217 replies to this topic

[APBT]

Rol82

I'm curious, as I'm sure are others, regarding the expense of your stack; I'm feigning bankruptcy at the mere thought.

Would you mind sharing, in US dollars, the monthly cost of the Rx and the OTC supplements you consume?

[Rational Madman]

Rol82

I'm curious, as I'm sure are others, regarding the expense of your stack; I'm feigning bankruptcy at the mere thought.

Would you mind sharing, in US dollars, the monthly cost of the Rx and the OTC supplements you consume?

Well, it's pretty expensive, but as I said before, I'm not in danger of becoming destitute. I'm not terribly comfortable with disclosing the exact sum, because not everyone is in the same financial situation, and I'm afraid it might engender ill-feelings.

Edited by Rol82, 21 September 2010 - 11:10 PM.

[Logan]

Rol, what about Zoloft? It is less likely to affect prolactin and it inhibits mTOR. I also like Zoloft as it does not seem to be as hard on liver metabolism as other SSRIs.

[Rational Madman]

Rol, what about Zoloft? It is less likely to affect prolactin and it inhibits mTOR. I also like Zoloft as it does not seem to be as hard on liver metabolism as other SSRIs.

Yeah, but it's a sigma 1 anatagonist. I'm wild about the sigma 1 receptor because of its critical role in neuroplasticity, and the creation of neurotrophic factors. This is not to say that Zoloft doesn't have the same properties of other antidepressants, but its antagonistic affinity for sigma 1, and issues with past usage turns me off.

[Rational Madman]

Rol82

I'm curious, as I'm sure are others, regarding the expense of your stack; I'm feigning bankruptcy at the mere thought.

Would you mind sharing, in US dollars, the monthly cost of the Rx and the OTC supplements you consume?

I'll tell you what, I'll give the cost in Confederate dollars, which is based on the assumption that it still exists as a sovereign entity, and that the level of inflation is unchanged.

[Logan]

Rol, what do you think about Afobazol as a sigma 1 receptor agonist?

[Rational Madman]

To answer your previous question: you get upregulation of mu receptors with LDN.

Regarding your regimen, your target dose of Rasagiline seems to be much higher than what you mentioned before. What's the motivation behind that?

Also, since you mentioned methylphenidate, dexmethylphenidate instead of amp perhaps?

How would Acitretin or Pioglitazone enhance learning? I haven't heard of either, any evidence for this?

Are you going to take varenicline to stop smoking or do you think it will work well with the nicotine somehow?

There is plenty of in vivo evidence supporting the notion that the Thiazolidinediones have a positive impact on cognition via activation of Peroxisome Proliferator Activated Receptors, which in concert with the drugs's interaction with other targets, reduces inflammation, influences glucose metabolism, lowers cholesterol, is neurotrophic, and corrects aberrant autoimmune responses. The problem with this class, though, is the disturbing incidence of cardiac events, fluid retention, and weight gain. So, I began looking elsewhere, and discovered Acitretin, which should have similar effects through its activation of retinoic acid receptors, and has the additional virtue of passing the blood brain barrier. Although, less well studied, the scientific rationale for use is sound enough for me to proceed. But, to answer your question, some preliminary findings do indeed support its use for cognitive enhancement. Additionally, it is has a much better side effect profile than the alternatives, so I decided to try it before possibly moving onto the the Thiazolidinediones.

My flirtation with Varenicline was based on a desire to upregulate alpha7 nAChRs, but I concluded that Donepezil is probably the best agent to be used in pursuit of that goal. But, I'll have to toy with the doses. As I suggested in the other thread, Varenicline is a full agonist at the alpha7 site, and I speculated that its use might save us the trouble of dosage calibration. However, it has a terrible side effect profile, and I mean terrible. Frankly, I'm shocked that it hasn't been pulled off the market, because a troubling percentage of users can expect to become exponentially more aggressive, and depending on their disposition, suicidal. Initially, I thought it might be possible to improve this outcome through 5ht2a/c antagonism, but there are unwanted side effects with one of these targets, and would not come close to addressing all of the correlates contributing to the progression of depression, or the acute behavioral disturbances that may arise with use. Further, the patient outcomes were far less than unequivocal, and in cases of positive findings, certainly not profound. The other alternative that I proposed, Wellbutrin, has still yet to be determined effects on nAChRs, and because my previous experience with the drug (and the other oft-mentioned upregulator, Memantine) was not a positive one, I lost interest, and returned to Donepezil. As for smoking cessation, well, that's one of the last of activities that I'll discontinue. It's the drug choice of sages for much of recorded history, and the most famous nootropic in history. If you're fond of historical biographies (which used to be requisite in my case), you'll be impressed with how many artists, writers, and statesmen depended on the substance. There are problems with usage of course, that I'm sure have become permanently embedded in our heads with a constant barrage of public service announcements, hair raising scientific findings, compulsory courses that elucidate the many hazards, and overt criticism and legally sanctioned segregation that users are subjected to on a daily basis. But, for every pleasurable and redeemable problem, there is a solution, so I remain undeterred.


So, as you can see, I'm coming pretty close to covering all the bases, because as should be painfully apparent, human enhancement is not monocausal. I've pretty much decided on the final ingredients of my formidable regimen, which will likely include(with the proper adjustments) Modafinil (or Armodafinil, if I can convince my very amenable psychiatrist), low dose Donepezil, low dose Clonidine (since Guanfacine is nowhere to be found, save a rogue dealer in Chad, and a likely terrorist front in Pakistan), and a twice weekly use of Rapamycin. But, my mind may change about Dimebon, Tropisetron, Varenicline, Cortexin, Cerebrolysin, Methylene Blue, Pioglitazone, Ritalin, and Etanercept. Additionally, I'm always on the lookout for a homemade transcranial magnetic therapy device---which would be infinitely cool, a reasonably priced floatation tank (none exist), and a way to get a crash course in self-administered acupuncture---beyond what I've already read. Throw in immunoglobulin therapy, and I think I'll be as close as presently possible to the elusive immortality/human enhancement goal that I set, which I evidently take far more serious than the average user. Unless Deep Brain Stimulation, and other promising therapies become cosmetic procedures, which might be already possible in less developed countries that cater to medical tourists, and where money unfortunately trumps much of everything.

On a separate---but not entirely unrelated---note, I think the outreach campaigns, the member funded research programs, and other forms of advocacy are abundant wastes of human capital because their impact and resonance have been quite limited. For our mission to gain legitimacy---which is already exceedingly difficult due to public skepticism seeding from towering normative and scientific barriers---we have to produce palpable evidence of human progress, which is contingent on the willingness of members to commit themselves zealously to the goals of human enhancement and longevity, to become undaunted by the multiple obstacles that litter this pathway, and to accept the inexorable risk of death in this endeavor, as any soldier or martyr would. I'm not advocating recklessness, but disinhibition, and matching our community's ardent desire for longevity with an equal, and not mutually exclusive commitment to self-perfection and the maximization of pleasure. I feel David Pearce shares my sentiments, and I'm very eager to enlist his support here, because I believe he would play an irreplaceable role in reconciling the goals of hedonism, longevity, and human enhancement. Not to mention skippering a movement that any honest assessment would conclude to be insubstantial, and in disarray.

Edited by Rol82, 22 September 2010 - 08:55 PM.

[Rational Madman]

Rol, what do you think about Afobazol as a sigma 1 receptor agonist?

Well, I'm not that familiar, but before you jump on the tranquilizer train, I would try the aforementioned, which are also anxiolytic, and bolstered by more evidence.

[Rational Madman]

Sirtuin 1 activation, and Phosphodiesterase 4 Inhibition: Luteolin, which I've concluded to be superior to Resveratrol.

Rol82,

just out of curiosity. How did you conclude that?.

It was a combination of several variables, that include: impressive findings in a University of Illinois study---which has been replicated, bioavailability issues, its possession of properties similar to Resveratrol like Sirtuin 1 activation, past experience, and its relative preference for phosphodiesterase 4, which when inhibited, can lead to a significant increase in NMDA receptor mediated cAMP concentrations.

[Rational Madman]

Personally i'm avoiding supplements that only target aging at this moment, as i'm still young and i beleive that in the near future we will have more research available, currently my focus goes to avoiding deseases (such as cancer) and supplements that increase my chances of survival in ischemic stroke for example.

At this time i'm sticking to my curcumin and resveratrol combo (wich i beleive look the most promosing for my goals) and will probably add in semax for its protective effects in ischemic stroke. All the rest is to counteract my anxiety, or other purposes. Altough i'm confortable of adding in galantamine into my regime for cognitive enhancement.

By not focussing on aging i can leave out supplements with potentially interfere with my current combo.

Anyway thx for sharing your regime, i find it very interesting and hopefully you will find long term succes and it will adress your goals.

Curcumin and resveratrol would be valuable constituents of any regimen, and are highly synergistic, so both are certainly good choices. Many of the Russian drugs also hold promise, but unfortunately, remain shrouded by professional indifference, and the absence of a sizable amount of data necessary to quantify their neurotrophic effects with drugs that promote similar factors. With Semax, though, it may be difficult to reconcile the effective dose with the allotment per unit, so Cerebrolysin might be a safer bet. However, if you're convinced of its effects---which seem to be impressive---don't let my doubts deter you, and allow the insatiable human hunger for discovery to neutralize confounding factors.

I applaud you for your demonstrated commitment to daringness, and urging caution when evidence and experience warrants it. What the ostensibly more rational minds that slavishly adhere to normative standards of inquiry and proof often fail to fathom is the crippling, and transformative effect of neuropsychiatric illnesses, which renders many of the afflicted invalid, and unleashes a compelling urge to utilize and examine every methodology with even the most remote prospect of success. While exiled in the depths of bleakness, and in a confinement devoid of light and marked by unremitting agony, you soon become liberated of many restraints, and sustained only by the desire to seek solace and sovereignty from your wretched state. With each step forward, a flickering light becomes less dim, and with each faltering, it vexingly disappears. Repeated failure either becomes sufficiently dispiriting enough to force a grudging acceptance of a miserable existence, and resign to the apathy that you loath, or it instills a fervent desire for not only emancipation, but for a level of certainty that makes a recurrence inconceivable, and for achieving an outcome that compensates for time and opportunities that are irretrievably lost. While perhaps sometimes the subject of ridicule, skeptical individuals should become resolved to live by your example, and add additional dimensions to their minds.

Edited by Rol82, 22 September 2010 - 08:38 PM.

[Rational Madman]

To answer your previous question: you get upregulation of mu receptors with LDN.

Regarding your regimen, your target dose of Rasagiline seems to be much higher than what you mentioned before. What's the motivation behind that?

Also, since you mentioned methylphenidate, dexmethylphenidate instead of amp perhaps?

How would Acitretin or Pioglitazone enhance learning? I haven't heard of either, any evidence for this?

Are you going to take varenicline to stop smoking or do you think it will work well with the nicotine somehow?

The question is, though, how sustainable is low dose naltrexone therapy, and what are the sacrifices for exchanging an analgesic with a genuine immune system modulator?

Edited by Rol82, 22 September 2010 - 05:45 PM.

[Rational Madman]

Some good points have been made, and before I address the questions about varenicline, I'll have to delve a bit further. There is some evidence, however, that the monotherapeutic use of varenicline has cognition enhancing properties, and because of its affinities for nicotinic receptors, it is being investigated for use in patients suffering from schizophrenia, Alzheimer's, and other conditions characterized by mild cognitive impairment, but the outcomes are mixed. Interestingly, when combined with bupropion, in concert, both deliver better outcomes than monotherapy, but without the full texts, I'm unable to determine the cognitive effects of this combination. But, I'm very curious, and may experiment should I encounter confidence brightening findings about this combination. Varenicline also carries the risk of promoting behavioral disturbances and suicidal idealation, which has dampened my enthusiasm somewhat, but adjunctive 5ht2a/c antagonism should resolve that problem. For now, though, I'm on the Rasagiline train, since I've concluded that it's safer than many feared, and have been heartened by a friend's experimentation with the substance. For cognitive enhancement, alpha 7 upregulation is certainly important, but there are other pharmacological targets that need to be considered, and I intend to personally investigate over the course of several months.

Reelin Promotion: Low dose Valproic Acid, Tianeptine, and or low dose Amisulpride.
Acetylcholinesterase Inhibition: Donepezil, but the ideal dosage remains shrouded.
Maintenance of Tyrosine Hydoxylase, Glial Cell Line Derived Neurotrophic Factor, and the promotion of SOD: Rasagiline, at doses of 1-4 mg/day.
Glutathione Promotion: Cabergoline, twice weekly.
Activation of Nuclear Receptors: Pioglitazone, or Acitretin.
mTOR and calciuneurin inhibition: Once or twice weekly use of Rapamycin.
Sirtuin 1 activation, and Phosphodiesterase 4 Inhibition: Luteolin, which I've concluded to be superior to Resveratrol.
Protein Biosynthesis Enhancer: Cerebrolysin, or Pioglitazone.
Neutralizing the Effects of Alcohol: Valdoxan, or something melatonergic.
Concentration: Amphetamine in conjunction with xanthines like green tea or freeze dried organic coffee (which is exceptionally rich in pyroglutamic acid).
Learning Enhancer: The racetams in conjunction with intramuscular choline alfoscerate, nicotine, Acitretin, or Pioglitazone.
Mitochondrial Energy: Rasagiline, Pioglitazone, Methylene Blue (pharmaceutical grade), or Dimebon, once the price falls inevitably.
Inflammation: Rapamycin, Pioglitazone, fish oil, flavonoids, Rasagiline, and xanthines.
Preventing the breakdown of Cyclic adenosine and cyclic guanosine monosphosphate: Perhaps Cialis, which has considerable appeal, and when used adjunctively with cranial electrotherapy, should induce oxytocin release without resulting in cognitive impairment. Anecdotally, I find Cialis to be an exceptionally pro-social drug.
Neuroplasticity: Tianeptine, Valdoxan, and one of the racetams.
Nicotinic receptors: Donepezil, Varenicline, Tropisetron, and nicotine (I haven't decided on the best delivery mechanism, but to my girlfriend's chagrin, my favorite has become pipe smoking).
Visual Processing: Probably Tolcapone or Entacapone.
Prepulse Inhibition and Prefrontal Efficiency: Either Tolcapone or Entacaopone, but most likely the latter because of serious safety concerns.
Executive Function: Agents that are dopaminergic and noradrenergic.
Reward: Running, at home acupuncture, or perhaps upregulation of opioid receptors with Naltrexone.
V2 receptor upregulation: Critical, but I have no ideas. Desmopressin or testosterone may work, but I'm dubious.
Telomerase Activation: Cycloastragenol, but there has to be something better out there.
Tumor Necrosis Factor Inhibition: Rapamycin.
Protein Kinase Expression: Copious amounts of phosolipids.
Promotion of Neurotrophic Factors: Valproic Acid and Rasagiline.
Mood Enhancement: Valdoxan, Tianeptine, a tetracyclic antidepressant, and light therapy.
Stress: Valdoxan, Tianeptine, meditation, sensory deprivation, massage, acupuncture, and cranial electrotherapy,
Environmental Richness: Exercise, socializing, and light and sound devices.
Diet: Flavonoid dense that closely resembles a Mediterranean or East Asian diet.
Sleep: Valdoxan, or single malt scotch whiskey (seriously, give it a try).
Reactive Oxygen Species: Luteolin, and Rasagiline.
Glucose Metabolism: Pioglitazone, and Acitretin.
Energy: Modafinil, and low dose hydrocortisone.
Blood Pressure: Guanfacine, and fish oil.
Vague, and Undefined Infections: Minocycline, and/or Valtrex.
Chelation: Valtrex (unsubstantiated pet theory of mine).
Liver: Intramuscular choline.
Stomach Ailments: Ondansetron, or Tropisetron.
Anxiety: Amisulpride, Tianeptine, amphetamines, Cialis, Sceletium Tortuosum, and/ or alcohol.
Obsessiveness: Salvinorin A, Sigma agonist, and/or intramuscular oxytocin.

Now, I should note that I have no intention of using all of these substances at once, but I believe that these maybe effective solutions to problems that pervade the message board, and that I've arrived at through personal research. In my regimen thread, these issues will likely be revisited, with a disclaimer attached, and without discussing the method of procurement. While I have moved quite off topic, I thought it was worth elucidating my thoughts on a comprehensive approach for cognitive enhancement, since it's is evidently a concern of all the thread participants.

I find your attitude towards neuropharmacology fascinating, I've never seen anyone so dedicated towards enhancing their cognition in such a capacious way. I am rarely complimentary towards people, especially since because I have extremely extensive scientific knowledge in general, I am difficult to impress. But I have to admit I believe pharmacologically I have something to learn from you. Can I ask if you have any formal qualifications? Not that it's relevant to the accuracy of your knowledge.

Initially I was sceptical about your aims, since it seemed from the amount of substances you were taking that there was a motive based on insecurity, as is the case with many people who excessively self-medicate. But the research and reasoning behind each pharmaceutical/supplement is undeniable. You may be the epitome of what a contemporary meta-cognitive individual can possibly be, given the limitations on current modulation of human consciousness, as hyperbolic as that sounds. Personally I am interested in human cognitive and physical enhancement in a more enduring way, and am performing research to that end, but it is far less immediate of course.

I would like to know what your experience has been with Amisulpride, and also what your opinion is of a combination of Agomelatine/Valdoxan and Tianeptine. I am currently on Agomelatine and have taken tianeptine in the past with excellent results, thanks!

Well, I appreciate the sincerity of your compliment, and am encouraged by your melting skepticism. And, while cognitive enhancement should be of towering importance to any life extension endeavor, I'm also motivated by the symbolic and affecting importance of standing athwart intractable problems such as ageing, and with a commanding voice, help to end its reign of terror (Forgive me for paraphrasing Buckley). As for my academic background, I'm a social scientist with postgraduate training, with eclectic interests that officially include history (where my scholastic emphasis was probably the greatest), political science, international relations, and international studies. For many years, I was unmoved by the physical and biological sciences, but my feelings were altered when I realized that my future happiness was contingent on a change in sentiment, so I adaptively taught myself in the areas that you find my knowledge to be noteworthy. But, because of institutional requirements, and requisites of my major areas of concentration, I began with a sufficient, and facilitating base of knowledge. Additionally, my extended family is filled with doctors (including a few psychologists), engineers, dentists, executives, lawyers, professors, and a solitary biochemist---which is probably of dubious importance, but may shed light on the imperative of success, and genetic determinants. Equally dubious, but perhaps worthy of note is a family drugstore owned by my late grandmother's family that has spanned several generations. If you can believe it, it's called Stoner Drug--- a name that never ceases to amuse my immature side.

Since much of what I do is in self-assured defiance of convention, I don't blame you for speculating about my motives and psychological state. But whatever insecurity formerly existed has been vanquished by an abiding desire to personally challenge assumptions about the permanence of some qualities, and more broadly, some limitations of science, which I suppose is mostly self-serving, and only faintly messianic. For the rest of my existence, I'll never fail to make calibrations when the explanatory power of beliefs change, and when new findings emerge. But, I refuse to allow it to become an obsession that deprives me of a separate life. So, it's a bit more healthy than the superficial appearance may suggest.

My experience with Amisulpride has been largely positive, and free of the dreadful side effects of antipsychotic use. But, I don't think its wise to use in the absence of a prolactin inhibitor that targets the D2 receptor: like cabergoline, or modafinil. In clinical practice, it's unfortunately underutilized in favor of less efficacious modalties, and particularly valuable for treating the melancholic, apathetic subset of depressives that are often refractory. It also is confirmed to be a promoter of the reelin glycoprotein, which is one of my pharmacological targets, but troublingly, strongly reduces the growth of neurotrophic factors provoked by other agents. But, these problems are unlikely to be significant, or even present at low, therapeutic doses, but it's something to be cognizant of, and to control for even if the incidence is unlikely.

The combination of Tianeptine and Agomelatine would certainly be effective for promoting neuroplasticity, protecting against impairing effects of stress if it's predominant, and improving pathologically important alterations in the circadian rhythm. But, if you're suffering from major depression, or a disorder with symptoms analogous to clinically recognized features of major depression, I'm not as sure, because individual responses vary, the amount of evidence remains limited, and both agents seem more indicated for anxious depressives, and valuable as adjuncts. I personally enjoyed Tianeptine, but its half-life makes maintenance a serious obstacle, and because I decided to return to SSRIs, for reasons that I illuminated in this thread, I'll probably discontinue use, and consider purchasing Valdoxan as a substitute for the melatonin that I use and deem critical for protecting against the effects of alcohol that I am loath to cease consuming. Valdoxan also has a half-life problem, and once it secures approval, I hope that improvements are subsequentially made when its market potential is proven. Since you've indicated that you suffer from an apathetic depression that may stem from chronic fatigue syndrome, then I would say amisulpride, with a MAO inhibitor like Azilect or Selegiline, Valdoxan, one of the more innocuous antidepressants, maybe a stimulant of some sort, and some sort of immune modulator that positively influences energy production. For the last constituent, I'm not ready to give any endorsements yet, but there are plenty of candidates worthy of consideration.

Edited by Rol82, 22 September 2010 - 08:36 PM.

[Rational Madman]

Animal perhaps your also interested in my own experience with amisulpiride.

It was the only pharmaceutical wich really adressed my anhedonia and motivational issues, it kept working for the 2 weeks i took it, however i stopped taking it due to the massive rise in prolactin it causes wich could cause trouble in the long run, i retried it a few times later but it never worked again.

I've been on it for 6 months at 50mgs/day and had no issue with hyperprolactinema, i.e. I don't have bitch tits. It's positive effects on prolactin only really occur at doses that begin to antagonise post-synaptic D2 and D3 receptors, which is anything over 100mgs/day.

The reason I was asking is because I stopped taking it 5 days ago and the dysthymia came back with a vengeance earlier on today. I took a 50mg tablet of Amisulpride, and within 3 hours I was back to my old self. It really works miracles for me.

How long did you trial it for the second time?

I always though prolactin was regulated by presynaptic dopamine receptors. I figured it may be a augmenting agent for folks with anxiety, but this study (pdf) showing hyperprolactinemia with low-dose amisulpiride put me off trying it.

Aripiprazole is the only drug that can produce these d2 antagonist-like benefits without raising prolactin levels IMO.

I personally disliked Abilify, even when taken at very low doses, since the effects were hardly apparent, and seemed to be vaguely cognitive dulling. When used at suggested doses for protection against the onset of psychotic episodes, it binds strongly to (if my memory serves me correctly) something like 90% of D2 receptors, but at doses less than 5mg, its binding affinity at higher doses isn't relevant. Further, its affinity for 5ht2a and 5ht1a maybe problematic for some subsets, and its value as an adjunct remains a bit uncertain. The latter target was likely contributing to my displeasure, and is something to guard against. If it's working, though, stick with it, but I'm wondering if something like Ziprasidone might yield a superior outcome---which looks exceedingly promising as an atypical upon initial examination. But, at some point, I may be tempted to move on from the D2 imbalance etiology.

Edited by Rol82, 22 September 2010 - 09:35 AM.

[Rational Madman]

Aripiprazole is the only drug that can produce these d2 antagonist-like benefits without raising prolactin levels IMO.

Another option is combine amisulpride and an agonist like pramipexole or ropinirole. From memory, there are hypotension issues there, so some folks have contemplated adding in bupropion or the like. I know, it all starts to sound like too much polypharmacy, but sometimes synergy actually happens (in theory at least).

My bigger reservation, as I have mentioned elsewhere, is with chronic administration of these anti-psychotics, even at low doses. I guess Animal's experience suggests that the rebound isn't too nasty, but I'd still like to be sure that I finished in better underlying shape than when I started.

The frequent administration of agents with a significant preference for D3 receptors could present susceptible patients with executive function difficulties, though, and it appears that cabergoline may be somewhat neutral in this regard. While less potent as prolactin inhibitors, the administration of either rasagiline or modafinil results in statistically meaningful reductions. So, there are plenty of options out there worth considering, especially since many Parkinson's drugs have a poor record outside of their original indication.

Edited by Rol82, 22 September 2010 - 05:29 PM.

[Rational Madman]

Are you planning to keep on taking mirtazepine?

What do you think of lisuride its a potent 5HT1A and 5HT1B agonist wich stimulate oxytocin release, its also a potent 5HT2A agonist, basicly has a very interesting pharmacological profile. Its also a D2 agonist wich could replace cabergoline, or do the benefits of cabergoline come independly from another mechanism?
http://www.imminst.o...st-in-lisuride/

Its also been shown to potentiate the antidepressant effect of other antidepressants in rodents.

I would say low dose SSRI+lisuride would be very interesting, downside of it is the price and the half life tough.

I'll be tapering off of Mirtazapine, and resuming my use of Luvox, beginning with a dose of 75 mg. As for Lisuride, it's certainly interesting, and worthy of further examination, and free of any obvious red flags that might deter users from trying. But, I thought you already tried it, and assumed that your enthusiasm had been dampened. Are you trying a different dose, or would this be your first time?

Edited by Rol82, 22 September 2010 - 10:30 AM.

[John Barleycorn]

Apologies for not quoting, but it's hard to keep up.

My understanding re 5HT-2A is that it comes down to tonic vs phasic DA release aspects, as Ex Dubio is so fond of repeating. Take an antagonist, and it may blunt the effects of an accompanying dopaminergic. A common scenario would be combining certain antidepressants with a more abusable substance. However, it doesn't necessarily follow that taking an agonist on its own will lead to anything useful (except possibly visions)! The situation is complicated by the fact that receptor adaptation happens fast, and so there is also a big difference between acute and chronic administration, and effects and aftereffects.

Re mu opioid receptors, there is an emerging view that the relative balance between mu and kappa is what is actually important. So in addition to asking how mu might be upregulated, it could also be asked how kappa might be downregulated. Both agonists and antagonists seem to do good things, but possibly on different timescales. Buprenorphine would appear to be an under-rated AD, partly because it is typically prescribed in much higher doses for opiate detox.

On a lighter note, and maybe this is just me, but I'm still ROTFL that someone could propose taking the concept of autoeroticism to new levels, without a trace of irony. Only on Imminst ...

Edited by John Barleycorn, 22 September 2010 - 10:08 AM.

[maxwatt]

Nicotine = dopamine agonist par excellence = parkinson's treatment.
and no doubt good for withdrawal, anhedonia.
Patch?

Edited by maxwatt, 22 September 2010 - 07:02 PM.
spellcheck

[KimberCT]

I'm not sure if you're already aware, but if not... donepezil is also a potent sigma-1 agonist.

I was also on sertraline, and while I liked it, I switched back to escitalopram because I wanted to use sigmaergics.  I tried fluvoxamine, but even as a CYP1A2 fast metabolizer, it killed my ability to process caffeine.

[medievil]

Are you planning to keep on taking mirtazepine?

What do you think of lisuride its a potent 5HT1A and 5HT1B agonist wich stimulate oxytocin release, its also a potent 5HT2A agonist, basicly has a very interesting pharmacological profile. Its also a D2 agonist wich could replace cabergoline, or do the benefits of cabergoline come independly from another mechanism?
http://www.imminst.o...st-in-lisuride/

Its also been shown to potentiate the antidepressant effect of other antidepressants in rodents.

I would say low dose SSRI+lisuride would be very interesting, downside of it is the price and the half life tough.

I'll be tapering off of Mirtazapine, and resuming my use of Luvox, beginning with a dose of 75 mg. As for Lisuride, it's certainly interesting, and worthy of further examination, and free of any obvious red flags that might deter users from trying. But, I thought you already tried it, and assumed that your enthusiasm had been dampened. Are you trying a different dose, or would this be your first time?

I havent tried lisuride yet but its definatly on my to try list, its pharmacological profile looks pretty much perfect, and i beleive that due to its 5HT2A agonism it can have major potential for anhedonia (its pharmacological profile is extremely simular to LSD wich also induces dopamine trough 5HT2A). Its also a demonstrated anxiolytic with a high intrinsic activity of the 5HT1A receptors, it just looks like the perfect antidepressant for me.

The reason i havent tried it yet is the price, and i think your mixing this one up with trivastal, wich i did try.

I'l have to rewrite my topic on this one, as the current one is a mess.

Edited by medievil, 22 September 2010 - 05:03 PM.

[Animal]

Nicotine = dopamine agonist par excellence = parkinson's treatment.
and no doubt good for withdrawal, anhedonia.
Patch?

I keep hearing such good things about Nicotine, I'm on Buproprion at the moment so it's effects are highly attenuated for me. I've tried the patch a few times at differing dosages, and it just makes me feel spaced out and oddly anxious. Anxiety is not something I'm accustomed to, since it just isn't part of my personality to be anxious about anything really. But the Nicotine seems to induce a general feeling of unease, without any real world basis, that makes me feel uncomfortable regardless of where I am or what I'm doing. It really puts me off from further experimentation. For the record I can take 200mg+ caffeine with 400mg+ Modafinil and have no anxiety at all. So it's odd that Nicotine, which isn't known for being an anxiogenic, would have this effect. Can anyone hypothesise an interaction with the Buproprion that may be responsible for this?

Rol82, thanks for such an in depth reply. It's ironic that you mention Modafinil as a potential prolactin inhibitor, as I consume it in high doses on a regular basis, and have for the majority of the time I have been using Amisulpride. Is it possible the Modafinil is responsible for my lack of bitch tits after over 6 months of Amisulpride use?

Rol I am very interested in your experience with Hydergine, since it is something I plan on taking in the near future; I know it is part of your current regime in a rather substantial dose.

Edited by maxwatt, 22 September 2010 - 07:03 PM.
spell check the quote of my post

[medievil]

Bupropion is a α3β4 nicotinic antagonist wich is i beleive is also a receptor nicotine acts on, this could completely alter the effects of nicotine.

[medievil]

J Pharmacol Exp Ther. 2000 Oct;295(1):321-7.
Bupropion is a nicotinic antagonist.
Slemmer JE, Martin BR, Damaj MI.

Department of Pharmacology and Toxicology, Medical College of Virginia of Virginia Commonwealth University, Richmond, Virginia, USA.
Abstract
Neuronal nicotinic receptors are ligand-gated ion channels of the central and peripheral central nervous system that regulate synaptic activity from both pre- and postsynaptic sites. The present study establishes the acute interaction of bupropion, an antidepressant agent that is also effective in nicotine dependence, with nicotine and nicotinic receptors using different in vivo and in vitro tests. Bupropion was found to block nicotine's antinociception (in two tests), motor effects, hypothermia, and convulsive effects with different potencies in the present investigation, suggesting that bupropion possesses some selectivity for neuronal nicotinic receptors underlying these various nicotinic effects. In addition, bupropion blocks nicotine activation of alpha(3)beta(2), alpha(4)beta(2), and alpha(7) neuronal acetylcholine nicotinic receptors (nAChRs) with some degree of selectivity. It was approximately 50 and 12 times more effective in blocking alpha(3)beta(2) and alpha(4)beta(2) than alpha(7.) This functional blockade was noncompetitive, because it was insurmountable by increasing concentration of ACh in the nAChRs subtypes tested. Furthermore, bupropion at high concentration failed to displace brain [(3)H]nicotine binding sites, a site largely composed of alpha(4)beta(2) subunit combination. Given the observation that bupropion inhibition of alpha(3)beta(2) and alpha(4)beta(2) receptors exhibits voltage-independence properties, bupropion may not be acting as an open channel blocker. These effects may explain in part bupropion's efficacy in nicotine dependence. Our present findings suggest that functional blockade of neuronal nAChRs are useful in nicotine dependence treatment.

[maxwatt]

...
I keep hearing such good things about Nicotine, ... For the record I can take 200mg+ caffeine with 400mg+ Modafinil and have no anxiety at all. ...

Modafinal* 200 mg, plus lots of caffeine from beverages, no anxiety. Nicotine in betel nuts is a light headed rush, I feel uncomfortable but up, not anxious.

*by prescription, of course.

[Rational Madman]

Nicotine = dopamine agonist par excellence = parkinson's treatment.
and no doubt good for withdrawal, anhedonia.
Patch?

For consistent and reliable activation of nAChRs, the patch is probably the best delivery mechanism. Especially relative to smoking, which delivers effects of a short duration. But, when I need to deliver an important speech, or if I want my romantic overtures to have some resonance, then I retreat to a dark corner to smoke a cigarillo with the other social outcasts---either Ashton or Macanudo, which are much more affordable than cigars of different gauge sizes, and much more tolerable. Combine this with some sceletium tortuousum, and a very small swig of scotch from a flask that I scandalously bring to work (but rarely use), and I'm ready to rock and roll.

Since I'm in the midst of preparing for the looming foreign service exam, and working off-site for a think tank that throws menial research and analysis tasks at me daily, I can certainly enjoy a few swigs during the day, and smoke my pipe like a libertine without fear of ostracization from my conservative employers. My immediate superior, and whom I can I most relate to, has been very cool about my habits, and has acted as a constant defender of my periodic acts of abrasiveness, and sometimes unforgiving peer review work---I made a few interns cry. He even allowed me to return to Iowa City to be closer with my girlfriend, who's in her last year at the Writers' Workshop, and required immediate attendance due to her discovery of my unfaithfulness. But, working at a think tank wouldn't be much of an existence---unless, you're at Brookings, CSIS, or CFR, which would still require the sort of sycophantry that I would have difficulty abiding, and a more impressive curriculum vitae.

Anyway, back to tobacco...
As Einstein could attest, pipe smoking seems better for creative endeavors. Swami Vivekananda, who was probably one of the few non-autistic savants that possessed a photographic memory, certainly concurred, and considered the substance to be especially critical for the encoding of memories, but he preferred the hookah as a delivery system. Well, in his opinion, his secrets were hookah delivered tobacco, an absurd amount of chili peppers, and celibacy---yikes. I've tried tobacco with a hookah, and I can confirm that it's immensely pleasurable. In fact, I have some Turkish friends in Turtle Bay that promised to shop around for some classy hookahs once they make their annual return to the home country to celebrate Republic Day with the dwindling number of Republican fanatics---a trip that invariably makes them exponentially more hysterical about the PKK, the ruling AKP, the progress of ascension negotiations, ostensible American designs for the region, and whatever conspiracy theories are being circulated within the body politic.

I have a biography of another famous tobacco advocate----Nikola Tesla---that I'm looking forward to consuming, and hope it will provide valuable insights abouts his personal life. Based on what I already know, Tesla was also a champion of whiskey drinking, which he considered integral to cognitive, and general health. This discovery didn't prompt me to become an avid whiskey drinker---since I've always enjoyed a combination of burgundy, cognac, and Islay scotch whiskey---but it did compel me examine the scientific evidence of its putative health promoting properties. Although there is a paucity of research---especially relative to red wine---there is convincing evidence that confirms the presence of significant antioxidant activity that appears to be a function of the length of maturation in oak barrels----which substantially increases the phenol content, the modification of phenols through malting, the sulphur reducing distillation in copper stills, the purifying and lignin metabolizing properties of charring oak casks (think activated charcoal), and the application of peat smoke into the kiln---therefore, the smokier, the better. If one uses single malt whiskey, the phenol content is considerably greater because of the phenol density of barley, and due to the critical role that ethanol plays in phenol absorption. Therefore, aged single malt whiskey should have a comparatively greater effect on plasma phenol levels than that of aged wine. But, that doesn't mean that we should cease drinking red wine, because its exceptional effects on blood lipid levels and platelet aggregation seem to be important correlates to its remarkable effect on health outcomes. But, in any case, it appears evident to me that there may be some validity to Tesla's claim, but the administration of aged whiskey alone is not sufficient to explain the profound effects that Tesla ascribed to use, since its effect on Gaba receptors (Gaba-A, in particular) seem to be most predominant feature, and the effects of its documented relationship with cognitive enhancement are probably not immediately felt. But, ethanol does have a significant impact on protein kinase activation, and causally increases the activity of nicotinic receptors. So, when combined with Tesla's copious nicotine consumption---which coincidentally, also activates protein kinase---there is a synergistic enhancement that may positively influence cognition. And, provide further illumination to the biographies of other famous users of this combination, such as Winston Churchill, James Joyce, Ernest Hemingway, George Bernard Shaw, Mark Twain, Dylan Thomas, Robert Burns, and more contemporarily, Christopher Hitchens.

But, there are other synergistic agents that need to be examined, and at this early stage, I think the best candidates would be the following:
-Low dose SSRI>opioid pathways>mesolimbic dopamine
-Modafinil>Gaba receptor blockade, and activation of D2 receptors, which are strongly correlated with creativity, and confirmed to be especially abundant and expressive in creative individuals.
-Coffee>powerful antioxidant, and demonstrated to attenuate alcohol induced performance impairment.
-Donepezil>To supplement acetylcholine receptor activation, and at the right dose, perhaps enhance this mechanism.
-Valdoxan>Would counteract alcohol's inhibition of melatonin synthesis.
-Inositol>Becomes reduced as a consequence of alcohol consumption.
-A cocktail of sodium chloride, potassium aspartate, zinc methionine, and inositol>To counteract dehydration and inositol depletion.
-Sceletium Tortuousum>In synergy with inositol, to maintain euphoria.
-Cabergoline>To counteract glutathione depletion.
-Methyl Donors>Would prevent the alcohol provoked reduction in adenosyl methionine levels.

I suppose we'll have to see if there is any merit to all of this.

Oh, and the scotch whiskey brands with the highest phenol content---as confirmed by assays---would be Ardbeg, Laphroaig, and Lagavulin. As previously noted, I'm a regular Laphroaig drinker, but I've heard wonderful things about Ardbeg, and am embarrassed by my failure to enjoy its widely noted brilliance. Indeed, the phenol content of the Ardbeg Supernova is quite extraordinary, and is on my wish list for the moment. But its high price will require significant shopping, and in all likelihood, their standard 10 year product will probably become the most frequently partaken. But, any of the aged Islay whiskies should serve the purposes of interested parties.

Edited by Rol82, 25 September 2010 - 08:05 AM.

[Rational Madman]

Apologies for not quoting, but it's hard to keep up.

My understanding re 5HT-2A is that it comes down to tonic vs phasic DA release aspects, as Ex Dubio is so fond of repeating. Take an antagonist, and it may blunt the effects of an accompanying dopaminergic. A common scenario would be combining certain antidepressants with a more abusable substance. However, it doesn't necessarily follow that taking an agonist on its own will lead to anything useful (except possibly visions)! The situation is complicated by the fact that receptor adaptation happens fast, and so there is also a big difference between acute and chronic administration, and effects and aftereffects.

Re mu opioid receptors, there is an emerging view that the relative balance between mu and kappa is what is actually important. So in addition to asking how mu might be upregulated, it could also be asked how kappa might be downregulated. Both agonists and antagonists seem to do good things, but possibly on different timescales. Buprenorphine would appear to be an under-rated AD, partly because it is typically prescribed in much higher doses for opiate detox.

On a lighter note, and maybe this is just me, but I'm still ROTFL that someone could propose taking the concept of autoeroticism to new levels, without a trace of irony. Only on Imminst ...

Well, firstly, Ex-Dubio would be a wonderful addition to the Imminst community, and if you don't find it awkward, please convey my sentiment as representative of the community as a whole---which I suppose is kind of pretentious, but whatever. Anyway, you're quite right, 5ht2a receptors exert a tonic inhibitory role on dopamine efflux in the prefrontal cortex, and inhibition should result in an increase of dopamine in the medial prefrontal cortex, an improved noise to signal ratio in this region if pathologically altered, and increased mRNA expression. That's great, improved executive functioning, less psychotic symptoms if present, and more neurotrophic factors, hooray. However, there is also a resulting reduction in cAMP dependent protein kinase activation, and a consequential reduction of calcium influx through NMDARs, which will unfortunately have an adverse impact on neuroplaticity and learning---associative learning in particular. So, in my opinion, its not worth it unless psychosis, or a profound disturbance in executive functioning is present. Even so, there are other targets, and better methodologies for improving functional outcomes---like catechol-O-methyl transferase inhibition, which can be achieved with repeated entacapone administration, or consuming an ungodly amount of green tea. Also, watch out for the oxytocin reduction induced by the blockade at this site, because you gotta love it at optimal levels.

As for the Buphrenorphine idea, very nice, and I'm surprised I overlooked it as a possibility in that regard. But, I think I'll try the more conventional SSRI path for now, which has multiple virtues that obsessive personalities have a tendency to overlook---largely because we accentuate the negative.

Finally, don't get me wrong, I found the paradoxical effects of Cialis to be immensely funny, and because of its therapeutic use, and alternative methods for achieving the same end goals, it will likely remain relegated as sexual enhancement drug, and the target of jokes. So, the absence of irony was probably due to me being laughed out on the subject. But, it is an anxiolytic, a useful adjunct to SSRIs, and an effective modulator of muscaranic receptor signaling. Even better, chronic administration may reduce amyloid beta plaque formation, and improve long term induction in Alzheimer's subjects. For a time, I was considering daily use, but I ultimately reconsidered. Rather, I'll likely reserve it for sordid sexual encounters, and forever feign SSRI induced erectile dysfunction.

Edited by Rol82, 24 September 2010 - 06:00 AM.

[Rational Madman]

I'm not sure if you're already aware, but if not... donepezil is also a potent sigma-1 agonist.

I was also on sertraline, and while I liked it, I switched back to escitalopram because I wanted to use sigmaergics. I tried fluvoxamine, but even as a CYP1A2 fast metabolizer, it killed my ability to process caffeine.

Yeah, I was aware of its affinity, which much to my delight, is an affinity shared by Lisdexamfetamine as well. But, thanks anyway, its good for the board to know, because I probably would've neglected to mention it unless I started a separate thread. Fortunately, I haven't had any problems with caffeinated beverages since I resumed use---I concluded that my previous disenchantment was unfounded. I like Fluvoxamine more because of its stronger influence on the serotonin transporter gene, which makes it more likely to reduce the onset of obsessive symptoms caused by dopaminergic drugs, and additionally, guard against disturbances to the HPA.

[medievil]

Anyway, you're quite right, 5ht2a receptors exert a tonic inhibitory role on dopamine efflux in the prefrontal cortex, and inhibition should result in an increase of dopamine in the medial prefrontal cortex,

That isnt correct, 5HT2A does not inhibit dopamine in the frontal cortext and antagonism does not increase dopamine in any brainregio either, will post my source later have to go sleep now.

[Rational Madman]

Anyway, you're quite right, 5ht2a receptors exert a tonic inhibitory role on dopamine efflux in the prefrontal cortex, and inhibition should result in an increase of dopamine in the medial prefrontal cortex,

That isnt correct, 5HT2A does not inhibit dopamine in the frontal cortext and antagonism does not increase dopamine in any brainregio either, will post my source later have to go sleep now.

Whatever its effects, the antagonism of 5ht2a provides symptomatic relief to dysexecutive disorders through its activation of the orbitofrontal cortex, which maybe hypoactive, and causally linked to the presentation of symptoms. Indeed, there is indisputable evidence that antagonizing this target improves functional outcomes for some dysexecutive disorders, but for reasons that I've outline before, it's not an ideal target, and for disorders with a hyperactive orbitofrontal cortex---like OCD---antagonism would be contraindicated. In my case, I have not completely ruled out 5ht2a involvement, and may return at some point to Mirtazapine, but given its serious drawbacks, I would like to try other strategies first.

Edited by Rol82, 25 September 2010 - 08:11 AM.

[chrono]

While I'm sure you're most interested in discussing the juicier items on your list, I wonder if you'd take a moment to relate your experience with atomoxetine? I'd be interested in any further elucidation of why you consider the mechanisms advantageous, but perhaps more in your subjective description of its effects. It's been much maligned on this forum, and the positive accounts on ADDForums are cursory, to say the least.

I finally got around to cracking open a sample bottle I've had for a few years, and have been very pleasantly surprised at the instant improvement in the social anxiety and motivational domains of my dopaminergic troubles. But I have a partially-irrational bias against medicines which change my subjective experience considerably, that I can't also take "breaks" from if I want (without weeks-long tapers both ways), so I'm trying to get some more informed opinions about what it might entail subjectively.

[Rational Madman]

While I'm sure you're most interested in discussing the juicier items on your list, I wonder if you'd take a moment to relate your experience with atomoxetine? I'd be interested in any further elucidation of why you consider the mechanisms advantageous, but perhaps more in your subjective description of its effects. It's been much maligned on this forum, and the positive accounts on ADDForums are cursory, to say the least.

I finally got around to cracking open a sample bottle I've had for a few years, and have been very pleasantly surprised at the instant improvement in the social anxiety and motivational domains of my dopaminergic troubles. But I have a partially-irrational bias against medicines which change my subjective experience considerably, that I can't also take "breaks" from if I want (without weeks-long tapers both ways), so I'm trying to get some more informed opinions about what it might entail subjectively.

I believe Atomoxetine has considerable potential for treating mental illnesses marked by fatigue, and is a useful adjunct to amphetamine salts in the treatment of the inattentive subsets of ADHD. With its activation of alpha 1 adrenoreceptor targets, it has been demonstrated to increase cortical volumes acetylcholine, and ameliorate the symptoms of frontal lobe disorders through an unclear mechanistic increase of catechoamines in the prefrontal cortex. Its effects on NMDA receptors, though, are of a yet to be determined therapeutic value, for reasons that I've elucidated in previous entries. But, when combined with an ample amount of psychostimulants, there should be less of an issue, and may create a useful synergy in preventing the onset of tolerance with the latter class of agents. Indeed, since many have used it as a monotherapy, that's probably the reason why it, and many classes of antidepressants, have been unfairly maligned. Luckily, it can also be cheaply attained----if your psychiatrist is not fond of the polypharmaceutical approach that I'm so evidently fond of----in addition to a serotonergic to help guard against catechloamine induced reduction in serotonin volume, or a disturbance of the HPA. Norephinephrine---Atomoxetine's target messenger for selective reuptake inhibition---it should be noted, is especially critical for long term induction and the retrieval of memories, and I believe, overlooked by clinicians in the treatment of memory disturbances. So, go forward, but again, I achieved the best outcome when Atomoxetine was combined with other agents---mainly the psychostimulants and antidepressants that formed the basis of my cocktail.

Edited by Rol82, 25 September 2010 - 11:54 PM.