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Clinical trials towards the legalisation of psilocybin and LSD


If we believe the newspapers (and we will argue that one should not), the next recreational narcotic to be legalised will not be MDMA (Ecstasy), as we have contemplated in an earlier article; but psilocybins, and by extension a drug called lysergic acid diethylamide (LSD). In this essay we explore the ongoing clinical research and debate.


Contrary to the prevailing congemporary norms, we are frankly very sceptical of this line of scientific enquiry and drugs policy direction.


This article is part of our series on the Belgrade Drug Policy Clinic.


A good place to start is the following article, which is worth reading in full before continuing, so as to understand the context of the debate.


https://www.bbc.com/news/health-63475630


Now let us define our terms.


'

Psilocybin is a naturally occurring psychedelic prodrug compound produced by more than 200 species of fungi. The most potent are members of the genus Psilocybe, such as P. azurescens, P. semilanceata, and P. cyanescens, but psilocybin has also been isolated from about a dozen other genera. Psilocybin is itself biologically inactive but is quickly converted by the body to psilocin, which has mind-altering effects similar, in some aspects, to those of LSD, mescaline, and DMT. In general, the effects include euphoria, visual and mental hallucinations, changes in perception, a distorted sense of time, and perceived spiritual experiences. It can also cause adverse reactions such as nausea and panic attacks.

'


Psilocybins as a recreational narcotic


Psiloycybin is the active ingredient in magic mushrooms, a recreational narcotic illegal in the vast majority of countries but legal in the Netherlands. Hence we have a lot of information about its use in recreational quantities.


Magic mushrooms are typically sold in the Netherlands in a small plastic box, containing about a dozen dried mushrooms with a total of between 4mg and 10mg psiloycybin in them. The mushrooms are consumed orally; they taste disgusting but their taste can be rendered more tolerable by mixing them with other food, for example a slice of pizza or a plate of pasta. They need to be chewed and then swallowed, so consuming them with a drink is not optimal.


Quality control for the mushrooms is high in the Netherlands but questionable elsewhere where the mushrooms are naturally picked and then sold by dealers. On the Netherlands the mushrooms are grown under light in controlled conditions and then boxed in accordance with a regulatory regime requiring disclosure of the quantity of psilocybin on the label and so on and so forth. Typically a box costs between 10 and 25 Euros, so they are a 'cheap hit'


Once consumed, like most narcotics processed in the stomacj their period of onset is about 30 minutes and then their period of effect is typically 4-5 hours. Here are the symptoms. Their strength depends principally on the quantity of psilocybin consumed and the body weight of the individual (a larger person needs a larger dose for the same effect).


  1. Ecstatic delirium, in which it is impossible to string coherent sentences together and motor skills are lost. Some people find they cannot stand up, walk around or even get out of bed.

  2. Total loss of orientation; people walk up and down the same streets and round in circles. They also forget where they have left regular everyday objects such as ther money or jacket. It is advisable, before commencing a psilocybin period of intoxication, that one empties one's pockets and just keep one's key, and a banknote for the taxi in one's shoe. You may lose many items on one's person; and hence the comedown occurs, it happens straight away. Then you find you are sober and you have in your shoe the necesaries to get home, irrespective of what you have lost.

  3. Finding everything absolutely hilarious. (This can be very trying for the people around you, as you refuse to stop laughing.)

  4. Attraction towards objects with bright colours. (This is why the Red Light District in Amsterdam, where a lot of magic mushroom eaters roam, is full of shops selling colourful items such as different brightly coloured dildos and giant slices of pizza with bright red pepperoni on them.)

  5. Increase in appetite; anything edible looks delicious. (This is why restaurants in Amsterdam's Red Light District have plasticated menus full of vivid images of food on the outer windows of their restaurants.)

  6. A propensity towards absurd behaviour and an attraction towards silly things. (This is why Amsterdam's Red Light District has a lot of giant soft toys and other completely silly objects, such as a giant plastic polar bear, dotted around it.) People can be seen licking windows, playing with objects on the counter in a bar, performing lewd acts in the lavatory, and so on and so forth. All inhibition tends to be lost.

  7. Reduced effect of alcohol or other recreational narcotics. People high on magic mushrooms often buy a beer in a bar, decide it is not very interesting, forget about it and then walk off. Hence all Amsterdam Red Light District bars require payment in advance.

  8. Absurd irrational paranoia, for example a belief that one is about to be shot or beaten up or that a store owner will call the Police because one stole something (which one did not).

  9. Taken in excessive quantities, magic mushrooms make you vomit. There is only so much psilocybin the body can absorb without catalysing a desire to expel it.

  10. Perceptual hallucinations will take place in virtually every person at an appropriate dosage level. This may involve swirling colours of objects, or seeing things in one:s lateral vision that are not there. This can be quite disconcerting and in many people the experience is sufficiently unpleasant that they feel the need to go to bed and wait until the effect has worn off.

  11. Increased sexual desire, although inchoate (one may want sex without realising that physically, due to the effects of the drug, one is quite incapable of it.)

  12. Sleepiness towards the end of the 'trip'; as the drug wears off one is inclined to cease movements

  13. If one takes psilocybin over more than one day, they become decreasingly effective and increasingly cause nausea, anxiety, paranoia and depression.


And they want to legalise psilocybin as a medicine. What a very curious idea.



Psylocybin as a medicine to treat psychological trauma


Here is a link to a recent conference held in the Netherlands in September 2022 focusing upon the putative medical benefits of psilocybins:


Full-ICPR-2022-Programme-Version-Sep-19
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Download PDF • 319KB

Here is a more or less complete list of the background scholarship.


ly2018
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Rebus Carhart-Harris Friston
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Griffith
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friston2009
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emotions
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does psychedelic therapy have a transdiagnostic
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carhart-harris2018
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carhart-harris2017
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carhart-harris2016
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[Scientific Reports vol. 7 iss
. 1] Carhart-Harris, Robin L_ Roseman, Leor_ Bolstridge, Mar
Download 1] CARHART-HARRIS, ROBIN L_ ROSEMAN, LEOR_ BOLSTRIDGE, MAR • 2.41MB

carhart-harris2012
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3e6db0745b0cfd2498b36ca0ed014281
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1-s2.0-S1053811920304663-main
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We are frankly sceptical of the quality of much of this scholarship. It is hard to sum up a series of scientific articles in a paragraph, but the essential gist is that patients with clinical depression are given large overdoses of psilocybins over periods of weeks, supervised by the research staff, and then they are asked whether they feel happier as a result. This is not a robust method of assessing whether psiloycbins are an effective treatment for clinical depression, because there are tapering off effects; happiness and the absence of depression are not the same thing; there is likely to be a placebo effect; there are many dozens of extraneous factors one must exclude in order to obtain a reliable correlation sufficient to establish causation, and insufficient data has been acquired to undertake a reliable regression analysis.


The reader of the BBC article above will note that the research it cites suggests a massive overdose of psilocybin (at least by recreational standards), at 25mg (contrast 4-10mg when consumed recreationally), with effects lasting 12 to 13 hours.


We consider that this counsel ought to be treated with extreme caution. While one might (at best) consider psilocybin intoxication at recreational levels 'a bit of harmless fun' )of having a generalised psychotic episode can be regarded as just 'a bit of fun'), it seems to us that the idea of a massive overdose for some imagined medicinal purpose is a potentially perilous proposition. Certainly any assertions about the medicinal efficacy of consumption at extreme high levels ought not to be countenanced without the highest levels of scientific rigour and scrutiny.


Here is the article abstract upon which the BBC article above was based:


https://www.nejm.org/doi/full/10.1056/NEJMoa2206443


One can click through to the full article (sign-up mag be needed, but consider a website such as 12-foot ladder to bypass the sign-up requirements):. We consider it undesirable that a scientific article about so important a contemporary subject, which implicitly argues for dramatic hangers in the regime of legal regulation of narcotics, is hidden behind a paywall. Instead all we have is a highly imperfect BBC journalistic summary of an article in a deeply controversial area.


The current studies about the medicinal uses of psilocybin boil down to the following propositions:


  1. Psilocybin can be a treatment for clinical depression.

  2. Its pathway of action in this regard is to cause increased disinhibition, which enables the 'patient' to talk about suppressed memories.

  3. The patient may undergo acute psychological distress in the course of this process, as though 'dreaming while awake'.

  4. The experience is so potentially distressing that the patient requires constant medical supervision (in contrast to the recreational use of psilocybins, which can safely be taken in proportionate and reasonable quantities without medical oversight).

  5. Ostensibly after the drug wears off, and after several sessions of 'therapy, the patient's clinical depression is somehow abated.

  6. There are no recorded beneficial effects after 12 weeks of this treatment; patients return to being clinical depressives.

  7. Nothing is known about the long-term effects of taking massive overdoses of psilocybins.

  8. Nor has any connection been made between the work on recreational use of psilocybin, at lower doses (that as observed above are known temporarily to scramble the mind) and these hyper-doaes of psilocybin for alleged medical purposes.

  9. The studies proferred make qualitative assessments (e.g. 'how does a patient feel' questions) that are inherently unreliable,and measure them against quantitative empirical measurements, e.g. how large a dose is taken and how often.

  10. Confining a drug taker to a room for 12 hours to observe psychadelic-induced psychosis by non-medical professionals (which is what has really happened in these studies) strikes us aa downright irresponsible and a wholly unsatisfactory control environment.


We think that these studies are for the overwhelming part specious. They do not exhibit scientific rigour; while consumption of massive quantities of psychosis-inducing narcotics is surely very dangerous for the patient / volunteer.



Psilocybin and Lysergic Acid Diethylamide


If psiloycybin, why not LSD? This question admits of no coherent answer. Yet nobody is advocating the legalisation of LSD for medicinal or any other purposes.


Let us define LSD.


'

Lysergic acid diethylamide (LSD), also known colloquially as acid, is a potent psychedelic drug. Effects typically include intensified thoughts, emotions, and sensory perception. At sufficiently high dosages LSD manifests primarily mental, visual, as well as auditory, hallucinations. Dilated pupils, increased blood pressure, and increased body temperature are typical.[16] Effects typically begin within half an hour and can last for up to 20 hours. LSD is also capable of causing mystical experiences and ego dissolution. It is used mainly as a recreational drug or for spiritual reasons. LSD is both the prototypical psychedelic and one of the "classical" psychedelics, being the psychedelics with the greatest scientific and cultural significance. LSD is typically either swallowed or held under the tongue. It is most often sold on blotter paper and less commonly as tablets, in a watery solution or in gelatin squares.

'


LSD is essentially artificially synthesised psilocybin. The chemical differences between the two are apparently insigmificant; they have the same chemical structure and LSD has much the same mental and physical effects as psilocybin, albeit over a longer period because LSD is a concentrated synthetic chemical as opposed to a naturally occurring organic one.


The effects of a recreational dosage of LSD 25μg to 150μg are the same as magic mushrooms, but with the following additional effects consequent upon the concentrated dosage involved in consuming a synthetic material:


  1. Extreme emotional reactions, usually of ecstasy,or love, but not always! A person in a poor initial mood can suffer extreme negative emotional reactions.

  2. Blinding and astounding perceptual hallucinations (e.g. objects changing colour; trees bending over into U shapes; people not being seen as people but as some other different object).

  3. Potential paranoid violence against people as the user imagines that he is not attacking people but addressing some other danger.

  4. Position of the body in dangerous circumstances, e.g. on railway tracks or leaping from balconies in the belief one can fly

  5. 12+ hours' effect after 30-minute onset; total inability to control one's actions or to appreciate one's environment rationally during this period.

  6. Other dangerous and foolhardy actions (e.g. consumption of unknown other drugs; dangerous or potentially even non-consensual sexual encounters).

  7. Incoherent relations with other people, such as getting into the car or going to the house of persons one does not know.

  8. Being attracted towards buying curious things and then being unable to pay for them or forgetful of the obligation to do so.

  9. Significant problematic interactions with the Police or other law enforcement agencies as a result.

  10. Inability to sense hot and cold. (So one might find oneself lying in a field with only a t-shirt in cold winter weather.)

  11. Repeat dosages are liable to cause extreme paranoia and severe mental distress, rendering one mute or incapable of moving even in the face of encouragement by friends.

  12. Forgetting who one's real friends really are; going off with strangers upon their capricious suggestions.

  13. Irrationally heavy consumption of alcohol over a short period.

  14. Acts in breach of the peace (public urination; violence; lying in the floor in a public or private establishment open to the public).

  15. Suicidal ideation; induced extreme depression in a vulnerable person.

  16. A variety of other forms of comprehensive psychosis.


The reason LSD is illegal in the Netherlands whereas magic mushrooms are legal is that the narcotic in LSD, which has substantially the same pathway of action as psilocybins, is too strong.


This is a compelling reason on its own not to legalise overdoses of psilocybins, whether for recreational purposes, medicinal purposes or anything else.



Conclusions


  1. Netherlands policy on legalisation of psilocybins is comprehensible and rational. However it does not entail that very high dosages of psilocybin have any valuable medical effect, nor that they ought to be used in clinical trials.

  2. The so-called science involved in recent clinical trials of high quantities of psilocybin both stink of charlatanry and are potentially dangerous for patients, as well as offering false promises in response to clinical depression.

  3. The evidence available of the side-effexts of LSD consumption corroborates this conclusion.

  4. Psilocybin research trials ought to be terminated immediately pending rigourous and conservative scientific review.

  5. Arguments for continued psilocybin clinical research should be distinguished from arguments for the legalisation of recreational narcotics more generally, namely that although it is understood that most or all recreational narcotics do a degree of harm, the level of harm they cause is less if they are sold under regulated conditions than if they are sold under criminalised conditions. These arguments do not involve medical science but social policy arguments.


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With thanks to several contributors - researchers, experimenters and Netherlands residents - who made this article possible.