Clinical potential of psilocybine as a treatment for mental health conditions
Jeremy Daniel & Margaret Haberman
Mental Health Clinician, 2017, Vol. 7, No. 1, pp. 24-28
Psilocybin was first isolated by Albert Hofmann in 1957 from the Central American mushroom Psilocybe mexicana. The first synthetic psilocybin product was created shortly thereafter in 1958 and continues to be widely used today, both recreationally and in spiritual or religious rituals.1 It has since been found in more than 100 mushroom species worldwide with varying potency. These mushrooms are both cultivated and found in the wild. Cultivated mushrooms tend to be more potent through selection of stronger mushroom strains with more active ingredient (up to 10 times that of some wild mushroom species).2
Psilocybin, a classic tryptamine hallucinogen, has similar properties to lysergic acid diethylamide (LSD) and mescaline with a slightly different chemical structure. Cross-tolerance between the different hallucinogens has been demonstrated, and research shows a common mechanism of action through serotonergic (5-HT) pathways. Psilocybin is a strong agonist at 5-HT2A as well as a moderate agonist at 5-HT1A and 5-HT2C.3 5-HT2A receptors are located within the thalamus and cortex of the brain. Activation of 5-HT2A receptors in the thalamus, the area of the brain responsible for sensory input, appears to decrease thalamic activity, thus leading to sensory alterations commonly referred to as hallucinations.4,5 Hallucinogenic effects typically onset within the first 20 to 40 minutes of use then disappear within 3 to 6 hours. Psilocybin’s threshold for intoxication is approximately 40 mcg/kg of body weight. There is a low percentage of psilocybin in most mushroom varieties, so this corresponds to approximately 1 to 2 g of dried mushrooms.2,6 Due to this alteration in sensory perception and serotonergic activity of the substance, much of the research for this agent has been focused on those mental health conditions with abnormalities in sensory perception, such as depressive disorders and anxiety or anxiety-related disorders. Psilocybin has also been researched for use in substance use disorders.
Since the Controlled Substance Act (CSA) of 1970, clinical studies using hallucinogens and psychedelics essentially ceased. Much of the research completed on these agents in the 1950s and 1960s was not taken seriously due to the small nature of the studies or methodology inconsistent with current research standards. However, interest in understanding the neuropsychiatric effects of these agents and their potential role in medical therapy persisted. Because of the CSA Schedule I status of these agents, clinical research in humans seemed unlikely and locating funding sources virtually impossible. In 1992, the National Institute on Drug Abuse worked with a Food and Drug Administration advisory committee that ultimately allowed for the resumption of research of psychedelic agents.7
The Heffter Research Institute, founded in 1993 by Nichols and colleagues, is the only institute solely dedicated to clinical research of the medicinal value of psychedelic agents. They ultimately have focused their research on psilocybin, the active ingredient in magic mushrooms or ‘shrooms.7 As the search for novel treatments for mental illness grows, new energy is being focused on older treatments, such as ketamine, and more Schedule I substances, such as marijuana, LSD, and psilocybin. This article will explore the literature behind psilocybin and the potential for the agent as a treatment for select mental health conditions. However, due to the CSA Schedule I nature of the substance, safety should first be reviewed.
In 2011, Studerus et al8 compiled data from 8 different studies involving psilocybin administration from 1999 to 2008. This pooled analysis consisted of 110 healthy human subjects who received 1 to 4 different oral doses of psilocybin for a total of 227 psilocybin administrations. The doses used throughout the studies ranged from 45 mcg/kg to 315 mcg/kg. All subjects underwent extensive screening prior to entering the studies and were excluded if they had any active Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) diagnosis or emotional liability.8,9 All of the studies used the Altered States of Consciousness Rating Scale, which is a visual self-rating scale. Short- and long-term safety was evaluated, and there was no indication of increased drug abuse, persisting perception disorders, prolonged psychosis, or other long-term deficits in functioning. The number of adverse reactions from psilocybin was few in number, resolved quickly, and was mostly associated with the highest doses of psilocybin. The subjects were followed for 8 to 16 months post psilocybin administration and exhibited no long-term negative side effects.8 The safety demonstrated in this study opened the door for more research on psilocybin. It should be noted, however, that the administration of psilocybin in these studies followed strict protocols and therefore may lack external validity to the general population.
There has been some concern that use of psychedelic agents in a mental health population could exacerbate the underlying disease or cause suicidal behavior despite little clinical data showing significant safety issues or development of addiction with the administration of hallucinogens. Johansen and Krebs10 set out to examine this claim and published a population study detailing their findings. This population study of 135 095 random adults in the United States included 19 299 psychedelic users (which included LSD, mescaline, and psilocybin). No significant association was found between lifetime use of psychedelics and increased mental health treatment or suicidal thoughts, plans, or attempts.10
Additionally, a review of psilocybin use in the Netherlands demonstrated similar findings. Per the authors’ conclusions, dependence potential was low, acute toxicity was moderate (few mild or severe adverse reactions), chronic toxicity was low, and public health risks were negligible.11 In contrast to this conclusion, 1 article describes severe adverse effects of high doses (approximately 420 mcg/kg), including a high incidence of significant fear and transient ideas of reference/paranoia (31% and 17%, respectively) in healthy volunteers.12 Per the Netherlands article, the average lethal dose (LD50) in rats was 280 000 mcg/kg, equating to approximately 17 kg of mushrooms ingested. The article details only 4 case reports directly attributing death to psilocybin use over a 41-year period. Many other fatal case reports mentioned in the article were in combination with other drugs of abuse (alcohol, heroin, and cannabis).11 It appears that low-to-moderate doses of psilocybin are fairly well tolerated although it should be noted that the number of articles describing psilocybin use is small, and there have been fatalities reported. However, compared to other common drugs of abuse, such as heroin, the death risk appears to be much smaller.