Let’s take a closer look at psilocybin

“Magic mushrooms” have officially entered the mainstream. Proponents in the media now regularly extol their potential for alleviating depression, addiction, and a host of other mental health issues, often linking their ongoing prohibition to a government PR blitz in the 60s and 70s. Today, psilocybin is the most commonly used psychedelic among people 34 and younger.

But hallucinogenic plants have been part of the human experience for thousands of years, with users aware of their potential for healing, transformation, and growth – as well as their dangers – since as far back as prehistory. Now that public attention has been captured by these extraordinary plants, it’s more important than ever to understand the history, pharmacology, and therapeutic potential of psilocybin and other psychedelics.

History

There are more than 100 species of psilocybin mushrooms worldwide, with samples found everywhere from Latin and North America to Europe and Asia. Given this geographic distribution, it’s unsurprising that various cultures throughout history have incorporated their use into ceremonial and religious practices.

For instance, the Aztecs reportedly served a Psilocybe species known as teōnanācatl – the “divine mushroom” – at the coronation of Emperor Motecuhzoma Xocoyotzin. In Spain, artwork depicting Psilocybe hispanica has led researchers to hypothesize that the ritual use of magic mushrooms may have begun in Europe as early as 4000BC. Some, like Terrence McKenna, have gone as far as to propound the Stoned Ape Hypothesis, which asserts that our long-term use of psilocybin mushrooms in prehistoric times led to epigenetic changes that were responsible for rapid increases in intelligence. While most academics are sceptical of such claims, there’s little doubt that psilocybin mushrooms have an extensive history of influencing human behaviour.

Although Albert Hoffman – the discoverer of LSD – identified the active ingredients in psilocybe mushrooms as psilocybin and its dephosphorylated counterpart psilocin in 1957, the modern psychedelic mushroom movement in the west began in earnest when Gordon Wasson’s essay, Seeking the Magic Mushroom, was published by Time magazine. Introduced to psilocybin by Maria Sabina of the Mazatec Indian tribe in Oaxaca, Mexico (both she and her tribe would come to regret this), Wasson recounted his experiences exuberantly, writing, “[t]here I was, poised in space, a disembodied eye, invisible, incorporeal, seeing but not seen.” Shortly thereafter, westerners began to flock to Sierra Mazateca, driven in equal parts by Wasson’s account and burgeoning countercultures centred around psychedelics.

Among those intrigued by Wasson’s account were Timothy Leary and Richard Alpert, who pursued their own psilocybin experiences in Oaxaca, before going on to establish the now infamous Harvard Psilocybin Project. Upon their firing, Leary and Alpert would spearhead psychedelic counterculture, with the pair – and others – eventually forming a communal group based at the Hitchcock Estate that continued to study psychedelics and publish their findings in the Psychedelic Review.

After becoming an essential part of the US countercultural movement in the 60s, public opinion on psilocybin and other psychedelics began to shift by the middle of the decade – in  no small part due to a PR campaign by the US Government – culminating in their prohibition. The golden age of psychedelic research (1950-1965), wherein more than a thousand scientific papers were published, had come to an end.

Upon psilocybin’s reclassification as a Schedule I substance in the 70s, research largely ground to a halt until after the turn of the century, when researchers at the University of Arizona discovered that psilocybin was associated with acute reductions in OCD symptoms. Since then, research has picked up pace, with UCLA, Johns Hopkins University, New York University, and Imperial College leading the way. Moreover, in 2018, COMPASS Pathways secured breakthrough therapy designation from the FDA for psilocybin for treatment resistant depression. 

Pharmacology and Toxicity

Upon ingestion, psilocybin is rapidly converted to psilocin by the liver. Psilocin then acts as a partial agonist for some types of 5-hydroxytryptamine receptors (serotonin receptors), which leads to the profound mood and perceptual changes reported by users. The psychomimetic effects of psilocin can be aborted with 5-HT2A antagonists (e.g. trazadone).

Additionally, psilocin indirectly raises the concentration of dopamine – a neurotransmitter linked to arousal and reward – in the basal ganglia, and since dopamine antagonists like haloperidol seem to block some subjective effects of psilocin, it is assumed that there is a dopaminergic component to the experience. Overall, psilocybin is approximately 100 times less potent than lysergic acid diethylamide (LSD), and its effects persist about half as long.

Although Psilocybin is generally well tolerated by healthy individuals, with hormone levels, liver function, and blood sugar typically remaining constant throughout an experience (one study found these levels to be constant for up to 21 days of consecutive use at increasing doses), there is evidence that those with a predisposition towards psychotic disorders are at risk of developing overt symptoms or dangerous behaviour (though psychotic disorders are not caused by psychedelics use).

Physical effects on the body include pupil dilation, changes in heart rate and blood pressure, changes in stretch reflex, nausea, tremor, and dysmetria. Overall, although psilocybin’s toxicity is very low (in intravenous administration of psilocybin the LD50 for rabbits was found to be 12.5mg/kg), those with cardiovascular issues like untreated hypertension should abstain from using psilocybin. Moreover, “bad trips” are relatively rare, and seem to arise at high doses and in uncontrolled environments for those who are already vulnerable.

Finally, abuse potential for psilocybin has been established to be low. A 2018 study by Matthew Johnson, PhD– assistant director at the newly opened psychedelic research center at Johns Hopkins – concluded that not only does psilocybin have therapeutic potential for various psychiatric maladies, compared with prototypical drugs of abuse, psilocybin poses little danger, especially when administered according to risk management procedures.

Therapeutic Potential

In any given year, more than 45mn Americans suffer from some form of mental illness, with about a fourth experiencing symptoms that are severe enough to interfere with daily functioning. Worldwide, the numbers are even more jarring.

The World Health Organization estimates that one in four people will be affected by mental illness at some point in their lives, with about 450mn currently living with such a condition. And although diseases like bipolar disorder and schizophrenia receive the lion’s share of attention, depressive disorders account for the vast majority of mental illness. With some 350mn people living with depression, of whom more than a third do not respond to available treatments, depression is the leading cause of disability worldwide. It is also one of the costliest: in 2013 alone, depression cost the global market $1tn in lost productivity, with an additional $71 billion spent on treatment. This is to say nothing of the personal toll depression can take.

In light of this immense unmet need, it’s perhaps unsurprising that psychedelics – and psilocybin in particular – have been viewed as a potential lifeline for hundreds of millions.

Since the 1960s, clinical trials have suggested that psilocybin might be efficacious in treating a bevy of conditions, but conclusive data on therapeutic applications are still being gathered. Non-exhaustively, psilocybin is purported be helpful in treating:

  • Depressive disorders (including treatment resistant depression)
  • Anxiety disorders
  • Substance abuse disorders
  • Anorexia
  • Obesity
  • Cluster headaches
  • Personality disorder

In 2011, Roland Griffiths and colleagues published a study suggesting that – in addition to promoting increases in aesthetic appreciation, creativity, and imagination in users – a single high-dose of psilocybin may result in durable personality changes, with approximately half of healthy participants recording increases in openness (as measured by the NEO Personality Inventory). A 2017 follow up study found that doses of 20-30mg per 70kg elicited mystical type experiences that brought about lasting changes in altruism, gratitude, and connection to others when combined with spiritual practices like regular meditation.

In 2016, researchers at imperial College London found that psilocybin coupled with psychological support seemed to “markedly reduce” depressive symptoms in twelve patients with unipolar treatment-resistant depression. Participants reported improvements in anxiety symptoms as well as their ability to take pleasure in their lives. Notably, while the effects of psilocybin last anywhere between two and six hours, the antidepressant effects appeared to persist at six months, with those who underwent the experience commonly reporting it as among the most meaningful in their lives.

The reasons for this effectiveness are still being investigated but may have to do with altered default mode network (DMN) activity. Neuroscientist David Nutt, who conducted an earlier study on the neural correlates of psychedelic states, found that psilocybin seemed to downregulate chatter between areas of the brain associated with sense of self. In an interview with Psychology today, Nutt commented that the brains of people who get into depressive thinking are overconnected in this area – leading to overwhelming self-negativity – and that loosening them could be the key to providing relief.

This interpretation seems to comport with the findings of a follow up to the 2016 Imperial College research. The study, wherein researchers used fMRIs to observe patients before and after their psilocybin experiences, found decreased cerebral blood flow in the amygdala, as well as changes in resting state functional connectivity within the DMN. Researchers proposed that the DMN – the overactivity of which has been linked to everything from depression to obsessive compulsive disorder – was being “reset” by psilocybin.

Regardless of the exact mechanism, interest in psilocybin and other psychedelics has now exploded, with researchers exploring effectiveness for everything from anorexia nervosa, nicotine and alcohol addiction, and even obesity. For instance, at the recently founded Johns Hopkins Center for Psychedelics and Consciousness Research, investigators have launched a novel human trial to determine whether two moderate to high doses of psilocybin can alleviate symptoms of anorexia nervosa when combined with motivational interview-based therapy. Moreover, studies examining the potential of psilocybin for smoking cessation and alcohol use disorder have been encouraging, with additional studies currently recruiting participants.

What’s next?

Despite positive early signals, data from large scale studies remains limited. Until organizations like COMPASS Pathways and others conclude Phase II and III clinical trials and secure FDA-approval, patient access will remain limited and confined to underground treatments or psychedelic retreats (both of which carry significant risks).

Moreover, as ATAI Chief Scientific Officer Srinivas Rao recently explained, the complex treatment protocols proposed for psilocybin therapy – which often involve supervised administration over several hours along with concurrent psychotherapy –might result in costs that exceed even those of ketamine treatments. To avoid passing this burden on to patients, demonstrating the long-term cost effectiveness of psilocybin therapy to insurers will be critical to broad access.

Despite the challenges that remain, there are clearly ample reasons to be optimistic. With the increased attention on psilocybin and other psychedelics, as well as a growing awareness that current interventions are not working, momentum has shifted in favour of these revolutionary substances. The trick will be to resist the urge to declare psilocybin a panacea, and ensure that we continue to prioritize patient safety, high-quality data collection, and engaging everyone in the healthcare continuum.

“This isn’t a place to be fast and loose,” said George Goldsmith, Co-Founder of COMPASS Pathways, in a recent interview with The Telegraph. “It’s a place to do the highest quality science at the biggest and best scale you can. But we need to get it absolutely right. Psychedelic research was out in the cold for 50 years. If we get it wrong, are we going to wait for another 50?”

Given the scale and urgency of the mental health epidemic, we’d say the answer must be no.