For decades certain drugs, intially used solely by doctors and researchers, have been ostracized from the world of legitimate science. Considered illicit, with no medical value, many of these substances have been nigh on impossible for scientists to legitimately investigate, yet a handful of pioneering minds have been tirelessly working to bring these drugs back into the light. Dubbed a "psychedelic renaissance," these drugs are slowly returning to the hands of doctors and researchers and the scientific world is pressing play on an entire field of work that has been on pause for over three decades.

Psychedelic Medicine 101 is a series investigating the past, present and future medical uses of these formerly taboo substances.

Psilocybin and the magic of mushrooms

For thousands of years humans have experimented in one way or another with hallucinogenic mushrooms. One of the oldest documented human uses of hallucinogenic mushrooms has been suggested in 10,000 year-old rock art discovered in the Central Saharan desert. But some researchers believe our profound relationship with these psychedelic fungi could go back much further than that.

Famous ethnobotanist Terrence McKenna's influential, and controversial, "stoned ape" hypothesis of human evolution posited it was the addition of hallucinogenic mushrooms to our early ancestors diet as recently as 100,000 years ago that kickstarted our transformation from Homo erectus to Homo sapien.

McKenna suggested the ingestion of magic mushrooms acted as an "evolutionary catalyst," not only sparking the higher consciousness that led to language, art and religion, but also simply improving visual acuity, which delivered an evolutionary advantage to those mushroom-eating humans and helped them to become better hunters.

The birth of psilocybin

When legendary chemist Albert Hoffman isolated psilocybin as the primary psychoactive compound in magic mushrooms in the late 1950s it was quickly embraced by many researchers around the world. At the time LSD was already deeply entrenched in research circles, but this new discovery resulted in a whole new breed of converts.

Some of the earliest psilocybin research came from psychologist and soon-to-be psychedelic guru Timothy Leary, after he was turned on to the drug following a visit to Mexico in 1960. Upon returning to the United States Leary founded the Harvard Psilocybin Project, a series of controversial research experiments that ultimately played a significant role in Leary's dismissal from Harvard in 1963.

One of Leary's most fascinating early experiments was called the Concord Prison Experiment. The research set out to evaluate whether psilocybin-assisted group psychotherapy could reduce the rates of recidivism when administered to criminals during a stay in prison. Leary's initially reported results were promisingly positive, with a paper initially stating the recidivism rates of those treated with psilocybin were 50 percent less than the regular recidivism rate for inmates from the studied prison.

As the years passed though, the numbers got worse and worse with Leary continually tweaking his data and interpretations to maintain the experiment was a success. A long-term follow up on the study, conducted in the 1990s, found that ultimately the experiment had no discernible effect, with most subjects returning to prison at the same levels as any other general criminal.

Leary ultimately reminisced about the failed experiment quite frankly in his final years, suggesting that its key flaw was the lack of a comprehensive post-release program, following up with the prisoners as they worked to integrate their experiences upon release.

Of course, as Rick Doblin, researcher on the follow up study in the 1990s succinctly noted, "... it is likely that post-release programs would be of some benefit to all people released from prison, regardless of whether they had received psilocybin-assisted group psychotherapy, drug abuse counseling, vocational training, non-drug psychological treatment, any other program intended to reduce recidivism, or even no treatment at all."

The Good Friday Experiment

Perhaps the most influential, and intriguing, early psilocybin experiment occurred in 1962, again part of the Harvard Psilocybin Project. Walter Pahnke was a Harvard student, a physician and also a minister. Pahnke was fascinated by the idea that psilocybin could facilitate a "mystical" experience, so for his PhD he devised an experiment to test his hypothesis out.

In "The Good Friday Experiment" Pahnke boldly gathered together 20 volunteers and divided them into two groups, a psilocybin and a placebo group. The volunteers were all Christian theology students and the idea was to have them participate in a familiar religious ceremony to understand how psilocybin could potentiate a religious experience.

The experiment was conducted in Marsh Chapel at the University of Boston during a Good Friday sermon and the results, both immediately and at a six-month follow-up, were definitive. Across all self-reported markers the psilocybin group reported having a more significantly meaningful religious experience than the control group.

Researcher Rick Doblin conducted a long-term follow up to the study about 25 years later, re-evaluating Pahnke's experiment and re-interviewing as many of the subjects as he could track down. While Doblin concluded that Pahnke's study frustratingly contained several methodological flaws, including an incorrectly implemented double-blind procedure and problems with the self-reported questionnaire, the long-term effects on the participants seemed to be profound.

"The experimental subjects unanimously described their Good Friday psilocybin experience as having had elements of a genuinely mystical nature and characterized it as one of the highpoints of their spiritual life," writes Doblin in his follow-up study.

Many of the participants in the experiment went on to become religious ministers and none seemed to question the sincerity of their experience. This seemingly was not an artificial drug-induced sensation to be wary of, but for the participants it was a genuine mystical experience with long-lasting and meaningful ramifications to their lives.

"No known therapeutic benefit"

The story of the rest of the 1960s is a well-told one. As psychedelics slipped out of the research labs and therapy rooms youth culture became electrified and obsessed with hallucinogenic substances. Senator Thomas Dodd, an outspoken critic of the youth "drug" culture, had his sights onto the serious evils of narcotics since the late 1950s and took a major aim at curbing the use of this new psychedelic thread.

While a 1965 bill outlawed the possession of "hallucinogenic drugs," it wasn't until 1968 that psilocybin was officially relegated under federal law, and in 1970 it was finally tarred with the brand of Schedule 1. Schedule 1 was the mark for an illicit drug, with no known therapeutic benefit, and once scheduled it became virtually impossible for any legitimate scientist to work with.

For the next three decades research into psilocybin was paused and it remained taboo until a psychedelic resurgence in the 1990s brought it back into the public discourse. And in 1999 a team at Johns Hopkins University kicked off the first major psilocybin study in over 30 years with a landmark experiment that played like a 21st century spin on the Good Friday Experiment.

The science of mystical experiences

The groundbreaking study, undertaken by Roland Griffiths, was published in 2006 and titled Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. It examined the way psilocybin generates strong mystical experiences using an impressively rigorous methodology.

Unlike Pahnke's experiment, Griffith did not prime the experience by placing participants into a spiritually heightened environment. Instead, his experiment involved participants simply laying on a couch in a comfortable room. Encouraged to wear eye-shades, participants directed their experience inwards and then were evaluated afterwards using questionnaires and interviews.

Another fascinating aspect of Griffith's study was his incorporation of an "active placebo." As well as all participants reporting as "hallucinogen-naive," meaning they do not know what the effects of psilocybin should be, the control group was administered methylphenidate hydrochloride, or Ritalin. This meant that the control group would still feel some kind of physical experience allowing them to not simply sense nothing and immediately know they are on a placebo.

The results were remarkable. Over 60 percent of the psilocybin subjects fulfilled the study's criteria of meeting a "full mystical experience," while one third self-rated it as the most spiritually significant experience of their entire life, and two-thirds rated it among the five most meaningful experiences in their life. The longer term effects were compelling too. A two-month follow up found 79 percent reported increased well-being and life satisfaction compared to the rates of the placebo group.

"What's most interesting to us is that under the right conditions—when participants are prepared well and feeling safe—they often have experiences that map onto naturally occurring mystical-type experiences," explains Griffiths in Richard Miller's book, Psychedelic Medicine. "These are experiences that have been reported by mystics and religious figures throughout the ages and have been carefully described throughout the literature of the psychology of religion—very prominently represented by William James in the early 1900s."

The wave breaks

The first psilocybin study in a patient population began in 2001 and unexpectedly focused on obsessive-compulsive disorder. The hypothesis was that many effective pharmacologic treatments for OCD targeted similar receptors to that of psilocybin. A significant body of anecdotal reporting also suggested that hallucinogenic compounds provided beneficial reductions in subjects with OCD symptoms.

The study was small, composed of just nine subjects, and involved four sessions with different dosages separated by at least one week. The results were mildly positive with 66 percent of subjects maintaining up to a 50 percent decrease in measurable OCD symptoms for at least 24 hours following a treatment. Longer term results were not exceptional though, with only two subjects reporting significant symptomatic improvements lasting up to a week, and only one subject reporting total remission at a six month follow up.

The most promising area of study in this new wave of psilocybin research seemed to be centering around the drug being used to assist psychotherapy for a range of psychiatric disorders, including depression and anxiety. One of the most exciting areas of research appeared in treating cancer-related depression, and also in helping late-stage cancer patients deal with the stress and anxiety associated with their potentially fatal condition.

Several studies have now been completed on this topic and while all have comprised of reasonably small cohorts the results have been strong. One study, led by Roland Griffith and the Johns Hopkins team, studied 51 patients with life-threatening cancer over two psilocybin doses five weeks apart. The actual psilocybin sessions were supported by sitters but notably non-guided, while follow-up psychotherapy sessions focused on deconstructing and integrating the experience.

The results were pretty significant, with an overall rate of symptomatic remission sitting around 60 percent after six months. Self-rated responses were even stronger, with over 80 percent of participants suggesting moderately or higher increased well-being or life satisfaction. These numbers mirror similar results from several other studies suggesting one to two psilocybin doses can notably reduce depression and anxiety in 60 to 80 percent of subjects for up to six months.

Psychological surgery

Looking forward, research into psilocybin for a variety of beneficial uses is booming, as each subsequent published report chips away at the global taboo that once stifled investigations into this potentially valuable compound.

Continuing the tradition of investigating psilocybin-influenced religious experiences, two simultaneous trials are currently underway recruiting priests, rabbis and other religious leaders to better understand how the compound can integrate or alter the beliefs of someone in a powerful religious position. One of the studies is of course being run out of Johns Hopkins with Roland Griffiths at the fore, while the other is being managed by New York University School of Medicine.

Not everyone in the research community is supportive of this kind of new-school approach to 1960s-styled psychedelic research. Some suggest that neuroscience should be front and centre in all future work with this controversial psychedelic compound. Ben Sessa is a researcher working at Imperial College London, and has been a high-profile campaigner for psychedelic research for a number of years. Sessa's work incorporates psychedelic medicine into psychotherapeutic contexts, and he suggests the best way to legitimize and integrate these substances into mainstream medicine is to undertake more rigorous scientific studies.

"Are you going to focus on the tie-dye and the dreads … or are you going to look at the cutting-edge neuroscience here?" said Sessa in a 2017 interview with The Guardian. "I can't tell you how to do your job, but if I was you, I'd not look back to the past, I'd look to the future."

In the field of addiction, several compelling studies are underway examining how effective psilocybin could be as a treatment for common forms of addiction such as smoking or alcohol. An early, and albeit small, study into psilocybin as a smoking cessation tool found the treatment remarkably effective, displaying quitting rates significantly higher to that of any other traditional pharmacological or behavioral therapies.

And perhaps one of the most intriguing newer areas of research has been in psilocybin as treatment for the debilitating condition of cluster headaches. For many years anecdotal evidence has pointed to individuals using magic mushrooms as a home remedy for cluster headaches. The first serious published review into the phenomenon came in 2006, investigating 53 patients who used either psilocybin or LSD to treat the condition.

Since that review, a great deal of interest but very little serious investigatory science has circulated around this correlation. Now a team at Yale University is currently recruiting participants for a clinical trial to examine whether this compound could actually work as a serious cluster headache treatment.

The renaissance in psilocybin research is profoundly exciting, not just in how it potentially can offer new therapeutic treatments for a variety of conditions, but in how it may ultimately revolutionize how we think about medicine and drugs. The compound will never really be a traditional take-home drug, but rather it seems to offer a multitude of benefits when delivered in controlled contexts with targeted outcomes. Roland Griffiths describes it as akin to psychological surgery where we could go into a treatment center for a day or so and undergo a psilocybin "procedure."

"One analogy is the idea of going in for a surgery, except the potential risks and benefits with the psychedelic experience are psychological not physical. For a surgery, you might have a huge potential benefit, but certain risks may come up acutely during the surgery, and it's not something that you would want to necessarily undertake on your own."

Next up in Psychedelic Medicine 101, we take a look at the potential medical uses of ketamine. Stay tuned.

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