Chill pills: why there are no Serotonin 5HT1A selective agonists RCs?

[DotChem]

I wonder why there no RCs that are selective 5HT1A agonist. Judging from the effect of 5ht1a activation, that's as close to the holy grail as it gets.. here is exert from the wiki entry:

5-HT_1A receptor activation has been shown to increase dopamine release in the medial prefrontal cortex, striatum, and hippocampus, and may be useful for improving the symptoms of schizophrenia and Parkinson's diseas ...
Other effects of 5-HT_1A activation that have been observed in scientific research include

• Decreased aggression^[47][48]
• Increased sociability^[30]
• Decreased impulsivity^[49]
• Inhibition of drug-seeking behavior^[50][51][52]
• Facilitation of sex drive and arousal^[53][54]
• Inhibition of penile erection^[55][56]
• Diminished food intake^[57]
• Prolongation of REM sleep latency^[58][59]
• Reversal of opioid-induced respiratory depression^[60]

Am I missing something? that's as good as it get. It combines all the "good" of stims + opiods without the "bad". I mean except "inhibition of penile erection" !.. There are literally dozens of all kinds of compounds in literature that are selective 5HT1A agonists.

5HT1A are classified as "Serenics" or antiagressive like MDMA .. wiki entry

A serenic, or antiaggressive agent, is a type of drug which reduces the capacity for irritability and aggression Examples

The recreational drug MDMA ("ecstasy") and a variety of related drugs have been described as empathogen-entactogens, or simply as entactogens.^[2] These agents possess serenic and empathy-increasing properties in addition to their euphoriant effects, and have been associated with increased sociability, friendliness, and feelings of closeness to others as well as emotional empathy and prosocial behavior.^[3][4] The entactogenic effects of these drugs are thought to be related to their ability to temporarily increase the levels of certain brain chemicals, including serotonin,^[5] dopamine, and, particularly, oxytocin.^[3][6][7] Certain other serotonergic drugs, such as 5-HT_1A receptor agonists, also increase oxytocin levels and may possess serenic properties as well.^[8] The phenylpiperazine mixed 5-HT_1A and 5-HT_1B receptor agonists eltoprazine, fluprazine, and batoprazine have been described based on animal research as serenics.^[9]

sorry for the long quote

 

[Cotcha Yankinov]

There are apparently many 5-HT1A full agonists but they supposedly have pretty bad GI tract side effects, and I believe lightheadedness? Partial agonists (see buspar) don't seem to have recreational value.

 

[Scrofula]

I wrote a big bullshit post on how maybe autoreceptors knock out any high, or the effects are only with chronic use, 1A isn't the whole story, precursors must be expensive . . .

Then I saw Osemozotan, a selective 1A agonist, that does pretty much what you say. AND it can help treat addiction too. Now take a look at the structure and tell me that doesn't look like it'd be familiar to an RC lab.

So, good question.

 

[DotChem]

There are apparently many 5-HT1A full agonists but they supposedly have pretty bad GI tract side effects, and I believe lightheadedness? Partial agonists (see buspar) don't seem to have recreational value.

I was not aware of the GI tract effects but the lightheadedness imo is probably due to 1B activation! yes? since tryptans used to treat migraines headaches are 1B agonist and it is pretty hard to separate 1A from 1B activity is it possible the lighheadeness has to do with 1B? There are some 1A (partial) agonist with pretty decent selectivity v 1B though. I am thinking along the line of miriads phenypiperazines like Buspar or fluprazine or mepiprazole..etc (nb: one problem with Buspar is priapism tho? I am not sure if that is related to 1A agonism specifically or to this particular drug?) + its VERY poor bioavailability (only 4% p.o!! which means most people would just s..t the dose

..Now take a look at the structure and tell me that doesn't look like it'd be familiar to an RC lab.
So, good question.

It should! I see pretty dirt cheap sesame oil precursors (no synthesis discussion allowed here but obviously it looks pretty straightforward to make from dirt cheap starting materials!)..I guess RC labs haven't catch up yet that could potentially very profitable. (Osemozotan half-life of 1.5-2h pretty short tho, yes? may be compounds like the standard 5HT1a full agonist 8-OH-DPAT

 

[adder]

If soon apart from recreational drugs RC vendors start including alternatives to available meds like antidepressants, anxiolytics, then maybe antibiotics because why not stock up just in case, this is clearly heading into the wrong direction. Well, the whole idea of introducing recreational drugs that have unknown side effects and long-term effects is wrong even though at a first glance cheap and legal MDMA alternatives seemed like a great idea. Take ketamine as an example, a drug that at the time when it was introduced on the black market as a recreational drug had been in use in medicine for a few decades, yet it was unknown that with regular use at higher doses it could produce serious problems with urinary tract.

 

[yessa]

I wonder why there no RCs that are selective 5HT1A agonist.

Although not selective for only 5HT1A, but AFAIK 5-MeO-DMT is mainly active at 5HT1A with a pretty good agonism (~1.7nM)

BTW: 4-F-5-MeO-DMT had an activity of 0.23nM at 5HT1A
And further replacement of the N,N-dimethyl substituents with a pyrrolidyl moiety, gave an exceptionally strong 5HT1A affinity.
(from the paper "Structure–activity relationships of serotonin 5-HT2A agonists", by David E. Nichols)

 

[bindingaffinity]

In animal tests the discriminative stimulus effects of 5-MeO-DMT are mostly mediated by 5HT1A, and some selective 5HT1A agonists without substantial 5HT2 activity substitute for 5-MeO-DMT. (I don't have the references for this available ATM but I'll try to dig them up.)

 

[Scrofula]

Maybe they're still waiting to find the right 5-HT1A subtype? I guess buspirone started a whole new subfield with its "biased agonism," and now research is about selective-
selective agonists: which brain region do you want to target?

This nature paper tested two of these and showed differential activation and effect in rats, also compared to 8-OH-DAPT:

F15599 has a strong preferential activity on cortical 5-HT1A receptors . . . translates to behavioural manifestations, e.g. an attenuation of PCP-produced deficits of memory/cognition at the same dose we used herein . . . are in accordance with this “procognitive” profile.

[. . . ]

In contrast, F13714 . . . preferentially activates somatodendritic 5-HT1A receptors and impairs cognitive performance in rat at low doses. . . impact on memory may be related to the activation of a hippocampo-striatal neuronal network . . .may also provide a basis for this agonist’s potent anti-dyskinetic effects, recently reported in a rat model of Parkinson’s disease.​

Pro- or anti-cognitive effects from the same receptor, depending on which suptype of subtype you look at. But you all here probably knew that, I didn't know there were any successes.

Why wouldn't exploring this further find one with recreational home research value?

 

[DotChem]

If soon apart from recreational drugs RC vendors start including alternatives to available meds like antidepressants, anxiolytics, then maybe antibiotics because why not stock up just in case, this is clearly heading into the wrong direction. Well, the whole idea of introducing recreational drugs that have unknown side effects and long-term effects is wrong even though at a first glance cheap and legal MDMA alternatives seemed like a great idea. Take ketamine as an example, a drug that at the time when it was introduced on the black market as a recreational drug had been in use in medicine for a few decades, yet it was unknown that with regular use at higher doses it could produce serious problems with urinary tract.

The prototypical 5HT1A agonist Buspirone has been used (is used) in clinics as long as if not longer than ketamine. At least since the 1950s. As I mentioned, it is anxlyotic antidepressant and serenic. I don't see a problem if someone looking to use (safely) an anxiolytic serenic to just chill and unwind (unlike alcohol, it won't get you addicted or drunk, drowsy or violent ..etc it has no GABAergic afaik!! way safer than a glass of vodka imho. One of the biggest problem with Buspar is priapism in males aged 20-40 (priapism is having an erection that can last for hours or days absent any sexual arousal.. medically dangerous and socially uncomfortable going around with a hard-on!) but there are lots of 5HT1a agonists with better profile that Buspar like phenylpiperazines class: "tons" of them have been studied thoroughly certainly more than most RCs. + Unlike MDMA, afaik they're not neurotoxic even thou they have similar effect. An example is this one Rx used in Spain as anxiolytic (cf mepiprazole). I see nothing wrong investigating similar piperazines as alternatives to MDMA..or alcohol!

And further replacement of the N,N-dimethyl substituents with a pyrrolidyl moiety, gave an exceptionally strong 5HT1A affinity.
(from the paper "Structure–activity relationships of serotonin 5-HT2A agonists", by David E. Nichols)

Yes. There are incredibly potent 5HT1a agonists described in the literature. As you said, one of the biggest problem with tryptamines is selectivity for a 5HT subtypes. Most of them have rather narrow index: They have pretty "dirty" pharmacology acting on a bunch of 5HT receptors. Especially, it is harder to separate 1A from 1B, AD and 1E and sometimes 2a/b and 5HT6 as well!. The highly potent 5HT1a agonist pyrrolidinyl analog of 5-MeO-DMT was described in TihKal as pretty weird depending on dose especially tinnutis (uncomfortable ear ringing) at high doses (3mg) probably due to 1D 1E activation in addition to 1A.. but who knows?

 

[Cotcha Yankinov]

A post-synaptic selective 5-HT1A agonist could be a very helpful antidepressant drug...

 

[DotChem]

Maybe they're still waiting to find the right 5-HT1A subtype?..... But you all here probably knew that, I didn't know there were any successes.
Why wouldn't exploring this further find one with recreational home research value?

Not yet afaik but yeah functionally selective agonists ie agonists that selectively activates a particular intracellular downstream signaling is a whole new ball game as far as neurochemicals are concerned. I am not sure though if selectively activating a particular downstream signal could translate into selectively activating certain brain regions. I would think it has more to do with pharmacokinetic of the drug ie differential distribution of the drug in the brain. Which is pretty hard to predict/design a priori. It is easier to make brain penetrant drugs but a different story to get them to specific brain areas once there. Educate me on that: am a chemist and tend to see molecules in isolation!

But if there is any indication of the potential of this approach tho, it seems to work with mu opioid agonists for making safer non addicting painkillers with no respiratory depression, constipation, tolerance or tolerance. (these people screened 3 millions+ compounds and came up with interesting molecules https://www.nature.com/nature/journal/v537/n7619/full/nature19112.html
Like with functionally selective 5HT1a agonists in the paper you mentioned though, the data is kind of confusing at least with opioids: some claims balanced mu opioid agonists (recruiting G protein + beta arrestin2) are nonaddicting opioids analgesics, some claim G protein but not beta arrestin .. In any case, one thing is for sure: selectively activation one or the other signaling lead to distinct pharmacological outcomes.

As for the Nature paper, I would be cautious interpreting the data: most structural class of 5Ht1a ligands are also dopamine D4-subtype receptor ligands (to some extent!.) This is only recently discovered (by Nichols among others). I would look at a range of receptors before drawing conclusion. For example, the anti-dyskenisic/Parkinson's effect in rats may be simply due to agonism at D4!! WAY-100-635 (and its major metabolite WAY-100-435) was thought as prototypical HT1A antagonist until recently when it was found it is also a D4 agonist! thus its dose-depending effect in animals .. (Check out the molecular structures of the Paper and that of WAY-100-635: they look incredebly close to me!! .. I would test those compounds in D4 assay if I was the authors!! ..but who knows?

A post-synaptic selective 5-HT1A agonist could be a very helpful antidepressant drug...

I thought it was 5HT1A autoreceptors activation that is responsible for the observed AD affect of 1a agonists? It wont be trivial though getting a drug to selectively activate post-synaptic receptors but not autoreceptors since they pretty much the same as far as the drug molecule is concerned. Once in the synapse, it would bind "equally" to both!! But what difference would it make though?? in terms of AD effect

 

[Scrofula]

Mr. Chem--not affiliated in any way, btw, i was just curious, the drug F15559 cited above appears to be what they claim, a highly selective biased agonist for HT1A post-synatptic receptors in the cortex, and avoiding autoreceptors.

Although, finally dragging up one table from an early paper, I only see data for 1A,B 2A,C, D1,2 and alpha1,2. Not computing pKi well, I can't readily say how selective they are (3 point spread, 1000 fold diff?) AND YET, they cite a paper describing exactly what you have, D4 activation, on a drug from their own lab, so they are aware of that issue, and yet no mention. Suspicious.

F15559 is apparently going clinical, but for Rett Syndrome. That's a much smaller market, I imagine, than for anti-depressants or anxiolytics, so I wonder if there are still unpleasant side effects, or just not clinical effectiveness. Or maybe its very pro-cognitive, but makes your penis explode, who knows.

Doesn't look like anyone picked up the "anti-cognitive" F13714 yet, but depending on what you're after, that might still be the more "recreational" one. It apparently calms the shit out of aggressive rats, compared to the first.

(And the bastards at Nature like to tease and only drop open access like crumbs)

 

[Scrofula]

I thought it was 5HT1A autoreceptors activation that is responsible for the observed AD affect of 1a agonists? It wont be trivial though getting a drug to selectively activate post-synaptic receptors but not autoreceptors since they pretty much the same as far as the drug molecule is concerned. Once in the synapse, it would bind "equally" to both!! But what difference would it make though?? in terms of AD effect

My understanding of this is shallow, but I believe we're talking about two different brain regions, autoreceptors in the raphe, which originates serotonergic neurons, and heteroreceptors elsewhere, like the cortex. Those two receptor populations are apparently different enough for drug targeting.

Activation of autoreceptors in the raphe turns the dial down across the whole brain, rather than just local presynaptic effects. I think.

Thus avoiding that or antagonising that, while activating post-synaptic receptors, would seem like a big boost to antidepressants; although that seems to counter the desensitization theory.

 

[adder]

The prototypical 5HT1A agonist Buspirone has been used (is used) in clinics as long as if not longer than ketamine. At least since the 1950s.

IMO that means nothing, buspirone is structurally unrelated to compounds discussed in this thread like 8-HO-DPAT or osemozotan. The problem with these potential anxiolytics/antidepressants is not their 5-HT1A agonism itself but any side effects that may be unknown at the moment - this is the danger associated with introducing drugs for human consumption without thorough testing. The case of ketamine is an example that even a drug that has been in use for many years may have unknown side effects if used in a different manner than tested. The situation with recreational RC's is paradoxical in the sense that people pay for untested or poorly tested compounds that statistically apart from desired effects may have many different side effects, some potentially irreversible, while in clinical trials healthy people get paid to take part in them due to the possibility of such side effects. We accepted the widespread use of certain RC's, such as certain cathinones or arylcyclohexylamines, in a similar manner to the use of long-known drugs such as MDMA, amphetamine, opioids etc. on the basis that they are structurally and pharmacologically similar to existing compounds that have been in use for a long time and have well established pharmacological and toxicological profiles, but even in the case of these compounds the margin for error is there. The apparent difference in both desired and undesired effects among compounds that differ in structure only slightly should make us wary of that, e.g. mephedrone & methylone vs. MDPV, a-PVP etc. or amphetamine vs. para-halogenated amphetamines (with the exception of para-fluorinated ones).

 

[Scrofula]

Someone explained to me that at least a small number of RC researchers actually ingest the materials, to get "high", usually in a dubious belief that the chemical's explicitly unscheduled status will protect them from prosecution. One way to get around the problem of flooding a market with potentially lethal experimental drugs is to stop prosecuting people for the tested ones, or at least prosecute less.

What percentage of RC enthusiasts actually put a sample of their purchase through some GCMS anyway? It's more likely you'll be sent rat poison than a drug-homolog that fries brain cells, if customs doesn't seize it first. It's a huge risk all around. That's apparently why you wait for the club kids to do it for a decade before trying something new.

 

[DotChem]

F15559 is apparently going clinical, but for Rett Syndrome. That's a much smaller market, I imagine, than for anti-depressants or anxiolytics, so I wonder if there are still unpleasant side effects, or just not clinical effectiveness. Or maybe its very pro-cognitive, but makes your penis explode, who knows...

It is probably a business decision: targeting Rett Syndrome would allow the company to claim orphan designation (google it) for the drug. This will allow the company to bypass "almost" all clinical tests and go straight to market with market exclusivity (big short cut). Since (at least in US) they can charge whatever they want (say $500,000/treatment ! or maybe $8000/pill) that could be VERY profitable: certainly more than peddling crack!!!! It could also be the molecule got problems (either not working for AD/anxiety indication or it has pretty nasty side-effects)..but who knows?

 

[DotChem]

IMO that means nothing, buspirone is structurally unrelated to compounds discussed in this thread like 8-HO-DPAT or osemozotan. The problem with these potential anxiolytics/antidepressants is not their 5-HT1A agonism itself but any side effects that may be unknown at the moment - this is the danger associated with introducing drugs for human consumption without thorough testing. The case of ketamine is an example that even a drug that has been in use for many years may have unknown side effects if used in a different manner than tested. The situation with recreational RC's is paradoxical in the sense that people pay for untested or poorly tested compounds that statistically apart from desired effects may have many different side effects, some potentially irreversible, while in clinical trials healthy people get paid to take part in them due to the possibility of such side effects. We accepted the widespread use of certain RC's, such as certain cathinones or arylcyclohexylamines, in a similar manner to the use of long-known drugs such as MDMA, amphetamine, opioids etc. on the basis that they are structurally and pharmacologically similar to existing compounds that have been in use for a long time and have well established pharmacological and toxicological profiles, but even in the case of these compounds the margin for error is there. The apparent difference in both desired and undesired effects among compounds that differ in structure only slightly should make us wary of that, e.g. mephedrone & methylone vs. MDPV, a-PVP etc. or amphetamine vs. para-halogenated amphetamines (with the exception of para-fluorinated ones).

Guess I misunderstood the point you made. I thought the issue you’ve raised was about 5HT1A agonism per se. That’s why I mentioned Buspar since it is a 5HT1A agonist and has been used in humans for quite some time. Which means pretty much “every” imaginable aspect including side-effects of the drug has been documented IF USED AS INTENDED (a pubmed search of the drug come up with close to 6000 citations!). If there were major problems we’ll probably know by now. That’s why I said I see no problem regarding possible issues related to the use 5HT1A agonism for recreational purpose. But of course, like ketamine (AND anything else in the universe) excessive abusive use would certainly lead to problems!! but the interesting thing with 5HT1A tho is that as I mentioned 5HT1A agonism in itself would actually prevent abuse (cf the OP: Inhibition of drug-seeking behavior^[50][51][52]


Now as to side-effects for the unintended use of drugs, or RCs for that matter (I mean the use outside indications they were approved/tested for) I think it is unfair to ask more of RCs just because they are used for (mostly)recreational purpose. The most widely recreational drug is alcohol! It probably kills as much as as the average RC stim (I dont have stat.. but most liver cirrhosis deaths are attributable to alcohol+straight alcohol poisoning deaths). Now, that doesn't deter people drinking. But if someone chose to use, we can make them safer (the science is there, I mean for most RCs, just have to look) which bring back my point: Most of the effects (AD, anxiolytic,serenic,empathy..etc) of most antidepressants, anxiolytics, empathogens..etc can be accounted for by 5HT1a agonism (not all .. most! put aside sigma activation for a while!). So if one is looking say for an anxiolytic without having to worry stim arousal, alcohol drowsiness, cognition pb with arylcyclohexylamines..etc just a pill to chill and relax, then 5HT1 agonists are pretty much his best bet. I am not talking about a specific agonist: 8-OH-DPAT or osemozotan were mentioned since they are pretty selective. But they are others with a better overall profile AND better safety profile that those(certainly way safer than most stims..

True, structurally different drugs may have same (similar) target activity profile (ie like they're all 5HT1A full agonists) but different off-targets profile therefore different side-effect profile...more on that later

 

[Limpet_Chicken]

I know it was a joke, but I think if the only side effect of a drug for Rett syndrome was that it makes people's penises explode, those on the Rett's end of the autistic spectrum would enjoy as close to complete safety. People with Rett syndrome do not HAVE penii.

Its X-linked. And one copy of the functional MECP2 protein at least is crucial to survival, males, having only the one X-chromosome do not survive birth, or if they do then for a maximum of hours to at most a few days.

I had the biology pretty well explained to me by a girl who has Rett's herself, a friend of mine. (god, that girl is a real breath of fresh air, she really is. Smart, beautiful, a physique to die for and the FUNNIEST snark-mouth I've ever born witness to. God damn, she is as funny as she is fucking hot)

And she would be PISSED off, if somebody came at her waving a needle full of 'cure'. If there is one thing she hates, its curebies. Autism Speaks and similar probably have posters of this girl in all their offices marked with the biohazard trefoil and the words 'WARNING! DO NOT ADMIT TO OUR PROPAGANDA RALLIES!!!', because she eats them alive. Rips 'em in half, snarks the bleeding halves to death whilst chewing them up and getting ready to gob them out in a gibbering, shrieking, screaming traumatized heap. Its a beautiful thing, it really is. A beautiful thing fro a beautiful girl. Shei is pretty much Autism Squeaks's public enemy no.1. A snark-salted nuclear bomb in a fox's clothing.

Lol...drives me absolutely crazy too One of the very few people I've ever known that I'd marry and spend the rest of my life with, have kids with, given the slightest chance.]
Although if ever I so much as suggested a cure to her, I'd probably end up tied up in her garage with her coming after me waving a power saw in between that cute stimming stereotypy hand thing she does and a grin on her face that says 'kassiane is going postal today, run away or end up as cat-food (she does love her GABA [her cat is named after y-aminobutyric acid) An angel and a devil rolled into one super-fucking-smart super-fucking-gorgeous, super-fucking-well weapons-grade snark warhead-tipped cruise missile-shaped girl)

One of the most amazing people I have ever been lucky enough to know. And if anybody suggested to her she should be cured of Rett's, I can only begin to imagine what would happen to those poor unfortunate souls before they eventually were given permission to die screaming. She'd eat them alive and gnaw on the bones for toothpicks after she'd finished roasting them so she could suck out the tasty marrow. Probably whilst the legs and arms were still attached to the victim being cooked, IF the curebies had caught her in a particularly benevolent mood towards their vile kind (and that is about as likely for her, as growing wings and taking flight is for me)

If there is one thing on this earth that Rett's girl does not like, it is curebies. (and hehehe she is as sexy as she is a killer snarker, as beautiful as she is deadly, at least to curebie trash)


As for 5HT1a receptors, it depends which populations of 5HT1aRs is targeted by the agonist ligand. 5HT1a agonists can either be anxiolytic, decreasing noradrenergic output from the the locus coeruleus or they can be anxiogenic and do the opposite. Postsynaptic receptor population selective agonists for 5HT1aRs sound like the ones that a desirable RC would target, having inhibitory effects. Also, in the Raphe nuclei, 5HT1a receptors are colocalized with neurokinin type 1 receptors and this can also result in anxiolysis via modulation of neurokinin and substance P release and/or effects, as well as dopamine-releasing properties.

Correct me if I am wrong, but doesn't N,N-DMT have some fairly strong effects as an 5HT1a receptor agonist in additionn to its being a 5HT2a agonist? unlike many other psychedelics, one thing I've noticed about DMT, is that after the full-blown in-your-FACE phase of psychedelic weirdness that is DMT's initial action, there is a long afterglow phase that makes one so incredibly relaxed, all one wants to do is laze around, stretch out in front of the fire with some music on, maybe spark a bong and lay back, mentally speaking, watching the shapes of the clouds pass by? its incredibly calming, and to me at least is one of the most wonderful aspects of DMT, that afterglow. Doesn't 5HT1a receptor agonism play a significant part in this? or is my understanding wrong in respect of that?

Always wanted to try both a highly selective postsynaptic 5HT1a receptor agonist, as well as either an antagonist or if they exist, inverse agonist at presynaptic 5HT1a receptors. Being able to replicate specifically the afterglow of DMT. It doesn't seem to possess addictive tendencies, yet that afterglow, its even more satisfying than intravenous prope. If the DMT afterglow could be refined down and packaged into vials that would be such an amazing thing, it'd sell like hot-cakes in a famine-plagued african country

Even IV strong opiates can't beat that afterglow.

 

[Scrofula]

Always wanted to try both a highly selective postsynaptic 5HT1a receptor agonist, as well as either an antagonist or if they exist, inverse agonist at presynaptic 5HT1a receptors.

As I mentioned, the drug above, that might explode your penis, shows all signs of being highly selective for postsynaptic HT1A receptors, while sparing the "somatodendritic" autoreceptors in the raphe. Most likely Mr. Chem is right and you can't differentiate pre- and post- receptors within the same synapse. But you can distinguish heteroreceptors in, say, the cortex, from the autoreceptors on the cell bodies of serotonergic neurons. Whether that's effective therapy for anything or not, fMRI on rats showed definite activation of different brain regions between those two drugs and from 8-OH-DPAT, not readily explained by another receptor being activated (granted it's fMRI, but they looked pretty distinct).

Maybe we can soon ask some Rett's individuals if it provides any afterglow.

I'm glad your friend is happy as she is; it'd be great if we could all feel like that. But then I think about my cousin. He certainly seems happy. I'd ask him but he wouldn't understand the question, if I could catch his attention in the first place. He doesn't have Rett's, obviously, but he is autistic and will need assistance for the rest of his life. Autism is quite debilitating for a lot of people, and doesn't give them special powers with numbers or patterns either. Some might welcome pharma therapy; their caregivers sure would.

 

[Limpet_Chicken]

I certainly welcome pharmacological assistance for various things, sensory overloading in particular. That just blows arse on an industrial scale. A veritable anal blast-furnace.

As for the Rett's friend/autie activist and all around amazing lass, I don't think she's ever tried DMT. I would bet she'd be curious though. (and my joking point that if something explodes peoples dicks, but is a Rett's drug, then nobody at all is going to have to worry about their dicks exploding, because nobody with Rett's HAS a dick. I'm pretty sure my friend doesn't, she is far too hot for that She could borrow mine any day mind you. But only on the proviso that it comes into contact with nothing of an explosive nature, not counting coming along for the ride whilst she goes to some autsqueaks rally and starts snarking curebies to death, or a fate worse than it But no directly blowing my balls up. I need them. And am rather attached to them, and intend to remain that way Born with them attached and I want them to stay attached

My friend, she is atypical, she's a chimaera, a mosaiic, in that due to skewed X-inactivation some of her cells are positive for the MECP2 knockdown mutation, whilst some are (and god help me if she ever hears me use the word, but 'normal'. and experss two functional copies of the allele for MECP2, as she explained it. Some squirreliness in her electron transport chain, health isn't perfect but then again neither is mine.)

And as for me, the very thought of being 'cured' and made neurotypical, I'd actually sooner put a bullet in my head than face that. It makes my stomach queasy just thinking about such an awful thing. And no, I'm not AS, but Kanner's autie, I like it that way and I wouldn't change things for the world. Maybe I'd take something to become more so, but certainly not less. I'd rather fucking throw myself in front of a speeding car than face something that fucking horrible. Jesus H, what a thought. It makes my skin crawl.

And as for the special patterns stuff etc. No, that isn't automatic, but we often do have some unusual talents, and SOME of us are lucky enough to be blessed with minds that would put a computer to shame.