A critical review of psilocybin and its effectiveness as a potential treatment of psychosis.
Psychosis is defined as a mental disorder which causes individuals to interpret and perceive things differently resulting in a vast array of symptoms such as hallucinations or delusions. The use of antipsychotic medicine (such as Quetiapine) has been well documented in the treatment of psychosis, however the use of psilocybin, a hallucinogenic molecule found in the Psilocybe class of mushrooms (referred to as magic mushrooms), has only been investigated as of 1992 due to the passing of legislation. A wide variety of studies have been investigated, testing various mental health diseases such as depression, anxiety, OCD and schizophrenia. This review will provide a critical overview of the results that psilocybin displayed over an example of each study and discuss the overall potential use in a clinical environment.
Psilocybin is a prodrug generally derived from members of the Psilocybe genus of mushrooms, examples of which are P. cyanescens, P. mexicana and P. azurescens. However, it is documented in a dozen other genera of mushrooms. The assigned term; prodrug states that psilocybin itself is not the active hallucinogen when interacting with the body. As the drug is metabolised by the liver, it undergoes dephosphorylation and produces the active hallucinogen; psilocin.1
The structure of psilocybin can be described as a tryptamine, common amongst hallucinogenic compounds. Psilocybin shares many structural similarities with mescaline and lysergic acid diethylamide (LSD) therefore patients who have experimented with multiple drugs of this category have built a tolerance as the mechanism of action between these drugs all correlate around the serotonergic pathways. Cross-tolerance can easily be justified when considering the 5-HT (serotonin) pathways, psilocybin and indeed many of the other tryptamine hallucinogens are strong agonists of the 5-HT receptors; specifically, 5-HT2A in the case of psilocybin.2 Psilocybin is also a moderate agonist at the 5-HT1A and 5-HT2C receptors, located with the cortex of the brain and also the thalamus. The thalamus is the centre of all sensory inputs, taking information in from motor neurones and receptors, The 5-HT2A receptor is known to decrease the activity of the thalamus, resulting in a warped view of reality, these hallucinations can last anywhere between 2-4 hours and usually onset within the first 20 minutes consumption.2
Fig. 1 – Structure of prodrug and metabolite.
History of Discovery
Psilocybin has long since been in use by humans for various tribal rituals before the advent of writing and documentation. In more contemporary times, the molecule was isolated by a Swiss chemist by the name of Albert Hoffman around 1957. They shortly then synthetically produced the molecule in 1958 and published a paper in 1959 documenting their findings.3 Hoffman had a record for identifying hallucinogenic compounds, his work in 1938 working under Arthur Stoll at the Sandoz laboratories in Basel put him at the fore-front of tryptamine derived substances as he was the first to synthesise LSD.4 His methods were considered very “hands-on”, even subjecting himself at times to the mushrooms to confirm the presence of psilocybin; he had built up an immunity to the hallucinogen due to the cross-tolerance developed by his indulgence in LSD.
History of Legislation and Safety
In the United States, the Controlled Substances Act of 1970 (CSA) brought about the end of studies into compounds of severe intoxication indices. Clinical trials of psychedelics predating this time, such as those into psilocybin between the late 50’s and throughout the 60’s, can hardly be investigated due to the nature of experiments in those times. Those studies generally performed procedures considered unethical or unacceptable in today’s modern standards or the studies themselves were too small to provide any significant data.5 The CSA came into action bringing with it a Schedule I rating for psychoactive drugs such as psilocybin. This resulted in funding cuts to many research projects looking to understand the psychiatric effects and the potential role in a clinical environment for such molecules. It wasn’t until 1992 when the National Institute of Drug Abuse teamed up with the FDA (Food and Drug Administration) to pass legislation and allow the continuation of research into psychedelics.6
In the United Kingdom, ever since 2005 psilocybin mushrooms have been considered a Class A drug under the 2005 Drugs Act.7 However, this review will be strictly keeping to research conducted in the USA to maintain consistency of legislation, safety and ethical procedures.
The LD50 (280mg/kg) of psilocybin is considerably low for the nature and class of hallucinogen, most tryptamines have a considerably lower dosage to produce toxic effects. Unlike LSD, a similar tryptamine compound, psilocybin shows no association with dopamine receptors, limiting the potential side effects. In higher dosage cases, association with noradrenergic systems has been documented.8 Physiologically, psilocybin arouses the sympathetic nervous system and can produce a variety of symptoms based on many features of the individual ingesting the compound. The known phenotypic observations include euphoria, synaesthesia, headaches, nausea, sweating, restlessness, dilated pupils and so on until the drug’s effects diminish; typically, 8 hours after ingestion. Psilocybin, and more specifically psilocin has no direct lethality. The drug is not documented to be addictive or produce withdrawal systems, even after chronic use.9 In very rare cases, the use of psilocybin has been documented to cause fatalities. Several articles describing the use of psilocybin in small quantities in an unsafe environment have reported fatalities but in contrast to the drug abuse of compounds like heroin and crack cocaine, the death risk is significantly smaller.
There has been much concern that the use of psychedelic compounds may be the cause of severe mental health issues; exacerbating underlying mental illness or cause suicidal behaviour. A study published in 2015 by Johansen et al.10 investigated the issue, using a random population of 135,095 US adults, 19,299 of which were chronic psychedelic users. The conclusions of the study found that the lifetime use of psychedelics had no significant association with the requirement of mental health treatment, suicidal attempts, plans or thoughts.
OCD (Obsessive-Compulsive Disorder)
Obsessive compulsive disorder is a difficult condition to live with for most people. One case study published in 2006 looked to test the effects that administering psilocybin would have on patients with said disorder. The case study looked to investigate the safety, tolerability and clinical effects that psilocybin would have on patients who displayed DSM-IV-defined OCD and no other major psychiatric disorders.11 The nine subjects would have a total of 29 psilocybin dosages in a double-blind study. These dosages would range from low (100mg/kg) to high (300mg/kg) with a 100mg/kg increment between each dosage. The double-blind factor would be the random introduction of very low dosages of 25mg/kg at any time after receiving the first dose. Each testing day was reserved for 8 hours in a controlled environment, with each testing day separated by a week. All patients were observed overnight in a psychiatric unit. The YBOCS (Yale-Brown Obsessive Compuslive Scale) was used alongside a visual analogue to measure the severity of their OCD at 4-hour intervals between 0 and 24 hours after ingestion. A hallucinogen rating scale was also administered at exactly 8 hours after each dosage, whilst vital signs were monitored at intervals between 0, 1, 4, 8 and 24 hours. The results seem quite promising from the study as it showed a marked decrease in OCD symptoms with varying degrees of success ranging from 23% to up to 100% in reduction of their YBOCS score. One subject appeared to suffer from transient hypertension, but no other significant adverse effects were observed. The study also found that there was no significant effect of dosage, but the effect of time did not yield a large increase in their YBOCS score. 66.7% of patients maintained a 50% decrease of their YBOCS score at 24 hours after the first dosage.
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It is unknown or not specified whether the patients returned with their displayed decrease in OCD symptoms. Through inference we can justify that after the 1-week grace period between dosages the patients would return to a state like the one which they had entered with before partaking in the study. This suggests that psilocybin may not be a one-time permanent fix for patients suffering from the Obsessive-Compulsive Disorder. If we contrast this to a drug such as Prozac, a commonly used drug for remedying anxiety and OCD over a short period of time, psilocybin may have advantageous properties. Prozac is known to have physical withdrawal symptoms when taken chronically, psilocybin does not show this observation. Prozac also causes sleeplessness and is commonly prescribed with benzodiazepines (sleeping pills) to reduce the effect of strange dreams and insomnia. The bombardment of different medications needed for a single disorder may be overcome by the prescription of psilocybin, improving the willingness of patients to accept treatment for the OCD condition.
Depression and Suicidality
A study published in 2015 by Hendricks et al.11 looked to investigate the potentiality of psychological distress and suicidality of users who had a historical use of psilocybin over their lifetime. The study collected data on the patient’s psychological distress over a period of one month. They also investigated the past-year suicidal thinking, suicidal planning and suicide attempts of a population of individuals with association to psilocybin. The data that was accrued came from the Nation Survey on Drug Use and Health between the years of 2008 and 2012. Of the 191,831-population tested, 7550 were categorised into psilocybin use only. Other categories included a control group with no psychedelic use in lifetime (164 595), psilocybin and other psychedelics (12,724) and non-psilocybin psychedelics (6963).11
In this study it was found that the psilocybin only group displayed lower results in suicidality, suicidal thinking and attempts than the control group. Furthermore, the psychological distress of the psilocybin only group was reduced in contrast to this very same control group. The psilocybin and other psychedelics group showed a slightly higher amount of suicidal thinking and planning in contrast to the psilocybin only group. This suggests that psilocybin may have more clinical potentiality in contrast to other psychedelics. In addition to this data, the psychological distress of the psilocybin-only patients was significantly lower than the non-psilocybin psychedelic group further fortifying the safety of the molecule. In relation to the article we can accept the idea that psilocybin may play an active role in reducing potential suicidal thought and depressive moods. However, it is not stated in the article whether these patients had prior mental health issues or depressive mental states. The large volume of such a study could potentially introduce limiting factors, such as varied states of mental health which were not considered by the parameters of the study. Ultimately, we can see that the effect of chronic use of such a drug in a large population yields limited variance in the mental health of a patient and does not produce any extreme cases of suicidal tendencies or depressive moods.
The primary research into psilocybin is flooded with studies used to treat anxiety symptoms. The most interesting of which is treating those with anxiety whom are afflicted with cancer. A study carried out over 6 months in 2010, published in 2011 by Grob et al.12 investigated the use of psilocybin in patients with advanced stages of cancer who suffered from anxiety induced by their state of health. The pilot study had a double-blind model and was controlled by placebos to ensure efficacy and to monitor the safety of psilocybin within the 12 patients. Each patient experienced extreme psychological distress onset by the existential crisis they were suffering from being at the end of their lives. The study took place in a clinical research unit of an academic medical centre in the US. The patients were all adults with severe anxiety onset by their aggravated cancer. The patients would be given a random dosage of either psilocybin at 200mg/kg or niacin 250mg as a control. This was chosen as control as the researchers were aware that niacin would produce the distinct warm flush effect that psilocybin would also produce, however the molecule is not psychologically active.
As the study progressed, it was documented that no unsafe physiological and psychological responses were present during the sessions. Psilocybin contributed no significant adverse effects to the patients. State-Trait Anxiety Inventory was used to quantify the level of anxiety each patient was experiencing. The results showed a significant decrease in the patient’s score of this index, 3 months after treatment. The Profile of Mood States also fortified these results by showing a general improvement of mood after the treatment with psilocybin. However, it must be said that the improvement of this index did not reach significance. Finally, the Beck depression inventory also identified a significant mood improvement after the final 6-month point of the study.
- T. Leary, G. H. Litwin, R. Metzner, Journal of Nervous and Mental Disease, 1963, 137 (6), p.561-573.
- D. Baumeister, G. Barnes, G. Giaroli, D. Tracey, They. Adv. Phsychopharmacol., 2014, 44, p.156-169.
- A. Hoffman, R. Heim, A. Brack, Helv Chim Acta, 1959, XLII, p.1557–1572.
- Hofmann, Albert, 1906-2008. LSD, My Problem Child : Reflections on Sacred Drugs, Mysticism, and Science. Mt. View, Calif. : Boulder, Colo. :Wiretap ; NetLibrary, 19901999.
- J. Daniel, M. Haberman, Ment. Health Clin., 2017, 7 (1), p.24-28.
- D. E. Nichols, J. Psychoactive Drugs, 2014, 46, p.20-26
- http://www.legislation.gov.uk/ukpga/2005/17/contents (Accessed on January 29th 2020, at 14:32)
- https://maps.org/research-archive/psilo/psilo_ib.pdf (Accessed on February 5th 2020, at 09:49)
- ISBN-13: 978-0023287640
- Johansen PØ, Krebs TS. Psychedelics not linked to mental health problems or suicidal behavior: a population study. J Psychopharmacol. 2015; 29 3: 270- 9
- J Clin Psychiatry. 2006 Nov;67(11):1735-40. Moreno FA, Wiegand CB, Taitano EK, Delgado PL.
- J Psychopharmacol. 2015 Sep;29(9):1041-3. Hendricks PS, Johnson MW, Griffiths RR.
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