17 replies to this topic

[birthdaysuit]

Abstract

 

http://www.ncbi.nlm....pubmed/23727882

 

 

Drugs that modulate serotonin (5-HT) synaptic concentrations impact neurogenesis and hippocampal (HPC)-dependent learning. The primary objective is to determine the extent to which psilocybin (PSOP) modulates neurogenesis and thereby affects acquisition and extinction of HPC-dependent trace fear conditioning. PSOP, the 5-HT2A agonist 25I-NBMeO and the 5-HT2A/C antagonist ketanserin were administered via an acute intraperitoneal injection to mice. Trace fear conditioning was measured as the amount of time spent immobile in the presence of the conditioned stimulus (CS, auditory tone), trace (silent interval) and post-trace interval over 10 trials. Extinction was determined by the number of trials required to resume mobility during CS, trace and post-trace when the shock was not delivered. Neurogenesis was determined by unbiased counts of cells in the dentate gyrus of the HPC birth-dated with BrdU co-expressing a neuronal marker. Mice treated with a range of doses of PSOP acquired a robust conditioned fear response. Mice injected with low doses of PSOP extinguished cued fear conditioning significantly more rapidly than high-dose PSOP or saline-treated mice. Injection of PSOP, 25I-NBMeO or ketanserin resulted in significant dose-dependent decreases in number of newborn neurons in hippocampus. At the low doses of PSOP that enhanced extinction, neurogenesis was not decreased, but rather tended toward an increase. Extinction of "fear conditioning" may be mediated by actions of the drugs at sites other than hippocampus such as the amygdala, which is known to mediate the perception of fear. Another caveat is that PSOP is not purely selective for 5-HT2A receptors. PSOP facilitates extinction of the classically conditioned fear response, and this, and similar agents, should be explored as potential treatments for post-traumatic stress disorder and related conditions.

 

 

 

• 1Lieber Institute for Brain Development, Baltimore, MD, USA.
•  
• "Memory, learning, and the ability to relearn that a once threatening stimuli is no longer a danger absolutely depends on the ability of the brain to alter its connections," Catlow told Real Clear Science. "We believe that neuroplasticity plays a critical role in psilocybin accelerating fear extinction."

http://www.ncbi.nlm....pubmed/14615876

 

"low doses of psilocybin were found to produce little to no differences in general well-being, emotional excitability, anxiety, depression, heart rate, or blood pressure, so the risk of adverse side effects seems minimal."

 

 

 

Edited by birthdaysuit, 13 February 2016 - 12:18 AM.

[Wingless]

It's really interesting that we're discovering all these positive cognitive/emotional effects from low-dose psychedelics. Some people even claim these meet the criteria of being a nootropic (in low doses of course)

Edited by Wingless, 13 February 2016 - 02:06 AM.

[normalizing]

the mice were INJECTED. those type of studies are always very encouraging!

[justabody]

I 'm desperate to experiment with psychedelics but using rc markets is too fucking sketchy. I was hedging my bets on microdosing 4-aco-DMT for depression but it must've been bunk because there was no effect.

I wish there were mushrooms growing outside on my lawn or something.

Edited by justabody, 13 February 2016 - 10:56 PM.

[Wingless]

I 'm desperate to experiment with psychedelics but using rc markets is too fucking sketchy. I was hedging my bets on microdosing 4-aco-DMT for depression but it must've been bunk because there was no effect.

I wish there were mushrooms growing outside on my lawn or something.

 

You can try growing them yourself, I don't think it's terribly hard.

[gamesguru]

You can try making LSD yourself, I don't think that's terribly hard.

 

In all seriousness, the negatives may outweigh the positives. Neurogenesis (+}, 5-HT/DA alterations/dysfunction (-)

there is a blank study entitled 'Alterations of serotonin and LSD receptor binding following repeated administration of LSD', aka loss of magic.  it's a real thing, people.

 

Substance abuse and depression

each drug abused followed the onset of depression, except for LSD, which coincided with the onset of depression.

 

Electrophysiological evidence for a dopaminergic action of LSD: Depression of unit activity in the substantia nigra of the rat

The inhibitory effects of LSD on dopamine-containing neurons are probably not attributable to the serotonergic properties of LSD, since 5-methoxy N,N dimethyltryptamine (25–100 μg/kg), which has central serotonergic properties similar to those of LSD, produced exclusively excitatory effects on the firing rate of dopaminergic cells.

 

Chronic LSD alters gene expression profiles in the mPFC

Chronic administration of lysergic acid diethylamide (LSD) every other day to rats results in a variety of abnormal behaviors. These build over the 90 day course of treatment and can persist at full strength for years after cessation of treatment.  The behaviors are consistent with those observed in animal models of schizophrenia and include hyperactivity, reduced sucrose-preference, and decreased social interaction ... RNA-sequencing on the medial prefrontal cortex (mPFC), an area highly associated with both the actions of LSD and the pathophysiology of schizophrenia and other psychiatric illnesses. We observed widespread changes in the neurogenetic state of treated animals four weeks after cessation of LSD treatment. QPCR was used to validate a subset of gene expression changes observed with RNA-Seq, and confirmed a significant correlation between the two methods. Functional clustering analysis indicates differentially expressed genes are enriched in pathways involving neurotransmission (Drd2, Gabrb1), synaptic plasticity (Nr2a, Krox20), energy metabolism (Atp5d, Ndufa1) and neuropeptide signaling (Npy, Bdnf), among others.

 

Dynamic_changes_in_prefrontal_cortex_gene_expression_following_lysergic_acid_diethylamide_administration

http://www.researchg..._administration

Hallucinogen persisting perception disorder and the serotonergic system
http://www.visualsno...rgic system.pdf

 

Serotonin and Lysergic Acid Diethylamide Binding in Rat Brain Membranes: Relationship to Postsynaptic Serotonin Receptors
http://molpharm.aspe.../12/3/373.short

Lysergic acid diethylamide administration selectively downregulates serotonin2 receptors
http://www.ncbi.nlm..../pubmed/1969270

[wanderlust]

this paper seems very exciting however it raises a few questions 

 

 

the first  problem with this is that pure psilocybin is  unstable and breaks down quite quickly. 

making it rather hard to work with 

a glance at the paper showed the following 

 

"Drugs 25I-NBMeO (4-iodo-2,5-dimethoxy-N-(2-methoxybenzyl) phenethylamine) was synthesized in the laboratory of Dr. David Nichols (Braden et al. 2006). PSOP was provided by Dr. Francisco Moreno from the University of Arizona. "

 

 

which leads me to state that his study is wrongly titled 

 

the correct title being 

Effects of 25I-NBMeO on hippocampal neurogenesis and extinction of trace fear conditioning.

 

 

i suspect that this is due to how dangerous  25I-NBMeO is 

with little human use it has so far claimed meany lives 

https://www.erowid.o...ome_death.shtml

 

mostly due to small mistakes relating to dosage and in-proper handling 

the level of care needed around this compound is extreme

 

as some one who takes massive stupid risks in the name of exploration and of fun 

 

i would advise against going anywhere near this stuff 

 if trained professionals with a lab wanted to check its purity then divide it into the correct dosage and seal it into something airtight  , then i would be keen to try it.

wonder where we would find some one to do that ? 

 

then there is the bomb shell 

 

now i am pretty terrible at maths (in fact i utterly failed at the subject (mainly as i got high on my lunch break) 

but i make optimum human dosage for extinction of fear based conditioning at around 350ug  with 50ug ether side

 

the problem is that it is at that dose you are "tripping" 

ie its effects as a hallucinogenic could felt . 

this removes any ability to function normally  or go about ones day. 

side effects 

positive 

 

• strong open and closed eye visuals, including trails, color shifts, brightening, etc.
• mood lift, euphoria
• mental and physical stimulation
• increase in associative & creative thinking
• increased awareness & appreciation of music
• life-changing spiritual experiences
• erotic, sexual thoughts and sensations
• feelings of love and empathy
• psychedelic ideation, grand insights, big ideas

NEUTRAL

• general change in consciousness
• pupil dilation
• difficulty focusing
• unusual body sensations (facial flushing, chills, goosebumps, body energy)
• change in perception of time, time dilation
• slight increase in heart rate
• yawning, especially when coming up
• does not suppress appetite at low doses
• visual strobing

NEGATIVE

• (likelihood of negative side effects increases with higher doses)
• 
  
• confusion, delirium
• looping, recursive, out of control thinking ('racing throughts')
• scrambled communication
• nausea
• insomnia
• paranoia, fear, and panic
• unwanted and overwhelming feelings
• unwanted life-changing spiritual experiences
• tachycardia, hypertension
• overheating, hyperthermia
• serotonin syndrome
• vasoconstriction, peripheral numbness, swelling of feet, hands, face
• shaking, clenching, dystonia, clonus, muscle spasms, seizure
• rhabdomyolysis (Gee et al.)

 

2C-I-NBOMe Dosages

Sublingual/Buccal

Threshold

50 - 250 ug (micrograms)

Light

200 - 600 ug

Common

500 - 800 ug

Strong

700 - 1500 ug

2C-I-NBOMe Dosages

Insufflated

Threshold

50 - 250 ug

Light

200 - 600 ug

Common

500 - 800 ug

Strong

700 - 1500 ug

 

 

  

i get that it all sounds like a lot of fun  but as a former psychonaught  , i would point out that there are meany mild hallucinogens with a long track record of human use  and very little risk of death or mental illness which also help people break out of fear based conditioning such as hawaiian baby woodrose or indeed magic mushrooms, this study simply states that tripping balls helps break out of conditioning something that is well known .

 

as for the 

"hippocampal neurogenesis"effects 

taking it for that purpose alone ,would mean risking death , mental illness and going on  6 to 15 hour hallucinogenic trip as a side effect 

even the most hardened old hippy will tell you that it is so mentally taxing  that it is best done no more then once every other month 

 

so i would rules this one out folks 

Attached Files

•  art%3A10.1007%2Fs00221-013-3579-0.pdf   731.31KB   0 downloads

Edited by wanderlust, 23 March 2016 - 04:06 PM.

[wanderlust]

there is a copy of "Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning"

for reference 

 

Attached Files

•  art%3A10.1007%2Fs00221-013-3579-0.pdf   731.31KB   7 downloads

Edited by wanderlust, 23 March 2016 - 04:25 PM.

[gamesguru]

the immediate effects of psilocybin are not as important for clinical benefit as the longer-term effects

psilocybin increases the expression of genes and signalling proteins associated with nerve growth and connectivity

Psychedelic drug cuts brain blood flow and connections

 

fwiw many impairments seen in psilocybin+thc polydrug groups arent seen in either monodrug group.

[William Sterog]

I 'm desperate to experiment with psychedelics but using rc markets is too fucking sketchy. I was hedging my bets on microdosing 4-aco-DMT for depression but it must've been bunk because there was no effect.
I wish there were mushrooms growing outside on my lawn or something.

What about Mucuna Pruriens?

www.ncbi.nlm.nih.gov/pubmed/5546268

NN-dimethyltryptamine and 5-MeO-dimethyltryptamine (bufotenin) in the seed.

Tryptamine compounds (hallucinogenic compounds) are at rather low dosages in the leaves and non-existent in the seeds; 0.006% Dimethyltryptamine, 0.0025% 5-MeO-Dimethyltryptamine, and 0.003% Dimethyltryptamine Oxide. 5-MeO-Dimethyltryptamine (Bufotenin) has been noted to be as high as 4.14ug/g in the root, but was not present in the pod.

http://web.idrc.ca/e...1-DO_TOPIC.html

http://redalyc.uaeme...93911288031.pdf

This plant cannot produce psychedellic effects: "the levels of the hallucinogens in Mucuna Pruriens are too low to feel" but may be a safe way of using DMT in nootropic doses?

Edited by William Sterog, 24 March 2016 - 02:20 PM.

[Adam Karlovsky]

@gamesguru 

 

You've misinterpreted those LSD studies.

 

The second study you posted is looking at the substantia nigra, which is mostly just involves planned motor control, but even if reward sections were being effected (which is not clear) you'd still need to show that this persisted long after the LSD had left the system. Acute altered reward could be a simple as change in reward from food (LSD makes food taste weird as), which does not persist after it's left one's system.

 

The third study  is using rediculously high doses (a HED of 11 mg) of LSD every other day for a long time That's not really applicable to human use. Further, behaviours such as hyperactivity, reduced sucrose-preference, and decreased social interaction could simply be from the environmental conditions... I'm pretty sure I'd turn into a lunatic and have a bad time if I was high on LSD in a tiny white room, with nothing but cardboard or slop to eat, nowhere to go, nothing novel to play with, etc. 
 

[gamesguru]

That dose is not so ridiculous, and continued abuse may very well dysrupt reward circuits (and other core features of cognition/personality) for some decades.  11mg mouse converted to human dose is a mere 0.9mg every other day for 3 months.  surely every curious chump with nothing but a pair of sticks to rub together would fall into such a pattern of use?

 

and you're also mistaking cause for effect, the decreased social interaction comes from the LSD and a cluster of induced schizotypal symptoms.. not the other way around!  the mice have a basal level of social interaction.  they are well-accustomed to cardboard slop and spiked water.  they deal with it in the same way feynman dealt with his bad trip in the aquatic sensory deprivation tank, by thinking happy thoughts.  The point of the matter is that this stuff really gets dangerous, and is best when not taken every other fucking day for three months.  The mice don't have problems til like the 45 day mark.  Are you speaking from personal experience, to suggest you've done this no problem?

Edited by gamesguru, 29 January 2017 - 06:07 AM.

[psychejunkie]

those LSD induced schizotypal symptoms would go away after 2-3 days, nothing very serious. But some experience continues effects and some even fall into schizotypal disorders.

which I actually think, those are the people with genetic background of such disorders in first place.

anyway, the probability of such serious side-effects are pretty low! as I know several guys/gals who took moderate amount (100-220ug) of LSD with genetic background of schizophrenia, and nothing serious happened to them.

Actually, I believe, due to my own experience and several research articles and news in media right now, that LSD does everything that's identical to an enhanced Cognition and Cognitive Abilities!

 

But there is something important to note, that few people seems to notice.

if you want nootropic effects from LSD, or Long-Term ones, the Set and Settings is pretty much important.

people only notice "Set and Settings" for avoiding bad trips, but the fact is, Set and Settings is all important, and not only with drugs like LSD. even Mary Jane would make you smarter if you smoke it in rich environment, like watching a Science Documentary or Philosophic Discussion and trying to think about the cosmos or nature's magic. So does LSD, both in greater effect and longer lasting, regarding to nootropic outcome.

[Adam Karlovsky]

First, the mice were actually rats and were given 0.16 mg/kg which is 11 mg Human Equivalent Dose (HED).

Even if they were mice and given an HED of .9mg every other day, that's 900 mcg, which is 4-7x the standard recreational dose (125-225 mcg). Recreational doses are only taken once a week tops, and the most hardcore psychonauts can't keep that up for long.

You seem to be on the backfoot and are misinterpreting what I meant to convey. I am not saying any of this is ok no problem - I am saying the data is practically irrelevant. Yes if someone took 11 mg every other day I'd imagine they'd quickly become psychotic. The everyday raver, pyschonaut or transhumanist has nothing of this magnitude to worry about taking 200 mcg every other week... and people microdosing 12 mcg every other day have even less to worry about.

You are making a lot of assumptions about the inner mental experience of mice (thinking happy thoughts!). You are also wrong about accustomization to bad environments, if you go to scientific conferences you'll find a lot of researchers complaining about the state of animal models for disease states and behavioural studies. Their main complaints are that too many studies are on mice and rats, and secondarily that the environments they're put in are not reflective of real-world environments (which is problematic because there is plenty of evidence that certain diseases and behaviours occur at greater rates in certain environments). Disease and behaviour is heavily context dependent, just look at the state of psychology and sociology research, and the difficulty real scientists have interpreting and generalising said research and accurately predicting every day humans.

[gamesguru]

I disagree that even 200mcg a week is safe, and some people are easily doing double that.  Especially if coupled with sustained cannabis use and less than ideal genetics, symptoms induced at this dose will take a lot longer to go away than just 2-3 days.  Even if you kickstart recovery with serotonin antagonists, dopamine modulators, exercise, etc, I wouldn't expect anything less than an 8 week recovery.  As the tolerance sets in, the magic disappears, and problems start to crop up.  This all takes time to reverse, more time than it took to initiate.

 

And how does that make it uncontrolled?  The mice who did not receive LSD exhibited a basal level of social interaction and were subjected to the same mundane environment as the dosed group.  Therefore, it is a well-controlled experiment.  And the lab setting may do well to simulate the monotony of civilized life and the burden of modern stressors?  Everybody just wave your hands and think happy thoughts

[Infinyte]

Seriously guys, 

Adam Karlovsky's point is completely valid.  The relative dosage strengths are so far from any reasonable human equivalent dosage levels that the results are more or less irrelevant.  Do we remember the basic laws of logic?  If the study is based on parameters that have no valid(or even CLOSE to valid) human equivalent values then any conclusions drawn can not reasonably be assumed to have some kind of human equivalence. Newton's Laser Sword?!?!?  It seems like many of these studies seem to follow this problem by using similarly unremarkable quantities either overly large or overly small sample H.E.D. values.  Is this happening on purpose because of restrictions placed on researchers and/or funding sources perhaps?  Another possible reason could be that studies like this one are trying to "Force" particular results mistakenly assuming that they will get more clear results from extremely high or low relative doses.   Any thoughts guys?  

[Ruth]

https://www.scienced...80926082159.htm Reclassification recommendations for drug in 'magic mushrooms'

https://pubs.acs.org...emneuro.8b00134 Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression
Depression and anxiety disorders are debilitating diseases resulting in substantial economic costs to society. Traditional antidepressants often take weeks to months to positively affect mood and are ineffective for about 30% of the population. Alternatives, such as ketamine, a dissociative anesthetic capable of producing hallucinations, and the psychoactive tisane ayahuasca, have shown great promise due to their fast-acting nature and effectiveness in treatment-resistant populations. Here, we investigate the effects of N,N-dimethyltryptamine (DMT), the principle hallucinogenic component of ayahuasca, in rodent behavioral assays relevant to anxiety and depression using adult, male, Sprague–Dawley rats. We find that while DMT elicits initial anxiogenic responses in several of these paradigms, its long-lasting effects tend to reduce anxiety by facilitating the extinction of cued fear memory. Furthermore, DMT reduces immobility in the forced swim test, which is a characteristic behavioral response induced by many antidepressants. Our results demonstrate that DMT produces antidepressant and anxiolytic behavioral effects in rodents, warranting further investigation of ayahuasca and classical psychedelics as treatments for depression and post-traumatic stress disorder.

[Ruth]

https://www.scienced...80926082159.htm Reclassification recommendations for drug in 'magic mushrooms'

https://pubs.acs.org...emneuro.8b00134 Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression
Depression and anxiety disorders are debilitating diseases resulting in substantial economic costs to society. Traditional antidepressants often take weeks to months to positively affect mood and are ineffective for about 30% of the population. Alternatives, such as ketamine, a dissociative anesthetic capable of producing hallucinations, and the psychoactive tisane ayahuasca, have shown great promise due to their fast-acting nature and effectiveness in treatment-resistant populations. Here, we investigate the effects of N,N-dimethyltryptamine (DMT), the principle hallucinogenic component of ayahuasca, in rodent behavioral assays relevant to anxiety and depression using adult, male, Sprague–Dawley rats. We find that while DMT elicits initial anxiogenic responses in several of these paradigms, its long-lasting effects tend to reduce anxiety by facilitating the extinction of cued fear memory. Furthermore, DMT reduces immobility in the forced swim test, which is a characteristic behavioral response induced by many antidepressants. Our results demonstrate that DMT produces antidepressant and anxiolytic behavioral effects in rodents, warranting further investigation of ayahuasca and classical psychedelics as treatments for depression and post-traumatic stress disorder.

https://link.springe...1007/BF00712985
Effects of age and of chronic antidepressant treatment on [3H]tryptamine and [3H]dihydroalprenolol binding to rat cortical membranes
1.

The effects of age and of chronic antidepressant treatment on [3H]tryptamine and [3H]dihydroalprenolol binding site density were measured in brain cortical membranes from male Sprague-Dawley rats.



2.

The density but not the affinity of [3H]tryptamine binding sites was increased in 18-month-old rats relative to 3-month-old rats. Neither the density nor the affinity of [3H]dihydroalprenolol binding sites was affected by age.



3.

Chronic administration (28 days s.c. via Alzet osmotic minipumps) of tricyclic antidepressant drugs (daily doses: imipramine·HCl, 30 mg kg−1; desipramine·HCl, 10 mg kg−1; clomipramine·HCl, 10 mg kg−1) resulted in decreases in [3H]dihydroalprenolol binding site density but no changes in [3H]tryptamine binding site density; no changes in affinity of either site were observed.



4.

Chronic administration (s.c. via Alzet osmotic minipumps) of monoamine oxidase inhibitor antidepressant drugs (daily doses: tranylcypromine·HCl, 0.5 and 1.0 mg kg−1; phenelzine sulfate, 5 and 10 mg kg−1, each for 28 days; clorgyline·HCl, 1.0 mg kg−1; (−)-deprenyl·HCl, 1.0 mg kg−1, each for 14 days) resulted in decreases in [3H]tryptamine binding site density, without any effects on the affinity of this site. In addition, each of these monoamine oxidase inhibitors except (−)-deprenyl resulted in a decrease in [3H]dihydroalprenolol binding site density. No affinity changes were observed.



5.

These data indicate that the [3H]tryptamine binding site exhibits physiological changes with aging and is differentially sensitive to the actions of tricyclic antidepressants and monoamine oxidase inhibitor antidepressants, respectively.