, suicidal ideation, vasomotor episode, arterial hypotension, palpitations, hepatotoxicity (genetic predisposition likely in all cases)
*Contra-Indications*- chorea, MAOI's, infants less than one year of age, known hypersensitivity to amineptine
*Dosing*- Information unavailable.
*Prescription Medicines*- Survector (France, Spain, Italy, Phillipines); Maneon (Italy)

2) Benzatropine mesylate -- (anticholinergic)


In addition to reducing the effects of acetylcholine, as all anticholingergics do, benzatropine also acts as a dopamine reuptake inhibitor, primarily targeted at all forms of parkinsonism as well as for extrapyramidal disorders/symptoms (such as akinesia and akathisia), however, it is not to be prescribed for tardive dyskinesia). Given these extrapyramidal disorders/symptoms are often the result of anti-psychotics used for treatment of schizophrenia, benzatropine is often prescribed alongside the anti-psychotic treatment.
*Interactions*- phenothiazines (largest class of anti-psychotics; includes aliphatic, piperidine, and piperazine groups), haloperidol, tricyclic anti-depressants
*Side Effects*- heat stroke, hyperthermia, fever, allergic reaction (skin rash), urinary retention, dysuria, blurred vision, dilated pupils, toxic psychosis, exacerbation of pre-existing psychotic symptoms, nervousness, depression, numbness of fingers, paralytic ileus, constipation, vomiting, nausea, dry mouth, tachycardia
*Contra-Indications*- patients under three years of age, hypersensitivity to benzatropine; has not been tested for use in pregnant women; aggravation and adverse effect in those with tardive dyskinesia and angle-closure glaucoma
*Dosing*- The drug is contained as a liquid for intramuscular injection. One mL of injection contains: 1mg benzatropine mesylate, 9mg sodium chloride, and 1mL. Usual daily dosage for parkinsonism treatment is 1-2mL, although the range of usage goes from .5mL to 6mL. For treatment and control of the effects of antipsychotic drugs, the recommended dosage is 1-4mL, either once or twice daily. In cases of acute dystonia, 1-2mL is the effective dose.
*Prescription Medicines*- Cogentin; generic

3) Bupropion (Amfebutamone) -- (atypical antidepressant/nicotine antagonist)

*Side Effects*-
*Prescription Medicines*- Wellbutrin, Zyban, generic (bupropion hydrochloride)

4) Cocaine -- (stimulant/appetite suppressant)


Cocaine's primary mechanism of action in the body is inhibition of monoamine uptake, which was demonstrated in rats at the ratio of 2:3 of serotonin to dopamine and 2:5 for serotonin to norepinephrine. The drug acts like all other MAOI's, by binding to transporters and preventing their function. Like many other dopaminergic drugs of abuse, cocaine is theorized to be highly linked to the ventral tegmental area, nucleus accumbens, and the frontal lobes of the cortex, since these areas are extremely rich in dopamine and receptors, as well as ties to the brain's "reward system."
*Other*- LD50 of cocaine is 95.1mg/kg in mice.
*Interactions*- [too many to list currently]
*Side Effects*- Common (at medical doses): loss of sense of taste/smell; Other: abdominal pain, chills, confusion, dizziness/lightheadedness, excitement, nervousness, restlessness, fast/irregular heartbeat, general discomfort, hallucinations, headache, increased sweating, nausea
*Contra-Indications*- allergy to cocaine, pregnant, breast-feeding, children, older adults, cancer, history of chest pain, history of convulsions, fast/irregular heartbeat, heart disease, high blood pressure, liver disease, history of myocardial infarction, overactive thyroid, Tourette's syndrome, history of drug abuse
Illicit use:

Doses for illicit use vary widely due to factors such as tolerance. In addition, use is often measured by the illicit user by number of lines. Therefore, accurate doses are hard to determine. Other sources denote one line, which ranges from 35-100mg, as an average dose
*Dosing*- Use is rare/undocumented and so estimated:

Medical use:
Doses are administered by a doctor or nurse in the smallest effective dose. It should be noted that 400mg is never exceeded.
*Illicit Use*-
*Medical Use*- Still used as a local anesthetic in crystal or solution form.

5) CFT -- (stimulant/RC)


CFT is also sometimes known as beta-CFT or (-)-2[beta]-Carbomethoxy-3[beta]-(4-fluorophenyl)tropane. For the sake on being concise, it will only be referred to as CFT here. CFT is a dopamine reuptake inhibitor which is structurally an analogue of cocaine. In tests on animals, it has been shown to be 3-10 times more powerful than cocaine as well as lasting seven times longer. CFT's most common forms are a naphthalenedisulfonate salts, hydrochloride salts, and a free base. Despite thirty years of research, little is known about the compound and it has not history of human abuse.
*Other*- Said to be a Schedule II by supplier Sigma-Aldrich, though it is not listed on the DEA's website as such. Regardless, it will fall under analogue laws.
*Interactions*- MAOI's, etc.
*Side Effects*- Said to be the same as cocaine although mere exposure is supposed to cause overdose-like effects.
*Contra-Indications*- Unknown. Likely similar to cocaine.
*Dosing*- Unknown. Rumored to be highly toxic, though thought to be a method of discouraging abuse.

6) Dexmethylphenidate -- (stimulant)


This is nothing more than the dextro-isomer-only version of methylphenidate (most commonly known as Ritalin). It is designed as a more practical form of methylphenidate since it is thought that levomethylphenidate cause many of metabolic and unwanted side effects. Further information that would apply here will be found at methylphenidate.
*Other*- While it seems the removal of levomethylphenidate does little to help with side effects, it does result in a dosage of about half that of racemate methylphenidate.
*Interactions*- acid suppressants, antacids (can alter release of drug); anticonvulsants, anticoagulants, SSRIs, trycyclicantidepressants (effects possibly potentiated by dexmethylphenidate); antihypertensive agents, pressor agents (effects can be decreased by dexmethylphenidate); MAOIs; [SWIM would like to note here something that may be of little concern to anybody but given it could potentially help, he will continue. If you are on beta-blockers for any condition (i.e. tremors, glaucoma), do not forget that they were designed as antihypertensive agents, it just happens that they treat other conditions at lower doses.]
*Side Effects*- fever, pharyngolaryngeal pain, dry mouth, dyspepsia, abdominal pain, nausea, anorexia, headache, decreased appetite, feel jittery, anxiety, dizziness, anorexia
*Contra-Indications*- anxiety, tension, agitiation, glaucoma, motor tics, family history or diagnosis of Tourette's syndrome, MAOI use, hypersensitivity to methylphenidate
*Dosing*- Focalin comes in tablet form at the following doses: 2.5mg, 5mg, 10mg; Focalin XR comes in extended release capsules at the following doses: 5mg, 10mg, 15mg, 20mg
*Prescription Medicines*- Focalin, Focalin XR, generic (dexmethylphenidate hydrochloride)

7) Dextromethorphan (DXM) -- (antitussive)


[pharmacological information will be added soon]
*Other*- High, usually recreational doses, cause DXM to act like dissociative hallucinogen.
*Interactions*- Amiodarone (Cordarone), Fluoexetine (Prozac), Quinidine, CNS depressants, MAOIs, avoid smoking tobacco
*Side Effects*- Uncommon/Rare: confusion, constipation, dizziness, drowsiness, headache, nausea, stomach pain; OD symptoms: blurred vision, confusion, difficulty with urination, extreme drowsiness/dizziness, severe nausea/vomiting, shakiness/unsteady walk, slowed breathing, unusual excitement, nervousness, restlessness, severe irritability
*Contra-Indications*- dextromethorphan allergy, pregnancy, breast feeding, children, older adults, asthma, diabetes, liver disease, chronic bronchitis, emphysema, mucus with cough, slowed breathing
*Dosing*- All dosages given will be those described as "Adults and children 12 years of age and older."Lozenge dosages: 5-15mg every 2-4 hrs; Syrup dosages: 30mg every six to 6-8 hrs; Extended-release oral suspension dosages: 60 mg every 12 hrs.
*OTC Drugs*- Benylin (Adult Formula Cough Syrup, Pediatric Cough Suppressant), Cough-X, Creo-Terpin, Delsym Cough Formula, Diabe-TUSS DM Syrup, Hold DM, Pertussin (CS, DM), Robitussin (Maximum, Pediatric), Sucrets 4 Hour Cough Suppressant, Trocal, Vicks 44 Cough Relief

8) Indatraline -- (monoamine reuptake inhibitor)


Also known as Lu 19-005, Indatraline, as a nonselective monoamine inhibitor, acts to block reuptake of norepinephrine, dopamine, and serotonin. It has also shown effects very similar to those of cocaine, however, less potent and may have potential as a treatment for cocaine addiction. [SWIM believes this is still a research chemical and this is all he has so far; look for updates]
*Side Effects*-

9) Lometopane -- (stimulant)


Also known by the chemical name "(-)-2[beta]-Carbomethoxy-3[beta]-(4-iodophenyl)tropane," Lometopane is a stimulant that is primarily used in research. Its structure is pheyltropane based and thus it potentially a cocaine analogue under US law. It is considered to be extremely potent and thus has use in measuring dopamine neuron damage and loss in Parkinson's patients. [SWIM, it seems, must delve deeper if he wants info about this one; check back.]
*Side Effects*-

10) Mesocarb -- (stimulant/antidepressant/anticonvulsive)


Due to it being a Soviet-developed drug, Mesocarb is still widely unknown and unsearched by the West. Acting as dopamine reuptake inhibitor it is said to be slower acting, longer lasting, and less neurotoxic than dextroamphetamine. [Beyond this SWIM doesn't want to detail much more because the only English-language source of info found was Wikipedia and due to the nature of the info and his inability to cross-reference with the Russian links he didn't want to put it on here yet; check back.]
*Side Effects*-

11) Methylenedioxypyrovalerone -- (stimulant/NERI)


Also known as MDPV or MDPK, this drug is a designer drug with no history of medical use. It inhibits reuptake of norepinephrine and dopamine, apparently with the potency of four times that of methylphenidate. Although it does not hold illegal status in any country, it may possibly be fall under analogue illegal status (bears a semblance to ecstacy and other MDxx's) in countries with analogue laws.[Information here will clearly be rough and possibly inaccurate; SWIM will post for now but check back later.]
*Other*- Despite being a methylenedioxyphenylalkylamine derivative, like ecstacy, it does not act anything like most of these MDxx substances. [SWIM predicts this will show up on a drug test as amphetamine like MDMA does; he will look into the nature of the test to make a better prediction.]
*Interactions*- [Check back.]
*Recreational Effects*- CNS stimulation, euphoric feeling, sexual urges, agitation, anxiety, insomnia; certain aphrodisiatic effects also noted
*Contra-Indications*- [Check back.]
*Dosing*- Erowid Experience Vaults showed doses ranging as follows: 10.5mg insufflated across 8 hours, 7.5 mg insufflated once, and 80mg insufflated across 6.5 hours. None of the experiences were negative or involved overdoses. The 80mg noted a strong stimulant "crash."

12) Methamphetamine -- (psychostimulant/sympathomimetic)


[Pharmacology will be up soon; SWIM wants to research a bit more and distinguish isomers.]
*Other*- The methamphetamine used in Desoxyn is the dextromethamphetamine isomer. The left-handed levo- isomer is found in Vicks inhalers and has virtually no effect on the CNS.
*Interactions*- insulin requirements may be altered in diabetics, guanethidine, MAOIs, trycyclic antidepressants, other sympathomimetic amines, phenothiazines,
*Side Effects*- elevated blood pressure, tachycardia, palpitation, cardiac arrest (cases of abuse), psychosis, dizziness, dysphoria, overstimulation, euphoria, insomnia, tremor, restlessness, headache, tics, diarrhea, constipation, dry mouth, unpleasant tast, urticaria, impotence, changes in libido, growth suppression in youth with long-term stimulant use
*Contra-Indications*- pregnancy, breast feeding, children under the age of 12, older adults, glaucoma, advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism, known hypersensitivity to sympathomimetic amines, history of drug abuse
*Dosing*- Desoxyn comes in tablet form at one dosage: 5mg. Initial dose is usually 5mg/daily. Dose is increased by 5mg/day each week until an effective dose is targeted. The usual effective dosage is reported as 20-25mg.
*Prescription Medicines*- Desoxyn, generic (methamphetamine hydrochloride)
b) levomethamphetamine -- aka levmetamfetamine --
a) dextromethamphetamine --

13) Methylphenidate -- (stimulant)


Though often deemed a dopamine reuptake inhibitor, not enough is known about the drug pharmacologically to make that declaration. The leading theory on its mechanism is that it activates the brain stem's arousal system as well as the cortex. As far as monoamines go, there have been some affinities noted. Studies show methylphenidate does have a affinity for bind to dopamine and norepinephrine transporters. Furthermore, the more active dextro- isomer of methylphenidate has a quite notable affinity for norepinephrine specifically. Both isomers also displayed an affinity for 5HT receptors but no acts of binding were recorded. Also noteworthy is a 2004 study which showed that methylphenidate does act as a reuptake inhibitor for dopamine and, like amphetamines, they cause a release of dopamine. However, methylphenidate seemed to release old stores of dopamine while amphetamines seemed to be using newly produced dopamine. Regardless, we still have no conclusive answers.
In regards to the 2004 study mentioned above, methylphenidate's release of dopamine already stored in pre-synaptic vesicles in comparison with amphetamine's release of newly-created dopamine could explain why some patients who experience the effects of amphetamine treatments are unable to get the same effects from methylphenidate. The method used to determine these theories on where each drug releases dopamine from is also quite interesting. The antipsychotic drug reserpine (which is actually widely discontinued due to its irreversibility and side effects) actually depletes the pre-synaptic vesicles of their monoamines and furthermore irreversibly blocks them from storing monoamines. Knowing this, researchers realized that reserpine completely negates the effects of methylphenidate while leaving amphetamine completely unaffected. Which brings up a curious possibility to the author:
*Other*- The extended-release mechanism in Concerta is considerably different than that of many other extended-release ADD/ADHD medications, such as Ritalin-SR, Adderall XR, and Dexedrine. The pill, which looks no different than most other tablet medications, has a specially designed core which regulates the rate at which water enters, thus controlling the release of the drug. Concerta, via this release mechanism, is known to help control the hills (describing the rising and falling of methylphenidate levels in the plasma when displayed on a graph; this also correlates with moment by moment effectiveness of the drug) which are common with methylphenidate.
[Note: The following is nothing more than a rant by the author comprised entirely of opinion and theory developed from his own mind's logic flow.] Since reserpine can negate the effects of methylphenidate, due to the inavailability of dopamine in the vesicles, theoretically this explains the ineffectiveness of methylphenidate in some people. In the case of individuals who suffer from a disorder which is theoretically caused by dopamine deficiency (see Part IV) as well as recieve no or little effect from methylphenidate, could this lead to an explanation for previously cause-less symptoms or problems? Input, opinions, or down-right insults/shutdowns of this theory are certainly welcome.
*Interactions*- acid suppressants, antacids (can alter release of drug); anticonvulsants, anticoagulants, SSRIs, trycyclic antidepressants (effects possibly potentiated by dexmethylphenidate); antihypertensive agents, pressor agents (effects can be decreased by dexmethylphenidate); MAOIs; [SWIM would like to note here something that may be of little concern to anybody but given it could potentially help, he will continue. If you are on beta-blockers for any condition (i.e. tremors, glaucoma), do not forget that they were designed as antihypertensive agents, it just happens that they treat other conditions at lower doses.]
*Side Effects*- fever, pharyngolaryngeal pain, dry mouth, dyspepsia, abdominal pain, nausea, anorexia, headache, decreased appetite, feel jittery, anxiety, dizziness, anorexia
*Contra-Indications*- anxiety, tension, agitiation, glaucoma, motor tics, family history or diagnosis of Tourette's syndrome, MAOI use, hypersensitivity to methylphenidate
*Dosing*- Ritalin comes in tablet form at the following dosages: 5mg, 15mg, and 20mg. Ritalin-SR comes in tablet form and is only available at the dosage of 20mg. Concerta comes in extended-release tablet form at the following dosages: 18mg, 27mg, 36mg, and 54mg. Note: Only dosages for patients over six years of age will be listed. For all forms of methylphenidate the lowest possible dosage with effect should be taken. All instant-release tablets are taken either once or twice daily and extended-release forms are taken once daily.
*Prescription Medicines*- Ritalin, Concerta, generic

14) Nomifensine


Sometimes known as Merital, nomifensine was a fairly typical dopamine reuptake inhibitor researched and used primarily in the 1970's and 1980's for use as an antidepressant. The drug was also researched for use in ADHD and Parkinson's, however, despite successful animal testing, the drug seemed not to benefit human subjects. Despite being originally quite well recieved due to effectivness, few adverse effects, and little abuse potential, it is no longer used in medicine due to stimulant abuse potential, anemia, kidney and liver toxicity, overstimulation, and hyperthermia. Despite this, it is still used in research of links between dopamine and addiction due to one of its more unique effects on the brain.
*Interactions*- [Likely MAOIs but need more research.]
*Side Effects*- dry mouth, headache, nausea
*Contra-Indications*- [Need more research; check back.]
*Dosing*- Common dosage was 50-225mg per day. Dosing as high as 400-600mg caused many of the side effects which led to itswithdrawal from the market.

15) Phen(-di-)metrazine -- (stimulant/anorectic)


Closely tied to older pharmaceutical methods of weight loss, phendimetrazine is chemically related to amphetamine. Little is actually known about the drug's mechanism though it is known that about 30% of it metabolizes into phenmetrazine once administered. Phenmetrazine is an ancestor pharmaceutical of phendimetrazine. Phenmetrazine, known as Preludin, was quite popular in the 1950's because it had less side effects and yet was more effective than amphetamine as a weight loss solution. However, the fact that it had less side effects, and also because the manufacturers claims that is was less euphoric was probably not true (it was considered more euphoric by some), led to it having quite an appeal among amphetamine addicts. The drug was pulled off the market by the late-fifties, though this was likely due to reports of psychosis similar to that which is amphetamine-induced. Regardless, the actual pharmacology of phendimetrazine is not well known and in recent years it is rarely prescribed in any case.
*Other*- The anoretic, and so probably the weight loss, effect of the drug tends to wear off in as little as 14 days due to tolerance.
*Interactions*- all other CNS stimulants, MAOIs
*Side Effects*- palpitation, tachycardia, elevation of blood pressure, overstimulation, restlessness, dizziness, insomnia, tremor, headache, psychosis, agitation, flushing, sweating, blurring of vision
*Contra-Indications*- known hypersensitivity to sympathomimetics, advanced arteriosclerosis, cardiovascular disease, moderate to severe hypertension, hyperthyroidism, glaucoma, notably nervous/agitated patients, history of drug abuse
*Dosing*- 35mg once or twice daily
*Prescription Medicines*- Bontril, generic (phendimetrazine tartrate)

16) Procyclidine hydrochloride -- (anticholinergic)


This drug is commonly used for treatment of parkinsonism and drug-induced extrapyramidal symptoms. [As far as the pharmacology of the drug, not even the FDA clinical/professional fact sheet has much more than that. SWIM will hunt; check back later.]
*Other*- LD50 (intravenously) is 60mg/kg.
*Interactions*- haloperidol, phenothiazines
*Side Effects*- tachycardia, palpitations, orthostatic hypotension, disorientation, confusion, memory loss, hallucinations, agitation, nervousness, depression, drowsiness, giddiness, lightheadedness, rash, urticaria, decreased sweating, mydriasis, blurred vision, dry mouth, nausea, vomiting, epigastric distress, constipation, paralytic ileus, urinary retention, urinary hesitancy, muscle weakness, acute suppurative parotitis, hyperthermia, heat stroke
*Contra-Indications*- angle-closure glaucoma, children, pregnancy,
*Dosing*- Kemadrin is only available in 5mg tablets. Common dose is between 15-20mg, gradually increased from a low starting dosage.
*Prescription Medicines*- Kemadrin

17) RTI-121 -- (highly selective DRI)


This phenyltropane (structurally similar to cocaine) based stimulant was developed in the 1990's and is reserved for research purposes. Its high potency and duration imply many risks for human abuse, however, due to its transporter binding process and speed it is theorized to have a lower abuse potential than cocaine. Due to its very specific binding with dopamine transporters it is most useful in mapping dopamine in research studies.
*Other*- No recorded human abuse. [SWIM will hunt.]

18) Troparil -- (stimulant/RC)


This is yet another research chemical that acts as a dopamine reuptake inhibitor and is phenyltropane based. It has been shown to be equal in potency to cocaine although the duration is much longer, due to the absence of the link, which was easily and quickly metabolized, that connects the phenyl and tropane parts. It is used in research for dopamine mapping. Human abuse has not yet been documented, likely due to high cost (see note below about legality).

E) Dopamine Agonists


*Other*- An interesting legality issue is raised with Troparil. Although Troparil is not currently a scheduled illegal substance in any country, it would theoretically fall under an analogue law at first glance since it is phenyltropane based. However, analogue laws only currently cover additions or substitutions to groups of illegal drug structures. Troparil, however, is a simplification of an illegal drug molecule, created by removing the link between the phenyl and the tropane rings. Therefore, this very instant it is not even illegal under analogue laws. Furthermore, in the case that someone decided to manufacture and sell this compound, as happened with methylone, they could likely get away with it, unlike the manufacturers of the methylone-containing Explosion, because even with the ability to set a precedence including simplification in analogue laws, it would have to be a broad change covering all simplifications of analogues. However, ethanol itself is an simplified version of GHB. Interesting.

1) Apomorphine -- (emetic)


This potent and non-ergoline dopamine agonist is primarily prescribed as a treatment for Parkinson's disease. The drug displays primary affinities for all dopamine receptors (from order of strongest to least: 4, 5, 3, 2, 1) as well as the 1D, 2B, and 2C adrenergic receptors. It is believed that the stimulation of the D2 receptors of the caudate-putamen is the drug's primary mechanism although that is just theoretical. The drug is also sometimes prescribed for erectile dysfunction.
*Other*- Despite being derived from morphine, the drug has no binding affinity, nor effect whatsoever on opioid receptors.
*Interactions*- 5HT-3 antagonists, antihypertensive medications, vasoldilators, dopamine antagonists, any drug known to prolong the QT interval (such as haloperidol)
*Side Effects*- yawning, dyskinesias, nausea/vomiting, somnolence, dizziness, rhinorrhea, hallucinations, edema, chest pain, increased sweating, flushing, pallor
*Contra-Indications*- known hypersensitivity to apomorphine or sodium metabisulfite
*Dosing*- Dosages should begin at 0.2mL and may be increased if ineffective by 0.1mL every few days, not exceeding a dosage of 0.6mL. Administration is intended to be subcutaneous only. Any interruption of treatment lasting longer than a week requires starting again at a 0.2mL dosage.
*Prescription Medicines*- Apokyn, generic (apopmorphine hydrochloride)

2) Bromocriptine mesylate -- (ergoline-based)

Ergotaman-3',6',18-trione, 2-bromo-12'-hydroxy-2'-(1-methylethyl)-5'alpha-(2-methylpropyl)-

This dopamine agonist, derived from ergoline, is primarily used in the treatment of pituitary tumors and Parkinson's disease.
*Side Effects*-

3) Dihydroergocryptine -- (ergoline-based)

*Side Effects*-

4) Fencamfamine -- (stimulant/appetite suppressant)

*Side Effects*-

5) Levodopa -- (prodrug)

*Side Effects*-

6) Lisuride -- (iso-ergoline)

*Side Effects*-

7) Mesulergine -- (ergoline-based)

*Side Effects*-

8) Metergoline -- (ergoline-based)

*Side Effects*-

9) Pergolide -- (ergoline-based)

*Side Effects*-

10) Pramipexole -- (non-ergoline)

*Side Effects*-

11) Ropinirole -- (non-ergoline)

*Side Effects*-

12) Rotigotine -- (non-ergotamine)


F) Dopamine Antagonists



1) Amoxapine -- (tricyclic anti-depressant)



2) Aripiprazole -- (aypical anti-psychotic)



3) Clozapine -- (atypical anti-psychotic)



4) Droperidol



5) Domperidone



6) Metoclopramide



7) Olanzopine



8) Quetiapine



9) Risperidone



10) Ziprasidone



G) Eugeroics

2) CX717

*Side Effects*-

1) Adrafinil -- (stimulant/prodrug)


Adrafinil is nothing more than the earlier and prodrug form of modafinil. Modafinil likely became preferred and thus manufactured due to quicker onset of effects.

2) CX717 -- (ampakine)


Researched drug which stimulates glutamate and presumably AMPA receptors and shows possible use for ADHD and Alzheimer's. The drug has some problems with the FDA.


3) Modafinil -- (stimulant)


[SWIM needs to really sift through this FDA report to get things straight. If you need the info it can all be found here: xxxx


H) Other


*Other*- The drug patent is presumably held by Cephalon under the name Olmifon although it has not been through FDA approval procedures.

1) Amphetamine -- (stimulant)


Amphetamine belongs in a seperate category from the other dopaminergics because it does not act like any of the either two main classes. Amphetamines only two mechanisms of action are a forced expulsion of dopamine contained in synaptic vesicles as well as amphetamines affinity for the DATs (dopamine active transporter), which takes control of it, denying it it's ability to clear the synapse of dopamine. Although this second act is technically reuptake inhibition, SWIM considers amphetamines to be certainly not dopamine reuptake inhibitors. [SWIM hopes that is the only time his personal opinion must be used.] Additional FDA material shows the drug to also act somewhat as an MAOI, preventing monoamine oxidases from breaking down dopamine to homovanillic acid, although methamphetamines, due to the additional methyl group, are much more effective as an MAOI.

2) Cathinone/Methcathinone -- (stimulant)


Cathinone is an alkaloid present in the leaves of the shrub, Khat, and methcathinone is one of its analogues, which is synthetic. Methcathinone does not cross the blood-brain barrier as well as methamphetamines due to a slightly polar bond in its structure, but in other ways acts quite similar. The drug acts as both a serotonin and dopamine reuptake inhibitor. It is not known to have any effects on the norepinephrinergic system. The lack of these effects is the likely reason for its placement as a Schedule I substance, since it likely has no uses in treatment of ADD/ADHD.
It should also be noted that weight, gender, build, and height have shown to have no effect on the metabolization and subsequently the plasma concentrations, and thus intensity, of d/l-amphetamines. However, even though equal doses are bioequivalent and are not effected by the above factors, this does not mean a dose safe for one "first-timer" is safe for another. Differing neurochemical systems can have huge effects on how the drug affects the body.
*Other*- Amphetamine absorbtion and expulsion is highly dependent on bodily pH levels. Presumably due to its high pKa level, even with average urine pH levels about half of the administered dose is found in urine as alpha-hydroxy-amphetamine with another 30-40% being found as pure amphetamine. Basic, or alkaline, body enviroments will cause a potentiated and more efficient metabolization of amphetamines. Possible methods of increasing bodily pH levels include:
*Interactions*- MAOI's, tricyclic antidepressants, SSRI's, SSNRI's, etc...
*Side Effects*- Common: loss of appetite, weight loss, insomnia, headache, dizziness; Other: nervousness, irritability, over-stimulation, restlessness, unpleasant taste, dry mouth, bruxism, nausea, stomach pain, euphoria, suspicion/paranoia, addiction, tolerance; Rare: tics, high blood pressure, rapid pulse, halluncinations, Tourette's syndrome, cardiomyopathy, amphetamine psychosis, death
*Contra-Indications*- arteriosclerosis, cardiovascular disease, hypertension, hyperthyroidism, hypersensitivity to sympathomimetic amines, glaucoma, history of drug abuse, MAOI use in the past 14 days
[Author suggests xxxx for further info, Dexedrine, etc.]
Adderall XR is available in the following doses: 5mg, 10mg, 15mg(blue pellets?); 20mg, 25mg, 30mg(red/yellow pellets)
Typical doses for treatment of narcolepsy range from 5-60mg daily, while 40mg is rarely exceeded in ADD/ADHD treatment.
XR capsules contain the following inactive ingredients:gelatin capsules (edible inks, kosher gelatin, and titanium dioxide), hydroxypropyl methylcellulose, opadry beige, methacrylic acid copolymer, sugar spheres, talc and triethyl citrate
*Dosing*- Adderall IR is available in the following doses: 5mg(white); 7.5mg, 10mg(blue); 12.5mg, 15mg, 20mg, 30mg(yellow)
*Illicit Use*- Known by the street name, "Speed," abusers and illicit users of amphetamines will either acquire prescription drugs via illegal means, synthesize amphetamine themselves, or purchase unprofessionally synthesized amphetamine. Most unprofessionally synthesized amphetamine is dextroamphetamine sulfate.
IR tablets contain the following fillers, binders, etc: lactitol, magnesium stearate, microcrystalline cellulose and colloidal silicon dioxide
*Prescription Medicines*- an amphetamine salt blend (using Shire Pharmaceuticals 72-28 d-/l-amp blend) is available as Adderall (instant-release), Adderall XR (extended-release; using the Microtrol delivery system), as well as by the generic name AMPHETAMINE SALTS (note: only instant-release currently; not extended-release version of amp. salt blends yet exists). Dexedrine, produced by GlaxoSmithKline, is the same essential drug, however it is 100% d-amphetamine sulfate. It also comes in instant-release tablets and sustained-release capsules (SPANSULE delivery system).
a) dextroamphetamine -- since amphetamines are chiral compounds they have left-handed and right-handed versions of the compound. Dextroamphetamine is the right-handed amphetamine isomer. D-amphetamine is recognized by many to be much more effective and potent than the levo-isomer of the same drug. While Shire Pharmaceuticals uses 72-28 blend of d-/l-amphetamines (the l-isomers help for a longer-lasting pill as well as a smoother pill), the generic extended release amphetamine is 100% dextroamphetamine.

3) 4-Methyl-aminorex



4) Pemoline



5) Lysergic acid diethylamide (LSD)



6) Benzylpiperazine (BZP)




NEED TO RESEARCH - - http://en.wikipedia.....henethylamines



4) THC


1) Alcohol



2) Caffeine



3) Ibogaine



4) THC (Δ9-tetrahydrocannabinol)






1) Gamma-Butyrolactone (GBL)



2) Gamma-Hydroxybutyric Acid (GHB)

4-Hydroxybutanoic acid


3) Nicotine








Causes of Dopamine Deficiency

Although we understand very little about the causes or underlying reasons for the understimulation of dopamine receptors and the conditions which can derive from that, we know that, if dopamine understimulation is the case, then it must be a case of either excessively low dopamine levels in the brain or permanantly damaged or faulty receptors. At this point in history we understand very little about these conditions but know that they can result from the following:

1) Genetics -

2) Diet -

3) Drug Abuse -

Just as often as the cause of a dopaminergic is discovered, one is given up on, without a diagnosis.

Symptoms of Dopamine Deficiency

-Inability to concentrate
-Difficulty with decision making and problem solving
-Cravings for meth, coffee, nicotine, or food
-Loss of interest in sex or inability to climax
-Lack of motivation, even for hobbies
-Depression (characterized by inability to feel joy and pleasure)
-Low energy levels
-Attention deficits
-Trouble with memory
-Social anxiety

Disorders Believed To Be Caused By Insufficient Dopamine Stimulation

-Restless Legs Syndrome (RLS)
-Parkinson's Disease



Disorders Believed To Be Caused By Excess Dopamine Stimulation

-Amphetmaine Psychosis
-Tourette's Syndrome
-Impulsive Behavior



II-D-13: http://findarticles....404/ai_n9356900



serotonin syndrome
xxxx broken link
receptor affinities!
*Other*- While the chemistry involved in methcathinone synthesis is quite simple, the resultant free base is very unstable and the reaction is reversed resulting in ephedrine from which it came.
*Effects*- Cathinone is described to have both stimulant and aphrodisiatic effects. Methcathinone has the following effects:
*Dosing*- No real great sources on the dosages needed here. Seems a considerable number of khat leaves must be chewed to get the effects of cathinone. Oral dosages for methcathinone ranged from 50-400mg and insufflated dosages supposedly are about 1/4 of that for equal effects or 15-100mg. Furthermore, intravenous dosages seem to run about 1/4 of the insufflated dosage or about the 10-20mg range. [Note: Due to the low number of experiences reported for this drug the dosages are estimated and may not be accurate. As with all drugs, start with lower dosages to err on the side of safety.]
-- euphoria, increased alertness, dilated pupils, rapid breathing, increased heart rate, inability to stop talking, increased emptathy, increased social ability, inability to understand the concept of priority and false understanding of importance, increased/decreased sexual function and desire, hypertension, tachycardia, decreased appetite


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#52 Synaptik

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Posted 23 October 2016 - 01:45 PM

If one is worried about oxidative damage in the brain, be it from amphetamine or other chemical neurotoxicity, I recommend a combination of Ginkgo Biloba and Turmeric (curcumin). Both are powerful brain oxidant scavengers and easily cross the blood-brain barrier. 


I just posted this table on another thread, but look what effect EGb 761 has ALONE on fluoride-induced lipid peroxidation in the brain. I believe Curcumin would have much of the same effect. Pretty powerful stuff.



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#53 Mr. Psychillogical

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Posted 14 November 2016 - 09:09 PM



#54 Mr. Psychillogical

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Posted 04 January 2017 - 06:09 AM

Lithium & Amphetamine 








Chronic lithium treatment effectively reduces behavioral phenotypes of mania in humans and rodents. The mechanisms by which lithium exerts these actions are poorly understood. Pre-clinical and clinical evidence have implicated increased mesolimbic dopamine (DA) neurotransmission with mania. We used fast-scan cyclic voltammetry to characterize changes in extracellular DA concentrations in the nucleus accumbens (NAc) core evoked by 20 and 60 Hz electrical stimulation of the ventral tegmental area (VTA) in C57BL6/J mice treated either acutely or chronically with lithium. The effects of chronic lithium treatment on the availability of DA for release were assessed by depleting readily releasable DA using short inter-train intervals, or administering d-amphetamine acutely to mobilize readily releasable DA. Chronic, but not acute, lithium treatment decreased the amplitude of DA responses in the NAc following 60 Hz pulse train stimulation. Neither lithium treatment altered the kinetics of DA release or reuptake. Chronic treatment did not impact the progressive reduction in the amplitude of DA responses when, using 20 or 60 Hz pulse trains, the VTA was stimulated every 6 s to deplete DA. Specifically, the amplitude of DA responses to 60 Hz pulse trains was initially reduced compared to control mice, but by the fifth pulse train, there was no longer a treatment effect. However, chronic lithium treatment attenuated d-amphetamine-induced increases in DA responses to 20 Hz pulse trains stimulation. Our data suggest that long-term administration of lithium may ameliorate mania phenotypes by normalizing the readily releasable DA pool in VTA axon terminals in the NAc.

#55 Mr. Psychillogical

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Posted 16 January 2017 - 10:56 PM

More options for ADD/ADHD-ers, also suffering Anxiety


The palliative anti-anxiety natural supplements I found useful are: 

inositol (10 to 15 grams daily). And take these when needed: vitamin B1 (100 mg), vitamin B6 (50 mg), vitamin B5 (1 gram), L-tyrosine (500 mg); taurine (1000 mg), L-carnitine (500 mg), picamilon (100 mg), arginine pyroglutamate (2 grams), theanine (200 mg)). 


Some anti-anxiety herbs include: 

ashwagandhaBacopa monnierachamomile (especially the apigenin extract of chamomile), lavenderpassionflowerHoly basil can dramatically improve anxiety in some people (holy basil is potent COX-2 inhibitor, however, thus its anxiolytic mechanism may actually be as an anti-inflammatory rather than a palliative; holy basil also lowers cortisol, and high cortisol is another source of some people's anxiety states - but watch out if you have low cortisol).

The antihistamines cetirizine (Zyrtec) and loratadine can reduce anxiety symptoms. Dose is 10 mg daily.

Transdermal magnesium cream used twice daily is also good. Transdermal magnesium is often used in autism, where there are very high levels of internal mental anxiety. Magnesium lowers NMDA receptor activation. (You can make your own cheap transdermal magnesium cream, simply using Epsom Salts mixed with some hand cream). Oral magnesium may help, but most people reach bowel tolerance (they get diarrhea) after about 500 to 1000 mg. The magnesium content of Epsom Salts (magnesium sulfate MgSO4) is 20%, so 5 grams of Epsom Salts provides 1 gram of magnesium.




On a personal note:

I'd like to add that I've experienced, roughly 3 months of,

benefits i guess by numerical terms (8 out of 10).

Anxiety, nervousness, social interaction, physical anxiety & OCD,

the symptom relief tremendously reduced,

I stack w/ my 40mg dexedrine:

AM: Lithium orotate 5-10mg/Taurine 2-3g/B-complex/Zinc 50mg 

After breakfast: 0.5 Etizolam (w/coffee or Magnesium orotate 250mg)

PM: 0.5 Etizolam(optional)/Taurine 2g/Theanine 100mg

#56 Mr. Psychillogical

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Posted 19 January 2017 - 08:23 PM

externalfile:drive-a6d7879d43d2357155f11472508b928b98093a4a/root/Landen'sDOCS/Screenshot 2017-01-19 at 12.21.16 PM.png

Increased levels of extracellular dopamine in neostriatum and nucleus accumbens after histamine H1 receptor blockade.

The dopaminergic system plays a central role in the processing of reward or reinforcement since drugs that have reinforcing properties all share the ability to elevate dopamine (DA) levels in the nucleus accumbens or neostriatum. Histamine H1 receptor antagonists are known to have reinforcing effects in humans and laboratory rats. Here, we examined the effect of systemic (i.p.) treatment with two H1 antagonists, chlorpheniramine and pyrilamine, on the extracellular levels of DA and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the neostriatum and nucleus accumbens of urethane-anesthetized rats. Dopamine and metabolites were measured using in vivo microdialysis and HPLC with electrochemical detection. Saline injections did not produce significant effects on DA, DOPAC, or HVA levels in the neostriatum or nucleus accumbens. In the neostriatum, chlorpheniramine administration (5 and 20 mg/kg) produced a sustained increase in DA to approximately 140 and 180% of pre-injection baseline levels, respectively. In the nucleus accumbens, chlorpheniramine (20 mg/kg) produced a transient increase in DA levels to about 300% of baseline. In both the neostriatum and nucleus accumbens, DOPAC and HVA decreased after chlorpheniramine treatment. Pyrilamine administration (10 and 20 mg/kg) produced a sustained increase in neostriatal DA levels to 140 and 165%, respectively, and accumbens DA increased transiently to 230% after a dose of 20 mg/kg. Levels of neostriatal and accumbens DOPAC and HVA decreased after pyrilamine treatment. These results show that H1 antagonists can potently enhance DA levels in the neostriatum and nucleus accumbens of urethane-anesthetized rats. The neurochemical effects on DA and its metabolites seen here (increased DA, decreased DOPAC and HVA) are similar to those commonly observed with drugs of abuse (e.g. psychostimulants). The interaction of H1 antagonists with dopaminergic transmission may explain the reinforcing effects and abuse potential associated with these compounds.


#57 Mr. Psychillogical

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Posted 19 January 2017 - 08:29 PM

Neurosci Biobehav Rev. 1997 May;21(3):341-59.
Behavioral functions of nucleus accumbens dopamine: empirical and conceptual problems with the anhedonia hypothesis.

Nucleus accumbens (DA) has been implicated in a number of different behavioral functions, but most commonly it is said to be involved in "reward" or "reinforcement". In the present article, the putative reinforcement functions of accumbens DA are summarized in a manner described as the "General Anhedonia Model". According to this model, the DA innervation of the nucleus accumbens is conceived of as a crucial link in the "reward system", which evolved to mediate the reinforcing effects of natural stimuli such as food. The reward system is said to be activated by natural reinforcing stimuli, and this activation mediates the reinforcing effects of these natural stimuli. According to this view, other stimuli such as brain stimulation and drugs can activate this system, which leads to these stimuli being reinforcing as well. Interference with DA systems is said to blunt the reinforcing effects of these rewarding stimuli, leading to "extinction". This general model of the behavioral functions of accumbens DA is utilized widely as a theoretical framework for integrating research findings. Nevertheless, there are several difficulties with the General Anhedonia Model. Several studies have observed substantial differences between the effects of extinction and the effects of DA antagonism or accumbens DA depletions. Studies involving aversive conditions indicate that DA antagonists and accumbens DA depletions can interfere with avoidance behavior, and also have demonstrated that accumbens DA release is increased by stressful or aversive stimuli. Although accumbens DA is important for drug abuse phenomena, particularly stimulant self-administration, studies that involve other reinforcers are more problematic. A large body of evidence indicates that low doses of dopamine antagonists, or depletions of accumbens DA, do not impair fundamental aspects of food motivation such as chow consumption and simple instrumental responses for food. This is particularly important, in view of the fact that many behavioral researchers consider the regulation of food motivation to be a fundamental aspect of food reinforcement. Finally, studies employing cost/benefit analyses are reviewed, and in these studies considerable evidence indicates that accumbens DA is involved in the allocation of responses in relation to various reinforcers. Nucleus accumbens DA participates in the function of enabling organisms to overcome response costs, or obstacles, in order to obtain access to stimuli such as food. In summary, nucleus accumbens DA is not seen as directly mediating food reinforcement, but instead is seen as a higher order sensorimotor integrator that is involved in modulating response output in relation to motivational factors and response constraints. Interfering with accumbens DA appears to partially dissociate the process of primary reinforcement from processes regulating instrumental response initiation, maintenance and selection.



#58 Mr. Psychillogical

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Posted 19 February 2017 - 09:01 AM

J Med Food. 2014 May;17(5):535-42. doi: 10.1089/jmf.2013.2950. Epub 2014 Apr 14.
Antidepressant-like behavioral, anatomical, and biochemical effects of petroleum ether extract from maca (Lepidium meyenii) in mice exposed to chronic unpredictable mild stress.

Maca has been consumed as a medical food in Peru for thousands of years, and exerts anxiolytic and antidepressant effects. Our present study aimed to evaluate the behavior and anatomical and biochemical effects of petroleum ether extract from maca (ME) in the chronic unpredictable mild stress (CUMS) model of depression in mice. Three different doses of maca extract (125, 250, and 500 mg/kg) were orally administrated in the six-week CUMS procedure. Fluoxetine (10 mg/kg) was used as a positive control drug. Maca extract (250 and 500 mg/kg) significantly decreased the duration of immobility time in the tail suspension test. After treatment with maca extract (250 and 500 mg/kg), the granule cell layer in the dentate gyrus appeared thicker. Maca extract (250 and 500 mg/kg) also induced a significant reduction in corticosterone levels in mouse serum. In mouse brain tissue, after six weeks of treatment, noradrenaline and dopamine levels were increased by maca extract, and the activity of reactive oxygen species was significantly inhibited. Serotonin levels were not significantly altered. These results demonstrated that maca extract (250 and 500 mg/kg) showed antidepressant-like effects and was related to the activation of both noradrenergic and dopaminergic systems, as well as attenuation of oxidative stress in mouse brain.


#59 Judithmcb94

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Posted 05 March 2017 - 06:24 PM

Huge Huge HUGE advocate of memantine here!  Changed my life!   I am able to take my ADHD meds and not abuse them!  It really is magical - I mean, it doesn't make everything go back to normal normal, but it's certainly a difference and if I were to take a long enough break I think the impact would be huge.  


I'll also say that magnesium can help, but it's nowhere near as effective as memantine.  Last thing, Do not use cough syrup.  It's a serious constrictor on your vascular system and it is just so uncomfortable when your heart gets going like that.  It really is impossible to not fixate on it. 

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#60 Mr. Psychillogical

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Posted 19 March 2017 - 05:51 AM

  1. Study,
  2.  study
  3. study,
  4.  study
  5. study
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  7. study
  8. study
  9. study
  10. study
  11. study
  12. study,
  13. study
  14. study
  15. study
  16. study
  17. study
  18. study
  19. study


A few Studies providing information relative to this threads topic  :-D

Also tagged with one or more of these keywords: adderall, dextroamphetamine, amphetamine, stimulant, adhd, dexedrine, vitamin, supplement, herbs, stack

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