Story at-a-glance

• In the largest controlled study of psilocybin to date, conducted at Kings College London, the "magic mushroom" substance was found safe for human consumption
• A "psychedelic renaissance" is occurring in which the medicinal properties of psilocybin, marijuana and ketamine are being explored
• Following the large psilocybin safety study, clinical studies will compare the mushroom-derived substance with conventional treatments, such as antidepressants
• Psilocybin may have usefulness in treating depression, post-traumatic stress disorder, obsessive compulsive disorder, eating disorders and anxiety
• The FDA has designated psilocybin treatment a "breakthrough therapy," which can fast track a drug's review and approval

There have been rapid changes when it comes to the embracing of psychedelic and hallucinogenic substances by mainstream medicine and municipalities. Marijuana, despite its longtime federal classification as a Schedule I drug, the FDA's most restricted class, is now legal in many U.S. states for medical purposes.1 States are also increasingly legalizing marijuana for recreational use, as Illinois did in 2020.2

Ketamine, a rapid acting anesthetic and established street drug sometimes called "Special K," was approved by the FDA for treating depression last year.3 And now there are signs that psilocybin, the ingredient in so-called "magic" mushrooms and also classified as a Schedule I drug,4 may soon be used medically for depression.

Psilocybin has already been decriminalized in Denver,5 Oakland6 and Chicago,7 perhaps paving the way for its consideration in medical uses. Now, in the largest controlled study of psilocybin to date, conducted at Kings College London, the "magic mushroom" substance was found safe for human consumption.8

The Largest Controlled Study of Psilocybin

In 2018, the FDA authorized Compass Pathways, a life sciences firm founded in London, England, to conduct initial clinical trials with psilocybin for possible use in treatment-resistant depression.9 The Phase I trials, as they are called, were designed to test the safety of Compass Pathways' psilocybin preparation, COMP360, not its effectiveness.10

Eighty-nine healthy volunteers who did not suffer from depression were given a 10- or 25-milligram (mg) dose of psilocybin or a placebo and followed up with therapy sessions to assess for adverse effects for up to 12 weeks.11

While some minor adverse effects of a psychedelic nature occurred,12 the effects resolved swiftly within hours,13 and the participants did not suffer residual cognitive or emotional effects or hallucinatory flashbacks in the weeks after taking psilocybin, said the researchers.14

The King's College London researchers and Compass Pathways representatives announced the results at the annual meeting of the American College of Neuropsychopharmacology in December 2019. The results establish the feasibility of using psilocybin to treat chronic depression, said the researchers.

The Next Step in Psilocybin Trials

Having established COMP360 to be well tolerated, Compass is now running a Phase II b clinical trial with 216 patients diagnosed with treatment-resistant depression to determine clinical efficacy of COMP360 and the correct therapeutic dose range.15

If the Phase II b clinical trial proves successful, Phase III studies will follow, which will compare the psilocybin preparation with conventional treatments, such as antidepressants.16

In 2018, the FDA designated Compass' psilocybin treatment as a "breakthrough therapy," a vote of confidence label that can fast track a drug's review and approval and usually means the drug is thought to have benefits over existing treatments.17 In January 2020, Compass announced that the U.S. Patent and Trademark Office had granted it a patent for its synthesized investigational psilocybin formulation.18

"Too many people are suffering with treatment resistant depression," said CEO and co-founder of Compass George Goldsmith.19 "We are committed to developing innovations, such as psilocybin therapy, to address this rapidly growing problem."

More Psilocybin Clinical Trials Are in Progress

The Compass trials are not the only studies to look at the possible effects of psilocybin on human conditions. A Phase II clinical trial with 80 participants at seven different U.S. sites is also planned by the Usona Institute, a Madison, Wisconsin-based nonprofit medical research organization.20

The group says it is "dedicated to supporting and conducting preclinical and clinical research to further the understanding of the therapeutic effects of psilocybin and other consciousness-expanding medicines."21

Like the drug used in the Compass trials, the Usona psilocybin compound has been granted "breakthrough therapy" status by the FDA.22 Unlike the Compass trials, however, which address treatment-resistant depression, the Usona trial will examine psilocybin's use in major depressive disorder (MDD).23

Usona's director of clinical and translational research Charles Raison said that MDD represents a much larger group of sufferers with an "unmet medical need" and that "psilocybin may offer a substantial clinical improvement over existing therapies."

While it is certainly true that many people suffer from sad and depressed moods, antidepressants including selective serotonin reuptake inhibitors (SSRIs) like Prozac and antipsychotics like Seroquel are not always the best option. Simple, healthy lifestyle practices can often lift depression.

Antidepressant drugs may not work at all and can cause serious and paradoxical side effects. If a natural substance such as psilocybin could help people avoid these strong psychiatric drugs, it is certainly a good a thing. Here is how the British paper, Independent, casts the issue:24

"UK is undergoing a burgeoning mental health crisis, which has created an urgent unmet need for the development of new treatments. Prescriptions for antidepressants more than doubled between 2006-2016 … and distressingly, suicide is now the leading cause of death among the young (with psychedelic usage linked to lower suicide risk).

Psilocybin-assisted psychotherapy can provide … a new approach to treating mental illness. Rather than putting the patient on a daily drip of SSRIs, which like a plaster hopefully suppresses the symptoms but leaves the root-causes unaddressed, psychedelics can increase neuroplasticity and reset the brain, so that maladaptive thought … patterns can be unlearned."

A Psilocybin Clinical Trial at a Psychedelic Research Center

Before the Compass trial, there have been several studies that support psilocybin benefits, some at Imperial College London, which launched the first formal center for psychedelic research in the world — the Imperial Centre for Psychedelic Research — in 2019.25

Imperial was the first research center to investigate the effects of psilocybin on severe depression and, using modern brain imaging, the effects of LSD on the brain.26

In a psilocybin study led by Dr. Robin Carhart-Harris, head of psychedelic research at Imperial, 20 participants who were suffering from severe depression were treated with the compound. After three months, they experienced greater antidepressant effects than from typical antidepressants and therapy, said reports.27,28

"Patients said they went from feeling 'totally disconnected' with themselves and the world to 'connected', and from repressing and avoiding emotions and memories to accepting them."29

The new connectedness sensations are thought to come from deactivation of the default mode network (DMN) of the brain that is active when not focused on the outside world. Here is how Carhart-Harris' study, published in Scientific Reports, explains the DMN phenomenon apparently induced by psilocybin:30

"Much recent research has focused on the involvement of the default-mode network in psychiatric disorders, and particularly depression. We previously observed decreased DMN functional integrity under psilocybin and LSD, and others have with ayahuasca.

Here however, increased DMN integrity was observed one-day post treatment with psilocybin, both via seed and network-based approaches. Previous work has suggested that increased DMN integrity may be a marker of depressed mood and specifically, depressive rumination.

On this basis, increased DMN integrity post psilocybin may be surprising. The post-treatment increases in within-DMN RSFC and sgACC-PCC RSFC did not relate to symptom improvements but vmPFC-ilPC RSFC did. This apparent divergence from previous findings is intriguing, and deserves further discussion."

Putting the research in laypeople's terms, Carhart-Harris says, "If you ask people who are taking SSRIs chronically, they often say 'I feel blunted.' With psilocybin therapy they say the opposite, they talk about an emotional release, a reconnection, and this key emotional center being more responsive."31

More Theories About Psilocybin Effects

The actions behind the apparent benefits of psilocybin may involve the same neurotransmitters that traditional SSRIs are said to affect, but possibly in different ways. Says Newsweek:32

"Psilocybin is known to bind to a receptor normally used by serotonin, one of the brain's most important neurotransmitters, which is involved in everything from mood to perception to sleep.

MRI studies done at Imperial College London show that this activity changes the activity of neurons throughout the brain, allowing different regions to communicate that aren't usually connected. This is thought to help facilitate breakthroughs that people report while under its spell."

Research published in Biological Psychiatry further analyzes the apparent ability of psilocybin to dramatically change behavior:33

"Psilocybin reduced associative, but concurrently increased sensory brain-wide connectivity. This pattern emerged over time from administration to peak-effects. Furthermore, we show that baseline connectivity is associated with the extent of Psilocybin-induced changes in functional connectivity …

These results suggest that the integration of functional connectivity in sensory and the disintegration in associative regions may underlie the psychedelic state and pinpoint the critical role of the serotonin 2A and 1A receptor systems.

Furthermore, baseline connectivity may represent a predictive marker of the magnitude of changes induced by psilocybin and may therefore contribute to a personalized medicine approach within the potential framework of psychedelic treatment."

More Encouraging Psilocybin Studies

Smaller studies than the large Compass study have also yielded encouraging results. A 2006 study at the University of Arizona found that psilocybin helped temporarily reduce symptoms of obsessive-compulsive disorder in nine subjects.34

A 2016 study by New York University and Johns Hopkins University researchers published in the Journal of Psychopharmacology found a single dose of psilocybin decreased symptoms of anxiety in cancer patients for eight months when compared to a placebo.35 Testing psilocybin on those with eating disorders is also being planned at London's Imperial College.36

A kind of "psychedelic renaissance"37 is occurring in which hallucinogenic compounds like psilocybin are viewed as potential therapeutic agents to treat serious mental illnesses like post-traumatic stress disorder, obsessive compulsive disorder and eating disorders as well as depression and anxiety.

Hopefully, psilocybin will continue to prove its safety and become more widely accepted and available for relieving the symptoms with which many suffer and freeing them from harsh medications.