The Science of Psychedelics

Hallucinogenic cacti, plants and mushrooms have been used by various cultures in many parts of the world for thousands of years.  Olmec, Zapotec, Maya and Aztec used peyote, hallucinogenic mushrooms and the seeds of ololiuhqui, which contain mescaline, psilocybin and lysergic acid amide, respectively, to induce altered states of consciousness in healing rituals and religious ceremonies (https://doi.org/10.1016/j.nrleng.2011.07.010). Archaeological evidence of peyote use by Native Americans in Mexico dates back over 5,000 years. Prehistoric rock art in Spain and Algeria provides further clues that Psilocybe mushrooms were used and revered in religious rituals.  There was also widespread historical use of psychedelics as sacraments in a variety of other cultures (PMID: 26841800).  Some of these substances are still in use today for medicinal purposes in many indigenous communities.

In the early- to mid-20th century, classic serotonergic hallucinogens (psychedelics) became an exciting new area of study related to their potential therapeutic value.  

Early pioneers paved the way in identifying and synthesizing some of these compounds.  Mescaline was first isolated and identified in 1897 by the German chemist Arthur Heffter and first synthesized in 1918 by Ernst Späth.  Dr. Albert Hofmann discovered and synthesized lysergic acid diethylamide (LSD) while working at Sandoz.  In 1947, LSD was marketed under the trade name Delysid and made accessible to researchers interested in investigating its pharmacological properties. In 1957, Dr. Hofmann identified and synthesized psilocybin, which was then made available by Sandoz under the brand name Indocybin. During the 1950s and ‘60s, mescaline, psilocybin and LSD were largely investigated for treating depression and anxiety disorders.  In more than 1,000 scientific reports, authors described the results obtained from the treatment of tens of thousands of participants. However, after classic hallucinogens were classified as Schedule I substances under the UN Convention on Drugs in 1967 - with many countries further restricting or outlawing the use of these substances - all research and patient therapy with psychedelics came to a halt.  

Interestingly, there has been a resurgence of scientific interest involving psychedelics that has produced promising results in the treatment of addiction, depression, and other mood disorders.  A recent review of the literature provides encouraging results in the use of psilocybin in the treatment of addiction and substance abuse disorders, major depression, and end of life anxiety (PMID: 35273885).  There is also growing evidence to suggest that a single psychedelic experience can have a positive impact on overall long-term psychological well-being, further stirring interest in psychedelics among the general population.  According to a review of the more recent literature, there has also been a shift in emphasis from preclinical studies especially with LSD towards more clinical studies, involving psilocybin. In 2020 alone, 13 trials involving psilocybin were undertaken.

In its natural form, psilocybin cannot cross the blood-brain barrier, but its active metabolite, psilocin, can.  In humans, if taken on an empty stomach, psilocybin is rapidly converted to psilocin, which is detectable in the blood within 20–40 minutes.  In animal studies, after oral administration, 50% of psilocin is absorbed and almost evenly distributed throughout the body, including the brain, exhibiting a half-life of 2.5 hours. Human studies show psychoactivity lasts for 2–6 hours.  Maximum psilocin blood concentrations are reached within 80–100 minutes. 

Classic hallucinogens including psilocin produce their psychoactive effects through agonism (activation) of the serotonin 5-hydroxytryptamine receptors (5-HT), especially 5-HT2A, with particular importance on those receptors expressed on apical dendrites of neocortical pyramidal cells in the brain.  The underlying mechanisms of 5HT activation by psychedelics and their influence on neurological processes and human behavior are complex and outlined in more detail in a comprehensive pharmacological review of psychedelics (PMID: 26841800), as well as numerous other publications.  Briefly, 5HT receptor activation alters many signaling pathways including an upregulation of the glutamate receptors (mGluR2/3) and release of glutamate in the prefrontal cortex of the brain (PMID: 35273885). Researchers have found that upregulation of the mGluR2/3 pathway plays a critical role in mediating craving and addiction, as well as cognitive function.  A recent study found that alcoholics may have a deficiency in prefrontal mGluR2 and impaired executive control and alcohol craving. In alcohol-dependent rats treated with psilocybin, mGluR2 levels were restored, and there was a statistically significant reduction in relapse in these animals (PMID: 34788104).  The authors suggest that targeting the mGluR2 pathway may be a therapeutic strategy for treating reduced cognitive function, craving, and relapse responses in alcohol-dependent patients. 

There is growing evidence that psychedelics produce rapid and sustained anti-depressant and anti-anxiety effects. A single moderate dose of psilocybin to terminal cancer patients in conjunction with psychotherapy led to an immediate and lasting reduction in depression and anxiety (weeks to months) (PMID: 27909164). Long-term improved effects on depression, anxiety, and addictive symptoms in patients after one to two doses of LSD, ayahuasca, or psilocybin, have also been observed in other clinical studies (PMID: 33125716). Researchers believe the persisting nature of the psychological effects beyond the presence of the substance in the blood may be related to a biological adaptation including changes in neuroplasticity (PMID: 34566723). Neuroplasticity is the brain’s ability to reorganize itself throughout life by forming new neural connections.  It allows neurons in the brain to compensate for injury and disease and to adjust their activities in response to new situations or changes in their environment.  Neuroplasticity is regulated by various factors, brain-derived neurotrophic factor (BDNF) being a primary regulator.  Psilocybin activates G protein-coupled receptors through BDNF and enables downstream effects that enhance neuroplasticity and neurogenesis. This is supported by studies that show diminished levels of BDNF in individuals suffering from anxiety, depression, and addiction and that a single dose of psychedelics can increase those levels resulting in changed neuroplasticity. 

The emerging scientific and clinical literature on psychedelics such as psilocybin show promise in the treatment of depression, anxiety, addiction and other psychiatric disorders with reasonably safe side-effect profiles. However, when it comes to mind-altering medications, conducting thorough double-blind experiments presents many challenges. Psilocybin is still regarded as harmful by many people because of its complicated cultural and legal past, and its acceptance as a treatment will take some time. More clinical studies will be needed to test the efficacy of psychedelic-assisted therapies. If they are proven to be safe and effective after their study in more diverse patient populations, these new treatment strategies could have the potential to benefit millions of people worldwide.