Phase III clinical trials are beginning to roll out for psychedelic medications like like psilocybin and MDMA – also known as magic mushrooms and ecstasy. But this is not the first time these drugs have been used to treat mental illness, and today we take a dive into the clinical reports on psilocybin from half a century ago.

Published On: 9/13/2021

Duration: 24 minutes, 52 seconds

Related Article: "Psilocybin vs Escitalopram for Depression," The Carlat Psychiatry Report, September 2021

Transcript:

Phase III clinical trials are beginning to roll out for psychedelic medications like like psilocybin and MDMA – also known as magic mushrooms and ecstasy. But this is not the first time these drugs have been used to treat mental illness, and today we take a dive into the clinical reports on psilocybin from half a century ago. 

Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief of the Carlat Report. And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.

Kellie Newsome: This month, we reported on a phase III randomized controlled trial of a new antidepressant that was published in the New England Journal of Medicine. There are thousands of clinical trials of antidepressants, many with much better designs than this one, so how did this one make it into the coveted pages of the New England Journal? This wasn’t just any antidepressant. It was psilocybin – better known as magic mushrooms – and it is part of a movement that hopes to harness the power of psychedelic drugs to treat psychiatric disorders. 

At the leading edge of that movement are psilocybin – aka magic mushrooms – which is seeking FDA approval for depression, and MDMA – aka ecstasy – which seeks the same for PTSD. But it’s not just the drug that’s on the FDA’s table. Both of these psychedelics are meant to be used as part of a psychotherapeutic experience that helps the patient learn from the unique experiences they create. 

If we look at this movement in the context of recent years, it’s a radical shift. But when we step back and take in a broader scope of human history, psilocybin and its psychedelic brethren are really nothing new. They’ve been used to augment healing rituals since the dawn of time. Today, we’ll put aside the New England Journal and take a trip to the Sahara desert, where early cave paintings tell the tale of psilocybin’s first clinical trials.

Beginnings

Dr. Aiken: Psilocybin is a natural extract of the mushroom, and it’s produced by about 200 species of mushroom from the genus Psilocybe, which first appeared on earth about 20 million years ago. Although mammals roamed the earth and sea in those days, we don’t know if any of them used this drug. Homo sapiens didn’t show up until about 10 million years later, and it probably didn’t take long for them to realize the mushroom’s potential. 

In the African Sahara desert we find cave paintings depicting rituals with a mushroom plant. A series of masked figures dance around lively geometric designs, each dancer holding a mushroom like object in their right hand. Parallel lines spring from the mushroom’s center and extend to the head of the dancer. Artifacts from the Egypt and Spain point to similar mushroom ceremonies, but it was in South America that psilocybin really took off, and it was there that Western Europeans first encountered psilocybin. 

In 1529 a Franciscan monk named Bernardino de Sahagún went on a cultural expedition of Mexico, documenting everything from the flora and fauna to the customs of the indigenous people. Buried in his 2000 page manuscript is a reference to a ceremonial mushroom called “God’s flesh” that the Mexicans used to induced mystical experiences. The existence of mushroom remained elusive for the next 450 years, when an American couple rediscovered it on an anthropologic voyage to Mexico in the 1950’s. The wife, Valentina Wasson, was a physician, and her husband, Gordon Wasson was the vice president of JP Morgan bank. After ingesting the psilocybin mushroom they had visions of “mountains” and “rivers” that left them “awestruck.”

The Wasson’s discovery attracted international attention – including a feature article in Life Magazine - but inspired little controversy. Back then hallucinogenic drugs were were largely unknown, and largely free of stigma. One of them – LSD – was already being used by prominent psychoanalysts to to speed up the analysis. This was a time when insight – not symptom reduction - was considered the true goal of psychiatric treatment. To give you a feel for that we’ll read from a 1960 article on LSD assisted psychotherapy from the Archives of General Psychiatry (known today as JAMA Psych) by Drs. Chandler and Hartman:

Kellie Newsome: “Our use of drug-facilitated psychotherapy has been to aid repressed material to become conscious and to increase insight. Any method or tool which facilitates these processes has the possibility of being a valuable psychotherapeutic tool. Certain drugs on which we have done research… have the capacity to broaden the patient's spectrum of awareness. If a patient uses this enhanced capacity to look inward, he is often enabled, particularly in the case of LSD, to see and experience many affects, childhood memories, conflicts, and impulse strivings which were previously blotted out by the repressive forces.”

LSD

Kellie Newsome: LSD has similar properties to psilocybin and was the first psychedelic to enter psychiatric practice. The Swiss chemist Albert Hoffman accidentally discovered this potent psychedelic in 1943 when he inadvertently ingested a trace amount of LSD while trying to create a cardiac medicine. He developed vivid illusions which most scientists would consider an unwanted side effect, but as we’ve said, these were different times. Dr. Hoffman worked for Sandoz – now called Novartis – and the company marketed LSD to psychiatrists under the brand Delysid. 

The package insert for Delysid tells the doctor exactly how to use it:

INDICATIONS AND DOSAGE

1) Analytical psychotherapy, to elicit release of repressed material and provide mental relaxation, particularly in anxiety states and obsessional neuroses. The individual treatments are best given at intervals of one week.

2) Experimental studies on the nature of psychoses: By taking Delysid himself the psychiatrist is able to gain an insight into the world of ideas and sensations of mental patients. 

This may be the only drug with an FDA indication to induce temporary mental illness in the psychiatrist.

Dr. Aiken: LSD became a popular treatment for alcoholism and neurosis, with reports of a single dose – given alongside psychotherapy – resulting in sustained cures for 50-80% of cases. None of these studies were controlled. Around 40,000 patients took LSD in the 1950’s and 1960’s, but it had one drawback. 

Kellie Newsome: Yea, I mean this drug can make people psychotic.

Dr. Aiken: Yes, but that was seen as part of the cure. Oddly, the main drawback to LSD was that it made patients anxious. Scientists were scurrying to find alternatives to it, like mescaline and ibogaine. So when Dr. Hoffman read about the Wasson’s discovery of psilocybin in Life Magazine in 1957 he went to work to synthesize the drug for a patentable, pharmaceutical use. Three years later, Sandoz released psilocybin in 1960, branded as Indocybin, with directions to use it that pretty much mimicked their directions for LSD. Here’s how Sandoz announced their discovery to the word:

Kellie Newsome: “The well-known mycologist, Roger Heim, entrusted our laboratories with the chemical investigations of [the Psilocybe mushroom, which the Mexican Indians use for use for magic purposes]. In a relatively short time our chemists isolated the active principles, obtained them in crystalline form and elucidated their chemical structure…

The mental effects of these pure substances, which were ascertained in volunteers, were identical with those of the mushrooms. Psilocybin …not only [has] certain chemical features in common with Delysid [LSD] but [is] also structurally related to serotonin, a finding that is of biochemical interest. [Its] effects on human beings are… are valuable tools in experimental psychiatry, and have also proved useful as drug adjuvants in psychotherapy, and more especially, in psychoanalysis.”

Dr. Aiken: “Proved useful” had a looser meaning back then, as the FDA did not require controlled trials to prove their efficacy until 1962, two years after psilocybin was released. They did require proof of safety, which Sandoz supplied through their experiements on normal volunteers. 

It’s only recently that we have controlled investigations of psilocybin, but there were a handful of open-label studies from the early days. Here is a NIMH report by Dr. Harris Isbell from 1959. 

Kellie Newsome: One hour after the drug [was ingested]… Anxiety became more marked and, in some cases was intense. Elation, when present, was great and in some patients was expressed by almost continuous gales of laughter. Alterations in practically all sensory modalities were mentioned… with hallucinations of colored lights which flickered and coalesced to form patterns varying in a kaleidoscopic fashion.

The patients reported increased difficulty in thinking, difficulty in concentration, and in carrying out simple arithmetical calculations or reading. They reported a "rush of thoughts", with one thought replacing another before the first was completed. A feeling of alteration in the individua'ls own body occurred consistently and varied from simple feeling of being light or heavy to marked alterations in size, shape or color. Some patients felt they had become very large, or had shrunk to the size of children. Their hands or feet did not seem to be their own, and sometimes took on the appearance of animal paws.

At times, patients had the sensation that they could see the blood and bones in their own body or in that of another person. They reported many fantasies or dream-like states in which they seemed to be elsewhere. Fantastic experiences, such as trips to the moon or living in gorgeous castles, were occasionally reported. Despite these striking subjective experiences, the patients remained oriented in time, place and person. In most instances the patients did not lose their insight, but realized that the effects were due to the drug. Two of the 9 patients, however, did lose insight and felt that their experiences were caused by the experimenters controlling their minds. [The reaction peaked] 1 and a half hours after the drug was given and remained intense for two to three hours. It subsided almost completely five to six hours after the drug was given.”

 A year later the New England Journal of Medicine published a small case series of 8 normal subjects who took psilocybin, concluding that psilocybin appeared therapeutic in neurotic disorders, but it was too early to draw definite conclusions about that. But it’s in this report that we find a side effect that raises concern about today’s use of psilocybin. The experiments did not produce true hallucinations in normal subjects – only benign illusions – but they did produce problematic hallucinations in one patient who was treated in France, and this patient had melancholic depression. After taking psilocybin, she saw herself surrounded by “terrifying figures.” 

Kellie Newsome: Still, those early reports were not alarmed by this reaction. Many of our psychotropics that we use every day can cause such terrifying reactions. Stimulants can induce psychosis, and antidepressants can trigger mania. So what actually brought these explorations into psychedelics to a hault? Was there a landmark study that revealed them to be dangerous or ineffective? Nope. To understand their downfall, we have to turn to a small group of psychologists at Harvard who started to believe that psilocybin could do more than reduce human suffering. They believed it could prevent crime, create world peace and overturn the power structures that have ruled the world since the days of ancient Greece, when the conquering Athenians declared that “might makes right…the strong do what they can and the weak suffer what they must." 

Timothy Leary

Dr. Aiken: On the surface, things looked pretty good for psychologist Timothy Leary in 1959. He had just accepted a teaching post at Harvard University, and his new textbook, The Interpersonal Diagnosis of Personality was lauded as "most important book on psychotherapy of the year." But on the inside, he was anything but sure. His wife had died by suicide 4 years earlier, leaving Dr. Leary raise their son and daughter alone. He struggled with alcoholism, and felt like an institutional robot at work. 

That’s when Dr. Leary read about the Wasson’s mystical adventures with Mexican psilocybin. In a last chance move, he boarded a flight to Mexico and retraced the Wasson’s step to try the drug himself. The experience, he said, was “‘above all and without question the deepest religious experience of my life.” The year was 1960, and Sandoz had just released a synthetic version of the mushroom, so Leary ordered samples of the drug to use in psychological studies. 

When researchers at the NIMH heard about this they contacted Leary with a warning. They too had looked into psilocybin (we quoted one of their papers earlier), but things went awry at the NIMH when the investigators started taking the drug themselves. 

Dr. Leary partnered with another Harvard psychologist - Richard Alpert – and the two set out to study psilocybin and other psychedelics. At first, their research was well funded and highly respected. They tested psilocybin in healthy volunteers. Then in divinity students to see how it altered their religious experiences during good Friday service (that study included a placebo control). Then in prisoners to test if the drug could reduce the recidivism rate after their release.

Dr. Leary may have listened to the NIMH’s warning, but he wasn’t exactly leary of it. He and his research team started taking psilocybin on their own, at first in private, and then as part of the research itself. Leary subscribed to the interpersonal school of psychology along with Harry Stack Sullivan and Karen Horney. He looked for truth not in the objective eye of the scientific observer, but in the interaction between the doctor and patient, or scientist and subject. So it didn’t take much for him to believe that his observations of subjects on psilocybin would be more accurate if he made them while under the influence of the drug himself.

This alarmed the rest of the psychologist department at Harvard, who began to see holes in Leary’s data. He was ignoring adverse reactions to the drug, and exaggerating its benefits. In his prison study he claimed that psilocybin lowered the recidivism rate, but a closer look at the data revealed he hadn’t taken a bite out of crime, not even a nibble. 

The psychology department soon split into pro- and anti- psilocybin factions. On the pro side were Leary, Albert, and a host of close followers who experienced consciousness raising effects of the drug. But to those on the outside, these effects were not so positive. The described their psilocybin-infused colleagues as a cult-like clique who were insensitive, impulsive, and had an unrealistic sense of omniscience. David McClelland wrote that “[Psilocybin] Initiates begin to show. . . a feeling of being above and beyond the normal world [since] the inner world of fantasy is valued more than the outer world of social reality…. They develop an appetite for finding God that grows and grows.”

Kellie Newsome: The final straw came when Leary and Albert started giving psilocybin to Harvard students. The administration demanded that they stop, but Dr. Albert continued to dispense it to students from his apartment and was fired from the university. Dr. Leary was fired around the same time, for skipping class without notice and neglecting his teaching duties.

The scandal caught the attention of the national press, but it was just a spark that lit a bigger fire. Within a few years, college students around the country were following Dr. Leary’s lead, taking psilocybin and LSD to expand their consciousness, and with that conscious-expansion came long hair, colorful clothing, and staunch opposition to the Vietnam war. The FBI and DEA saw psychedelics as a direct cause of this counter-cultural activity, and they probably had a point. In a recent controlled trial of treatment-resistant depression, psilocybin didn’t just improve mood. It also altered political beliefs in ways that might be threatening to some government administrations – the patients were more likely to endorse liberal, humanistic ideals, and less likely to endorse authoritarian ones. They felt more connected to nature and more open to new experiences. 

As the government started to crack down on psilocybin, Sandoz withdrew the drug to avoid further troubles. Albert and Leary left Harvard and tried to establish independent institutions for psilocybin experiments, but these collapsed in the chaos and disorganization that tend to erupt when idealists set out to create utopian societies free of rules and expectations, particularly when drugs are involved. Leary kept up the mantle to the end of his life in 1996, but increasingly it looked like he was on the wrong side of history. Hunter S Thompson summed it up in his raw prose: 

Dr. Aiken: [Tim Leary] crashed around America selling "consciousness expansion" without ever giving a thought to the grim meat-hook realities that were lying in wait for all the people who took him seriously... What Leary took down with him was the central illusion of a whole lifestyle that he helped create... a generation of permanent cripples, failed seekers, who never understood the essential old-mystic fallacy of the Acid Culture: the desperate assumption that somebody... or at least some force - is tending the light at the end of the tunnel.”

A Sober Path to Enlightment

Kellie Newsome: Leary’s colleague Richard Albert turned away from chemical enlightenment and went in a different direction. After his dismissal from Harvard, Albert moved to India to study transcendental meditation. When he returned he had new name: Ram Dass, and the US had a new leader, Richard Nixon, who was struggling to control a divided nation that had culminated in the killing of 4 student protestors by the national guard at Kent State University on May 4th, 1970. Nixon had had enough, and decided it was time to put the genie back in the bottle. On October 27, 1970, six months after the Kent State shooting, he signed the controlled substance act, which brought harsh punishments to anyone in possession of psilocybin, LSD, marijuana, and other substances that were fueling the protest movement.

The law forced a whole generation of people to find new sources for the enlightenment they had glimpsed on the magic carpet ride of psilocybin, and Ram Dass was there with an answer. His best selling book of 1971, Be Here Now, guided them toward a more sober method of enlightenment: transcendental meditation, and as this practice spread through the 1970’s it inspired a new generation of psychologists to develop psychotherapies that drew on Eastern ideals. We’re talking about dialectical behavioral therapy, acceptance and commitment therapy, and mindfulness. 

Dr. Aiken: The 1970 controlled substance act brought a hault to psychedelic research, but those rules began to loosen in the 1990’s when the courts ruled that psychedelics could be used in religious ceremonies. That opened the door for scientific exploration of the religious use of these drugs, and in 2006 the first studies of psilocybin were published that proved – with a controlled design – that the drug does induce the kinds of mystical states Dr. Leary had become so enamored of. This lead leaders at the NIMH to wonder – if psilosybin could induce spiritual states – could they it depression? And that brings us to where we are today.

And while these new studies of psilocybin in depression are promising, we are a long way from understanding the risks and benefits of this drug. In the early clinical studies, the authors made the point that the drug had the potential to do good and to cause harm, and that the direction it took often depended on the setting it was given in and the mindset of the researchers who gave it and the subjects who took it. Indigenous cultures have used psilocybin for millennia without causing major problems, but it was reserved for a specific purpose in a specific setting – to bring the community together through a ritualized ceremony that connected them to a greater purpose. If it gains FDA approval, this magic mushroom will find itself in a very different world: An America where everyone is bowling alone. Religious affiliation is on the decline, depression is on the rise, and healthcare is consumer good, a basic human right, or both, depending on whom you ask. 

Already people are travelling to Europe to pay thousands of dollars for a dose of psilocybin at Norwegian retreats. And the owners of those retreats are already setting up unrealistic expectations about this drug. One center calls it a “prescription-based panacea for depression” and goes on to claim the drug is FDA approved: “Psychedelics are powerful, and can transform your life. Indeed, it is this increasingly strong evidence base for its benefits that has helped transform psilocybin from a banned substance to an FDA-approved medicine.

And now for the word of the day…. hyperaesthesia

Hyperesthesia is an increase in the sensitivity to any of the 5 senses, such as sight, sound, touch, and smell. We see it in mania, and in patients with neuropathies who are more sensitive to aversive sensations like pain or temperature or – in the case of migraines – light and noise. Hyperaesthesia is a common reaction to psychedelics like psilocybin. People who take the drug become exquisitely in tune with the sensory world. Beyond heightened sensations, they often find profound meaning in mundane objects like a door knob or a glass cup. Hyperaesthesia is not always a positive experience, and the first step to relieve this symptom is to cut back on caffeine, which can exacerbate it.

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