Permanent psychedelic tolerance due to past antipsychotic use?

[Napdmd]

I hope I'm posting this in the correct section.

When I abused high doses of pregabalin (6 grams EOD) and cold turkeyed from that. I got a severe psychotic and suicidal depression with major anxiety. They put me on 30mg of olanzapine and 45 mg mirtazapine for 3 months. I was healed from the pregabalin withdrawal within 4 months.

However, I cant trip on psychedelics anymore. Its been over 6 months since I quit both olanzapine and mirtazaline and I still cant trip. I tried multiple tryptamines and LSD from legit sources, and no matter what dose, nothing happens.

I know both olanzapine and mirtazapine block 5ht2a receptors. But I would assume that my now they are out of my system and dont bind to any of these receptors anymore.

Did the use of these medications changed the expression and sensitivity of the 5ht2a receptor longterm or even permanent? Anyone has any knowledge on this or experience with this?

 

[polymath]

Yeah having your 5-HT2A receptors blocked for a long time will make your CNS produce less of them, opposite to what happens if you block your mu receptors with naltrexone.

Effects of repeated risperidone exposure on serotonin receptor subtypes in developing rats

Risperidone is an atypical antipsychotic drug that is widely prescribed to young patients with different psychotic disorders. The long-term effects of this antipsychotic agent on neuronal receptors in developing brain remain unclear and require further ...

www.ncbi.nlm.nih.gov

Risperidone is an atypical antipsychotic drug that is widely prescribed to young patients with different psychotic disorders. The long-term effects of this antipsychotic agent on neuronal receptors in developing brain remain unclear and require further investigation. In this study, we examined the effects of long-term treatment of risperidone on two serotonin receptor subtypes in brain regions of juvenile rat. Levels of 5-HT1A and 5-HT2A receptors in forebrain regions of juvenile rats were quantified after 3 weeks of treatment with three different doses of risperidone (0.3, 1.0 and 3.0 mg/kg). Findings were compared to previously reported changes in 5-HT receptors after risperidone treatment (3.0 mg/kg) in adult rat brain. The three doses of risperidone selectively and dose-dependently increased levels of 5-HT1A receptors in medial prefrontal and dorsolateral frontal cortices of juvenile animals. The higher doses (1.0 and 3.0 mg/kg) of risperidone also increased 5-HT1A receptor binding in hippocampal CA1 region of juvenile but not adult rats. In contrast, the three doses of risperidone significantly reduced 5-HT2A labeling in medial prefrontal and dorsolateral frontal cortices in juvenile as well as in adult animals in an equipotent fashion. 5-HT1A and 5-HT2A receptors in other forebrain regions were not altered by repeated risperidone treatment. These findings indicate that there are differential effects of risperidone on 5-HT1A and 5-HT2A receptors in juvenile animals, and that the 5-HT system in developing animals is more sensitive than adults to the long-term effects of risperidone.

I personally find that those meds don't completely block the effects of psychedelics, even if I have them in my system at the same time when I dose rivea corymbosa seeds or something like that. But someone else may react to it in a different way. Another paradoxical thing is that atypicals sometimes make HPPD worse unlike expected.

 

[dopamimetic]

Oh yeah, nasty bastards they are, the antipsychotics. I know some/many will disagree with me but I deeply hate them, even got repeated psychotic reactions to risperidone especially, also to chlorprothixene (Truxal, this one less a surprise as it's an anticholinergic) but the risperidone really got me wrong. I was in acute mental hospital care due to an accident (actually just wanted to have my vital signs monitored during the night as I feared to have overdosed on a weird RC, which wasn't the case and would have killed me if it was, as they did not monitor me but think I'd be psychotic, well.. I truly went psychotic after risperidone. Didn't know where I was, who I was, what time it was, and on top of all, I heard voices for the second time in my life. First one was on high dose DXM.)

Two years or so past, again in fucking mental care, they wanted to help me against recurring thoughts and similar stuff, by giving low dose antipsychotic - risperidone 1mg/d. Felt weird. When they upped it to 2mg/d, I began to hear voices in the noise of running water and ventilators, also became very irritable and uneasy when among other people - which you can't avoid in such a setting. Got into a dispute with my teen and pretty immature roommate because of which they threw me out. Best decision, the day after I've stopped the risperidone everything went back to normal.

Just a specific substance intolerance you might say? An unknown, low dose of haloperidol (yay, in parts of Germany it's still used as a first line tranquilizer) made me feel similarly weird, just w/o the voices. An hour or so passed when the cramps set in and I could barely breathe, so after heavy begging I got injected with akineton - made me euphoric and unable to sleep for more than 24h straight. Quetiapine 600mg/d made me panic and nearly collapse.

There are a few more incidences just as weird that I don't remember really anymore because they co-administered benzodiazepines to cover the reactions. Psych docs just don't believe that antipsychotics can be bad. Also I know of a bunch of other people with similarly strange reactions, also some which quality of life had been destroyed by docs forcing them to take antipsychs for years just as precaution for a single, isolated psychotic episode. Besides DXM I don't know of any recreational drug which is as weird by far. Oh, also I tolerate dopaminergics pretty well, even meth. I don't really like it but I tolerate it, it's got nothing psychotic at all.

Mirtazapine, while not a true antipsychotic by itself in that it doesn't share the heavy anti-dopaminergic (side) effects, but nevertheless it's got similarly weird qualities. It was one of the first meds I got, and I remember this strange side effect - you know, when a loud noise or something behind you scares you, and you get the shivers down your spine. Mirtazapine just inserted like a 1,5s delay between the shock and the shivers. Completely conscious, I knew what was going on, just the somatic reaction was delayed. Weird bunch of shit.

But what destroyed my ability to trip was venlafaxine (effexor). I've been on that for most of my adult life, even now I struggle to quit. Brain zaps and dysphoria without end, think I managed it through 3 weeks or so for the longest. They shouldn't say it might make teenies suicidal, but a straight no-go for anyone below 22 years or so. When given while the brain's still developing, it builds a hefty and pretty irreversible tolerance.

Disassocitives help, maybe due to their release of brain growth factor, activation of mTOR or whatever, but unfortunately only for so and so long, usually a few days (span has been longer earlier, when I still got week-long afterglows from that dirty chick of DXM.. nowadays I don't tolerate it anymore, makes me psychotic too. Ket & co aren't a problem at all.)

 

[AlphaMethylPhenyl]

There are lots of antipsychotics, experiences vary. Low doses of the D2 partials are often used to augment antidepressant treatment.

I don't know about the behavioral neurosci behind it, but I'd say that you should take a long break from hallucinogens before pondering their use. You don't want to be forced on antipsychotics again, right? Both 5-Ht2 agonists and antagonists downregulate 5-Ht2a. And both zyprexa and remeron are 5-HT2a antagonists. So, theoretically they are downregualted, but not forever.

What is the issue, though? Depression? There are probably less risky manners of addressing your grievances.

SSRIs and SNRIs are not dangerous chemicals, and tend to work for a long time, if not for ever. So there isn't significant toxicity in being on them--much mroe toxic is the brain in a depressed state. The same goes for untreated psychotic disorders. Do your own researh on this, but some antipsychotics are generally more hard on the brain than others. But again, treated psychotic disorder is safer than not, as a pretty reliable rule.

One ketamine infusion works for a week in depressed people, and 3-4 days in those with bipolar, as studies state. But this class of medication is particularly risky if you've been treated with antipsychotics. These dissociative hallucinogens (DXM, ketamine, and more) mimic both parts of the schizophrenia symptoms, whereas psychedelic hallucinogens (serotonergics like LSD and psilocybin) mimic one of the two categories.

 

[Napdmd]

Sorry for the late reply. I had to take olanzapine for sleep deprived induced pychosis a couple of weeks ago, so could never take a break from anti-psychotics. I have not touched LSD in over a year and needed 500 ug to see some visuals. So yeah, anti-psychotics mess with your 5HT2A receptors. I read somewhere in a study where they found out they paradoxically create reverse tolerance to the 5HT subtype receptors by downregulating or desensitizing them. Which is strange for an antagonist.

Now it makes sense that shrinks give people anti-psychotics because of the effect it has on the serotonergic receptors. More 2A and 2C receptor expression leads to less dopamine projection to different brain area's. Antagonizing these subtype receptors makes sense as an adjunct with SSRI's against depression.

What they found is, most people who comitted suicide had a higher amount of 5HT2A receptors in their brains.

I still have tolerance to all psychedelica except 5-MeO-DMT. But that stuff just knocks me out and feels like I took midazolam. Never had any "god" encounter or mystical experience. Prolly bacause my 5HT2A is downregulated by them neuroleptics. MDMA also has become a dopaminergic stimulant with a cosy feeling to it for me now, no introspection. Means a lot of MDMA's effect are mediated by the 5HTA2R (My hypothesis).

Serotonin has such paradoxal effects. One subtype receptor works like an anti-depressant (5HT1A agonism) by increasing dopamine and oxytocin in the frontal cortex and other area's, while 2A and 2C agonism make you depressed or delusional. Agomelatine (an atypical antidepressant that is almost identical to melatonin) antagonizes the 5HT2CR and thereby increasing dopamine. Like I said; serotonin is one hell of a paradox.

I did smoke some Changa with normal N,N, DMT. It gave the most intense CEV's but no open eye hallucinations/distortions. Maybe N,N DMT is somewhat resistant to 5HT2A tolerance?

My question is: will it reverse?

 

[Napdmd]

Source: Wikipedia:

"
Downregulation of post-synaptic 5-HT2A receptor is an adaptive process provoked by chronic administration of selective serotonin reuptake inhibitors (SSRIs) and atypical antipsychotics. Suicidal and otherwise depressed patients have had more 5-HT2A receptors than normal patients. These findings suggest that post-synaptic 5-HT2A overdensity is involved in the pathogenesis of depression.[10]

Paradoxical down-regulation of 5-HT2A receptors can be observed with several 5-HT2A antagonists.[11] Thus, instead of tolerance, reverse-tolerance would be expected from 5-HT2A antagonists. However, there is at least one antagonist at this site which has been shown to up-regulate 5-HT2A receptors.[11][12] Additionally, a couple of other antagonists may have no effect on 5-HT2A receptor number.[13] Nevertheless, upregulation is the exception rather than the rule. Neither tolerance nor rebound is observed in humans with regard to the SWS promoting effects of 5-HT2A antagonists.[14]"

 

[Napdmd]

I guess one of the reasons psychedelic serotonergic agonists work well in depression because of 5HT2A downreglulation and neurogenesis. (+ The meaningful mystical experience these tryptamine, phenethylamine, ergoline molecules might give depressed patients.

 

[xtcgrrrl]

I was on olanzapine for years. I did attempt to trip on lsd during this time but I was unable to do so. After I got off the Zyprexa, my ability to trip gradually came back. LSD was not so good for this, but shrooms appeared to help heal my brain and I was able to have a full-fledged trip recently, visuals and all. I’m hopeful that I’ll be able to continue tripping in the future, and I’m never going back on these horrible meds.

 

[Atomic_Decay]

Given that the full mechanism of action for LSD is not fully understood it’s hard to be definitive about historical AP use permanently damaging an individual’s. ability to trip.

My understanding is that two ways 5htp2a is critical to a trip. The first is that it directly moderates typical visual effects. But for full psychedilc effects from LSD and all that entails this receptor is now more understood as a kind of gate/relay station/router (all of these - can’t think of a singular metaphor).

Most importantly in LSD is the next step when 5htp-2a increases glutamate transmission in the pre-frontal cortex.

But modulation of 5htp-2c and 5htp-1a also seems necessary.
But the full effects of LSD are produced through multiple cascading downstream neurochemical changes across multiple monoamine systems. How actually happens is cutting edge research with some competing theoretical directions. One of the most recent research directions I have seem is here:

Receptor-informed network control theory links LSD and psilocybin to a flattening of the brain’s control energy landscape - Nature Communications

There are several models of how serotonergic psychedelic drugs affect brain activity. Here the authors use network control theory and functional MRI data to provide evidence that serotonin receptor agonists LSD and psilocybin flatten the brain’s dynamic landscape, allowing for facile state...

www.nature.com

With long term use AP’s can make unique semi? permanent neuroplastic changes to brain structure and chemistry all over the place. Potentially making drug experiences very different across time.

 

[kongoman]

hi @xtcgrrrl I think I'm in a similar situation. Ive been treated with all kind of meds and druggs that I added, but anthipschycotics are the worst meds ever taken. Risperidone, olanzapine, quetiapine and etumine. The last Id never read about it this forum. I think that is only used in Europe. Benzos, methadone and other ilegal substances taken since I was 17 and now I'm 43. All of this finished with a Hard depression and insomnia. A very hard insomnia that lasts 5 years. Now I found the medication that works. I began with:
10mg lorazepam
40mg etumine
200mg quetiapine
The are large dose of meds and now I take:
5mg lorazepam
40mg etumine
50mg quetiapine
But I feel my brain Have been injured. My CNS is damaged, Thats only my theory. My doctors have never said that. But why cannot sleep after 5 years of depression?
Well I wont extend much more...
Send love to all People that is suffering a mental desease

 

[Snafu in the Void]

I was on high doses of risperidone and olanzapine for 2 years. I never noticed any sort of permanent tolerance or change in my ability to trip afterwards.