Effects of psychedelic drugs on psychotic patients

[BlueZenith]

I'm new here; if this is in the wrong place or has come up before, I apologise.

Given these facts:

• 5-HT2A and 2C receptor activation is associated with psychotic symptoms;
• Blockade of these receptors using antagonists (e.g., atypical anti-psychotics) relieves the symptoms of psychosis;
• Said receptors appear to be down-regulated by almost any type of ligand, including both agonists (e.g., psychedelic drugs) and, paradoxically, antagonists (van Oekelen, Luyten & Leysen, 2003);
• Treatment with psychedelic drugs can produce psychotherapeutic effects at sub-psychedelic dosages and without significant side effects (Moreno, Wiegand, Taitano & Delgado, 2006), conceivably through said receptor down-regulation.

Is it possible that chronic low-dose administration of 5-HT2A/2C receptor agonists might produce an anti-psychotic response in psychotic patients through receptor down-regulation, without causing the potentially severe side effects typical of regular anti-psychotic drugs, analogous to the short-term tolerance experienced by recreational users of psychedelic drugs?


Van Oekelen, D., Luyten., W.H.M.L., and Leysen, J.E. (2003) 5-HT2A and 5-HT2C receptors and their atypical regulation properties, Life Sciences, Vol. 72 Issue 22, 18 April 2003, pp2429-2449

Moreno, F.A., Wiegand, C.B., Taitano, E.K. and Delgado, P.L. (2006) Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder, Journal of Clinical Psychiatry, Vol. 67 Issue 11, November 2006, pp1735-1740

 

[pharmakos]

sounds like a solid theory to me. i've considered doing that exact treatment on myself, just as an experiment to see how 5ht2a/2c downregulation affects me.

 

[deez_nuggs]

Extremely solid indeed. Im no neuroscientist and maybe its not as simple as activation or overall regulation of receptors, but it sounds to me like psychedelics can obviously play a very invaluable role in psychology and mental health research. Its a shame that the US, or most other countries for that matter cant acknowledge the incredible power and positive ramifications that come from aproppriate hallucinogenic use.

 

[madsci]

Thought psychosis was more complicated 5-HT not the only receptors involved, also there are 5-HT orphan receptors that might respond to the drug

 

[Phener]

a very complicated one from an ethics perspective. E.g say if it goes WRONG, doesn't work and aggravates the condition.

Particularly consent (the Dr MADE me take the LSD - yes the mind alterating HPSD inducing psycadelic - etc etc).

What is interesting is the population that TAKE lsd/mind altering drugs probably (I'm guessing) have a higher incidence of schizophrenia (a bit of cause and effect going on there)

 

[fryingsquirrel]

I'm sure you could start the dose of LSD in the single mcgs and work the dose up and the patients would never trip if you increased it at the right rate relative to tolerance. I don't think it's so much a ethical problem (every drug has to have a first clinical trial with uncertain results) as a legal and liability one. Getting approval seems pretty unlikely. And pharmaceutical companies are making to much money off of their anti-psychotics to try anyway.

 

[MyExcuse]

I know I sure feel a lot more crazy the longer I go without using some type of psychedelic, and the same goes for a handful of psychedelic users I've had a chance to be acquaintances with.

 

[BlueZenith]

Thought psychosis was more complicated 5-HT not the only receptors involved, also there are 5-HT orphan receptors that might respond to the drug

Of course psychosis is more complicated, but one of the ways in which we're currently treating it is using 5-HT2A/2C antagonists that are often prone to side effects (not to mention expensive due to all the R&D that went into them) and have in many cases been shown to actually worsen long-term outcomes. My hypothesis is that low-dose daily administration of psychedelic drugs can have the same effect, and that if a patient could be stabilised on a psychedelic drug, the patient would have better outcomes in terms of side effects, sustained remission after possible cessation of treatment, and (if the drug is derived from nature and not from the pharmaceutical money machine) his wallet.

a very complicated one from an ethics perspective. E.g say if it goes WRONG, doesn't work and aggravates the condition.

Particularly consent (the Dr MADE me take the LSD - yes the mind alterating HPSD inducing psycadelic - etc etc).

That's always a factor in clinical trials, and it's why everyone who takes part in them is given a thorough explanation of the process and signs an informed-consent form before participating.

What is interesting is the population that TAKE lsd/mind altering drugs probably (I'm guessing) have a higher incidence of schizophrenia (a bit of cause and effect going on there)

Which, if true, would probably be a result of them using the drugs for tripping, and not for psychotherapy using sub-psychedelic dosages, which would most likely have the exact opposite effect.

 

[fryingsquirrel]

Corrolation is not causality. Are people schizophrenic because they use phychedelics, or do they take psychedelics because they have schizophrenia? Or neither?

 

[Phener]

That's always a factor in clinical trials, and it's why everyone who takes part in them is given a thorough explanation of the process and signs an informed-consent form before participating.

Precisely my point, drug companies have a hard enough time with ethics committes trialing anti-psychotics. There are obviously SERIOUS issues of INFORMED-CONSENT when you are treating a schizophrenic. What with LSD still being seen as a "dangerous drug" by the public, any law suit involving a patient whose symptoms worsened would involve a JURY made up by the lay public. As such a GIGANTIC fund would have to be prepared in order to prepare for this.

I am totally FOR LSD, Psilocybin, MDMA etc being used in clinical trials (as hard as it is to pursuade + fund as they are all generic) but this one would be one of THE hardest to realistically inititate in todays climate.

 

[BlueZenith]

Precisely my point, drug companies have a hard enough time with ethics committes trialing anti-psychotics. There are obviously SERIOUS issues of INFORMED-CONSENT when you are treating a schizophrenic. What with LSD still being seen as a "dangerous drug" by the public, any law suit involving a patient whose symptoms worsened would involve a JURY made up by the lay public. As such a GIGANTIC fund would have to be prepared in order to prepare for this.

I am totally FOR LSD, Psilocybin, MDMA etc being used in clinical trials (as hard as it is to pursuade + fund as they are all generic) but this one would be one of THE hardest to realistically inititate in todays climate.

Well, where I come from, legal proceedings are conducted entirely by learned, impartial judges. Trial by jury is seen as an unjust thing of the past; we abolished it in 1813.

A clinical trial with LSD, psilocybin or suchlike would be possible with government permission, though the simplest course of action would probably be to use a fully legal drug like 4-AcO-DMT or 2C-x, which would make it no different from any other clinical trial from a legal perspective.

 

[/navarone/]

From my point of view, since i've been falsely considered psychotic (and later on received the confirmation that I wasn't psychotic since I had full ability to reconize truth from non truth but rather had a confusional disorder that impaired my memory and ability to study or pursue tasks that required a lot of concentration, this was also accompained by a form of anxiety derived from the discomfort and ebarrassment of the way I felt) I've read quite a lot about psychosis and my conclusion was that what plays a major role in the development of this disorder is the attitudes of the indiidual itself which can affect some neuronal pathways to an extent where they begin to function abnormally.

For someone who doesn't really know what psychosis is it is hard to understand it from various encyclopedic articles since they are pretty vague on the definition mostly because psychosis separated into various subtypes of disorders. So far the most accurate definition of psychosis I've found is: "difficulty in distinguishing sensorial truth from inner thoughts that develop into convictions" also there are many after effects that alter deeply mood and the capability to concentrate or focus as a normal person would. Psychotic people tend to remain 'stuck' in their bubble and being so convinced that their listening a comprehending skills tend to deteriorate resulting into massive thought disorder that manifests through incoherent speech writing and other forms of comunication.
It has been proposed by psychotherapists that the major factor in the development of psychosis is purely a behavioural issue, that is mostly 'self arrogance' and a very high but distorted sense of ego that motivates the individual into not double check what he is thinking or suspecting leading to a form of depersonalization. Also there is a particular emotional susceptibility that keeps the individual from being critical about its own psyche but rather listen to any intuition or suspition even if completely non objective and irrational. All These factors throughout the development of the disorder stress certain areas of the brain especially in the individuals that are not full mature to an extent where the actual chemestry of the brain.
What i said is to point out that IMO treating psychosis merely by using pharms is uneffective unles followed by an intense psychotherapy wich aim is to slowly induce the individual to 'get real' and stop living inside his own head. This also is very hard since most psychotic patients deny that they have some sort of disorder (this behaviour is a refelction of their ego and arrogance') and think that the whole world did not understand something that they think they did. Dealing with stubborn patients like them turns out to be harder than anybody could think of (just like dealing with stubborn idiotic bigots, i'm sure each one of you experienced that at some point) so normally what psychotherapicts do in theese cases is to try to 'fol tem at their own game inducing the individual itself into finding a conclusion that destroys previous convictions and make them understand that 'they where wrong'.

To ease this process and the recovery from the self caused neurological instability it would be very beneficial to use the proper drugs in order to induce a state of hypersusceptibility wih shoudl be heavil monitored since it could go bothn ways, that is, either the individual starts to listen to what it should and get more in touch with reality and the outside world or it will do the complete opposite and listen to the 'voices' or biased intuition in his/her head wich have been amplified by the drug leading him/her to fully accept them and derailing into a one way road to full detachment from the outisde world i.e. complete insanity.

Having done many psychedelics myself and seeing the efects fo theese drugs on some other people I knew and though they where 'smart' but 'somehow' turned nuts makes me believe that probably psychedelics are not that safe to be used as antipsychotics. Psychedelics like LSD are very psychologically involving in their nature and tend to cause a full blown creativity that can turn agaisnt you if not hadled with a minimal degree of intelligence and criticism (to make it more understandable, many people kow that despite the intensity of their feelings under LSD, whatever they see or experience is all caused by the drug so they take advantage of the situation to enjoy the chemically amplified potentials of their mind and simply have a good experience to remember and ponder on. Some others people who are a bit more 'less real' or simply more suceptible due to a weaker mind might get way to involved in the expeience and start to believe that what they are seeing and feeling is some sort of 'hidden truth' that no one else saw, and since the feeling is so intense they do not bother to think twice over it leading them to belive in mystical and supernatural things).
I would rather use them to treat some forms of depression like anhedonia, avolition, and other emotional disorders that can manifest in perfectly sane induviduals that are simply experiencing difficulties in handling their emotions, their creativity, their insight ausing them to feel blunt and numb.
I've seen way to many 'normal' and also smart people going cou cou banana after just a few months of psychedelic raving.
I would opt for psychotherapy especially CBT along with a very responsable use of antipsychotics even if so far it seems that there isn't any truly effective antipsychotic.

 

[BlueZenith]

Having done many psychedelics myself and seeing the efects fo theese drugs on some other people I knew and though they where 'smart' but 'somehow' turned nuts makes me believe that probably psychedelics are not that safe to be used as antipsychotics. Psychedelics like LSD are very psychologically involving in their nature and tend to cause a full blown creativity that can turn agaisnt you if not hadled with a minimal degree of intelligence and criticism (to make it more understandable, many people kow that despite the intensity of their feelings under LSD, whatever they see or experience is all caused by the drug so they take advantage of the situation to enjoy the chemically amplified potentials of their mind and simply have a good experience to remember and ponder on. Some others people who are a bit more 'less real' or simply more suceptible due to a weaker mind might get way to involved in the expeience and start to believe that what they are seeing and feeling is some sort of 'hidden truth' that no one else saw, and since the feeling is so intense they do not bother to think twice over it leading them to belive in mystical and supernatural things).
I would rather use them to treat some forms of depression like anhedonia, avolition, and other emotional disorders that can manifest in perfectly sane induviduals that are simply experiencing difficulties in handling their emotions, their creativity, their insight ausing them to feel blunt and numb.
I've seen way to many 'normal' and also smart people going cou cou banana after just a few months of psychedelic raving.
I would opt for psychotherapy especially CBT along with a very responsable use of antipsychotics even if so far it seems that there isn't any truly effective antipsychotic.

What I'm suggesting is not to administer psychedelic drugs for psychedelic effects or insight, but to down-regulate the main receptors they act on.

Basically, there are two kinds of receptors in your brain called 5-HT2A and 5-HT2C. Psychedelic drugs like LSD, psilocin and 2C-E bind to these receptors and 'switch' at least one of them to 'on'. These receptors are also turned on by a chemical that is a normal part of brain function (serotonin) and additionally they sometimes turn on of their own accord, without being bound by serotonin or a drug (this is called constitutive activity). In each case, the receptor has a certain effect on the cell it is a part of.

When you take a reasonable dose of a psychedelic drug, you turn a lot of these receptors on at the same time, and this somehow causes a psychedelic experience. But they also have a lot of natural activity that is there even if you haven't taken a psychedelic drug, and this appears to be involved in psychosis - possibly people who are psychotic have a natural excess of activity at these receptors that cause psychedelic effects.

It turns out that after someone has taken a psychedelic drug, his cells massively scale down the number of 5-HT2A/2C receptors on their surface, resulting in an insensitivity to both psychedelic drugs and serotonin, and a reduction in constitutive activity, and it only takes a little bit of a psychedelic drug to produce this effect; so little that the dose would have no noticeable psychedelic effect whatsoever. This is the reason why tripping multiple days in a row is ineffective, and it is also the reason why low-dose daily administration of psychedelic drugs might have an anti-psychotic effect: the subject would essentially be in a state of permanent tolerance to both psychedelic drugs and the natural psychedelic-type activity of the brain.

 

[/navarone/]

Hmm i sort of get what you are saying, basicaly you're proposing to administer a dose of 5-HT2a and 5-HT2c agonist that would result in an immediate worsening of the symptoms but though a constant regulated dosage it would downregulate the receptors responsable for the psychedelic effects and possibly also for SOME of the symtoms of psychosis (remember that dopamine also plays a big role in psychosis, especially in the frontal cortex wich is responable for concentration, motivation and many other functions that play a big role in psychosis).
Let me remind you something about the 5-HT2a receptor, it downregulates really fast unpon exposure to a strong psychedelic like LSD (that is why taking LSD the day after doesn't really do much at all) but after only a few days cessation the receptor up regulates back to its previous state (or almost), in this case you would have to administer a constant low dose (but big enough to stimulate the receptor) in order to slowly downregulate and keep the receptor downregulated. Don't realy know if the 5-HT2c behaves just like the former one i mentioned.
It sounds kind of fishy for some reason, it would be almost like giving stimulants to someone who is experiencing a dopamine hyperactivity making him freak da fuck out until the receptors will eventually downregulate.
Also I would exclude LSD as a possible candidate for your theoretical treatment since it has a consistent activity on some dopamine receptors and to a lesser extent on some adrenergic receptors:

If we where to test this proposition I would go for a selective 5-HT2a/5-HT2c agonist since most if not all of the 'street' psychedelics inevitably affect some dopaminic and adrenergic receptors. That is why almost all antipsychotics act as antagonist to some dopamine receptors as well causing some sort of sedation.

I don't know how much more I got to say, I would honestly stand by and wait for MuphyClox, Vector or Fast&Bulbous to scatter some light on the matter.

 

[BlueZenith]

Hmm i sort of get what you are saying, basicaly you're proposing to administer a dose of 5-HT2a and 5-HT2c agonist that would result in an immediate worsening of the symptoms
[...]
It sounds kind of fishy for some reason, it would be almost like giving stimulants to someone who is experiencing a dopamine hyperactivity making him freak da fuck out until the receptors will eventually downregulate.

I would tentatively expect no significant worsening of symptoms as the dosage would be below the threshold for psychoactivity.

Let me remind you something about the 5-HT2a receptor, it downregulates really fast unpon exposure to a strong psychedelic like LSD (that is why taking LSD the day after doesn't really do much at all) but after only a few days cessation the receptor up regulates back to its previous state (or almost), in this case you would have to administer a constant low dose (but big enough to stimulate the receptor) in order to slowly downregulate and keep the receptor downregulated.

That's the idea.

Don't realy know if the 5-HT2c behaves just like the former one i mentioned.

It would appear that it does (see the first article I cited in the original post).

Also I would exclude LSD as a possible candidate for your theoretical treatment since it has a consistent activity on some dopamine receptors and to a lesser extent on some adrenergic receptors:

If we where to test this proposition I would go for a selective 5-HT2a/5-HT2c agonist since most if not all of the 'street' psychedelics inevitably affect some dopaminic and adrenergic receptors. That is why almost all antipsychotics act as antagonist to some dopamine receptors as well causing some sort of sedation.

The horizontal line in the graph you've got there is an approximation of the plasma level in recreational use; the receptors with a Ki underneath the line are the ones that are significantly affected at a recreational dose, being serotonin receptors 1A, 2A, 2C (barely), 5A (barely), 5B and 6; no dopamine or adrenergic receptors.

5-HT1A activation is not undesirable and is also part of the pharmacology of some atypical anti-psychotics.
5-HT5B is not expressed in humans.
5-HT6 activation reduces dopamine release in...

but though a constant regulated dosage it would downregulate the receptors responsable for the psychedelic effects and possibly also for SOME of the symtoms of psychosis (remember that dopamine also plays a big role in psychosis, especially in the frontal cortex wich is responable for concentration, motivation and many other functions that play a big role in psychosis).

... the frontal cortex.

Anyway, as I said, that's at a recreational dosage. The dosage used in this application would be much lower and would probably only significantly affect 1A, 2A and 6, and would be expected to have desirable effects at each.

Regardless, LSD's legal status means that it would be much easier to use a newer synthetic drug like 4-AcO-DMT or 2C-x.

 

[Phener]

on the BIG assumption this hypothesis stands + pyshosis is dependant on the 5ht2a etc receptor(s):

surely one of the LONG acting DOX type compounds would be best suited, could even build up plasma level slowly (+ as stated the very quick downregulation of 5ht would allow quite high levels to build up), although then you do get peripheral stimulation/hypertension from the amphetamine part. Long acting tryptamine??

 

[BlueZenith]

on the BIG assumption this hypothesis stands + pyshosis is dependant on the 5ht2a etc receptor(s):

There is no question that 5-HT2A antagonism relieves psychosis, that the receptor displays constitutive activity, and that the administration of ligands for the receptor causes it to be down-regulated. The hypothesis follows logically from these facts. How could it not be correct, especially in light of Moreno et al.'s results with OCD (see first post)?

surely one of the LONG acting DOX type compounds would be best suited, could even build up plasma level slowly (+ as stated the very quick downregulation of 5ht would allow quite high levels to build up), although then you do get peripheral stimulation/hypertension from the amphetamine part. Long acting tryptamine??

It seems likely that any ligand would do. Psilocybin was used in the OCD trial, which I surmise involved the same mechanism.

 

[Phener]

There is no question that 5-HT2A antagonism relieves psychosis, that the receptor displays constitutive activity, and that the administration of ligands for the receptor causes it to be down-regulated. The hypothesis follows logically from these facts. How could it not be correct, especially in light of Moreno et al.'s results with OCD (see first post)?

5ht2a antagonism (or down regulation) ALONE does not solve psychosis, if it did then mirtazapine, Pizotifen, trazadone, Nefazodone and cyproheptadine would show efficacy in treating psychosis.

Pimavanserin (ACP-103) is a drug developed by Acadia Pharmaceuticals which acts as an inverse agonist on the serotonin receptor subtype 5-HT2A, with 10x selectivity over 5-HT2C, and no significant affinity or activity at 5-HT2B or dopamine receptors.[1] As of September 3 2009, pimavanserin has not met expectations for Phase III clinical trials for the treatment of Parkinson's disease psychosis,[2] and is in Phase II trials for adjunctive treatment of schizophrenia alongside an antipsychotic medication.[3] It is expected to improve the effectiveness and side effect profile of antipsychotics.

Even pimavanserin is expected to IMPROVE effectiveness and side effect profile of antipsychotics (not treat it ALONE).

As concerns all the recent Atypical antipsychotics they DO block 5ht2a but they DO also block D2 receptors directly as well as other receptors.

 

[bgju38]

i cant talk about pharmacology. all i can say is that i have some psychotic disorders and psychedelics and therapy with my girlfriend is the most effective treatment ive ever had... at higher doses psychedelics DO cause my psychotic symptoms to increase... my paranoid delusions will be blown wayyy out of proportion. i realized this last time and had to abort with a benzo. the thoughts were really outrageous. but at low doses weed and serotinergic psychedelics totally bring me back to sanity and normalcy. i regain my ability to speak normally and be mentally healthy and stable and carry out my daily activities in a stable way. the fact that i risk prison to be able to take the organic medicines that god has given us is sickening. its apparent that our civilization is extremely primitive and bigoted, and has a long long way to come yet.

 

[SNR]

This is seriously one of the coolest ideas I've heard all day. Makes perfect sense!

And for use of 5-HT2A/C agonists to cause receptor downregulation, there are 5-HT2A/C selective agonist ligands that do not cause psychedelia.
http://en.wikipedia.org/wiki/Lisuride
etc.

~snr

You might also consider reading through this thread. Some really informative stuff in there that relates.