Psilocybin May Be a Psychiatry Game Changer

Two similar randomized controlled trials in late-stage cancer patients suggest that a single, high dose of the psychedelic drug psilocybin has rapid, clinically significant and lasting effects on mood and anxiety. The findings may be a therapeutic game changer for psychiatry.

The new findings have "the potential to transform the care of cancer patients with psychological and existential distress, but beyond that, it potentially provides a completely new model in psychiatry of a medication that works rapidly as both an antidepressant and anxiolytic and has sustained benefit for months," Stephen Ross, MD, director of Substance Abuse Services, Department of Psychiatry, New York University (NYU), Langone Medical Center, told Medscape Medical News.

"That is potentially earth shattering and a big paradigm shift within psychiatry," Dr Ross told Medscape Medical News.

The findings were published online December 1 in the Journal of Psychopharmacology.

Expert Enthusiasm

Experts in the field, including former presidents of the American Psychiatric Association and heads of major academic psychiatry departments, have described the results as "remarkable," "very promising," and "a critical advancement" that might "open a new era" in drug treatment in psychiatry.

According to these experts, whose commentaries appear with the two studies in a special issue of the journal, the new findings warrant more extensive studies to replicate the outcomes in diverse populations. Some urge more consideration of the unique legal, ethical, and regulatory issues surrounding the clinical use of psilocybin and related drugs.

Psilocybin, the active ingredient in "magic mushrooms," is a serotonergic hallucinogen that acts as a 5-hydroxytryptamine 2A (5-HT2A) receptor agonist.

It was first synthesized in 1958 and was used in psychiatric research until 1970, when its widespread recreational use and association with cultural and political upheaval resulted in it and other psychedelics being reclassified as a Schedule I drug. However, in the past few decades, there has been a renewed interest in psilocybin.

According to a commentary by Alasdair Breckenridge, MD, FRCP, Department of Pharmacology and Therapeutics, University of Liverpool, United Kingdom, and Diederick E. Grobbee, MD, PhD, Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, the Netherlands, recent work has shown that this drug can be administered safely to patients with treatment-resistant depression and psychological distress associated with life-threatening illness, as well as those with alcohol or tobacco dependency and obsessive compulsive disorder.

The research also suggests that the drug is not habit forming, does not cause dependence, and has "extremely low toxicity," Dr Breckenridge and Dr Grobbee note.

These encouraging findings have opened the door for clinical trials, which are now emerging.

Both new studies used a double-blind, crossover design and were carried out in a supervised setting. Each employed a number of validated psychological tools to examine a range of effects and to assess safety.

The primary outcomes in both studies were depression and anxiety – conditions that are highly prevalent among cancer patients, whose conditions are often resistant to antidepressants, anxiolytics, or psychotherapy.

Secondary outcomes included assessment of spirituality, existential distress, death anxiety, and mystical experiences. For example, some patients report a profound sense of unity, transcendence of time and space, or a deeply positive mood and quality of life.

The main difference between the two studies was with respect to the control drugs that were used. One study used niacin, which mimics psilocybin; the other used a low dose of psilocybin.

Important Therapeutic Experience

The study by researchers at NYU included 29 persons, almost two thirds of whom had either stage III or IV cancer. All patients had been diagnosed with an anxiety-related disorder. Most met diagnostic criteria for an adjustment disorder, and the rest met criteria for generalized anxiety. Almost two thirds had previously been treated with antidepressant or anxiolytic medication, but none were taking these at the time of the study.

The mean age of the participants was 56 years. About 55% had used a psychedelic at least once in their life, which the researchers said was not surprising.

"During the '60s and '70s, there were tens of millions of people using psychedelics. It was quite common to experiment at least once with LSD or marijuana," said Dr Ross.

Patients in this study first took psilocybin (0.3 mg/kg, or about 21 mg/70 kg) or niacin (250 mg), or vice versa, with crossover at 7 weeks. Both groups received psychotherapy with supportive, psychodynamic, and existential elements. Patients took the drug in a living room–like setting, said Dr Ross. The patient and therapists held hands in a circle, and the patient vocalized his or her intentions for the session. After taking the pill, the patient was given art books, preselected music, and eye shades and was asked to focus internally. The trained therapists checked on the patient regularly.

The Hospital Anxiety and Depression Scale (HADS) and the Beck Depression Inventory (BDI) were used for patients' self-reports. The study showed that psilocybin produced an immediate and ongoing anxiolytic and antidepressant response.

With respect to scores on the BDI, in the psilocybin-first group, about 83% met criteria for antidepressant response 7 weeks after receiving dose 1; in the niacin-first group, 14% met criteria for antidepressant response. With respect to scores on the HADS-A, in the psilocybin-first group, 58% met criteria for anxiolytic response 7 weeks after receiving dose 1; in the niacin-first group, 14% met criiteria for anxiolytic response.

At 6.5-month follow-up, antidepressant or anxiolytic response rates were in the 60% to 80% range, depending on the measure.

Dr Ross's study also showed that psilocybin was associated improved quality of life and spiritual well-being, as well as less existential distress. The mystical experiences, as measured by Mystical Experiences Questionnaire, were highly correlated with clinical response.

"There's definitely something about the intensity of the mystical experience that is the main driver of patients getting better," said Dr Ross.

About 70% of patients rated their psilocybin experience "as the singular or top five most meaningful experiences of their life. They were highly instructive, memorable, important therapeutic experiences that people remembered, and they would tell us about them," he said.

There was no difference in response between patients who had used hallucinogens in the past and those who had not. It also made no difference whether or not patients had a religious affiliation.

Aligned Results

The second study, by researchers at Johns Hopkins University, in Baltimore, Maryland, included 51 cancer patients; 65% havd recurrent or metastatic disease. All participants met DSM-IV diagnostic criteria for chronic adjustment disorder with anxiety, chronic adjustment with mixed anxiety and depressed mood, dysthymic disorder, generalized anxiety disorder (GAD), major depressive disorder (MDD), or a dual diagnosis of GAD and MDD.

Patients either took a high dose of psilocybin (22 mg/kg) followed 5 weeks later by a very low dose (3 mg/70 kg, which was reduced to 1 mg/70 kg during the study and which mimicked placebo), or they received a low dose followed by the high dose 5 weeks later.

As with the NYU study, patients were in a controlled environment. They, too, were encouraged to lie on a couch, use an eye mask to block external visual distractions, and listen to music. They were also encouraged to focus their attention on their inner experiences throughout the session.

In this study, patients were given instructions that helped minimize expectations. They were told that psilocybin would be administered in both sessions, that the psilocybin doses might range from very low to high, and that the doses in the two sessions might or might not be the same.

"We were maximizing expectations both on the part of the volunteers and the monitors," lead investigator Roland R. Griffiths, MD, professor, Departments of Psychiatry and Neuroscience, Johns Hopkins University, Baltimore, Maryland, told Medscape Medical News. "The instruction was, 'We don't know the dose, so try to get the most that you can from this experience.' "

Although this group did not receive formal psychotherapy like the patients in the NYU study, they did receive extensive support from study personnel.

The results of this study "line up extremely well" with those of the NYU study, said Dr Griffiths.

The analysis showed that the high-dose psilocybin produced large effects on the two primary clinician-rated outcome measures, which were depression, as assessed using the GRID-HAMD-17; and anxiety, as assessed using the HAM-A. Large effects were also observed on most of the secondary endpoints.

Clinically significant response was defined as a 50% or greater decease relative to baseline in scores on the GRID-HAMD-17. At 5 weeks after session 1, 92% in the high-dose-first group showed a clinically significant response. In the low-dose-first group, 32% showed a clinically significant response.

At 6 months, the clinical response averaged 78% for depression and 83% for anxiety. "So about 80% of people are showing clinical response," said Dr Griffiths.

The remission rate at 6 months was 65% for depression and 57% for anxiety.

The absence of trained psychotherapists did not affect outcomes. In fact, the effect size at 6 months was somewhat greater in this study compared to the NYU study.

"There may have been other site differences that could have driven effectiveness," said Dr Griffiths. "Our sense is that we have yet to work out optimal training, but I would say we had very good clinical people."

Mystical Experiences

Participants taking the high dose reported positive changes in attitudes about life, self, mood, relationships, and spirituality. This study included community observer ratings, which also showed significant positive changes in attitudes and behaviors of participants.

Reports from community raters "are most telling," said Dr Griffiths. "If you have a spouse saying that their loved one was really doing much better, that's very powerful."

As with the NYU study, this study showed significant effects of mystical-type experiences on various outcomes, including spiritual significance, life satisfaction, and meaningfulness.

It was difficult to enroll cancer patients for this study because many are understandably fearful of using psychedelics, owing to the drugs' reputation and possibly because of having had a bad personal experience with them, noted Dr Griffiths.

He said he was "not 100% confident" that the intervention would have significant effects, because the patients were "remarkably vulnerable." They were all dealing with a life-threatening cancer, depression, or anxiety, and in some cases, the patients' prospects were "compellingly grim."

"I thought there was a possibility that they would come out more afraid or more damaged or traumatized," he said. "So the amazing thing to me was that this worked just like it did in the healthy volunteers" who had been involved in an earlier study.

The mystical-type experiences that some patients experience with psilocybin "allows them to move forward, not feeling depressed, not feeling anxious, but with optimism, and I would even say joy," said Dr Griffiths.

Many had "a larger understanding that life and death are intermixed in some profound way that speaks to the very nature of human consciousness" and that is "deeply therapeutic."

The research raised no new safety concerns. In both studies, the adverse events were limited and included expected increases in blood pressure and pulse, nausea and vomiting, and transient anxiety or occasional psychotic symptoms. These appeared to remit rapidly.

Who's Who of Psychiatry

In an accompanying editorial, David Nutt, MD, PhD, Imperial College London, called the studies "landmark" and the "most rigorous controlled studies to date" using psilocybin. When asked to provide commentary on these studies, experts in the fields of psychiatry, trial design, and end-of-life care all agreed to do so, despite short notice. This, said Dr Nutt, "is a testimony to the interest that these two studies have sparked."

The list of commentary contributors reads like a "who's who" of American and European psychiatry and "should ensure any waverers that this use of psilocybin is well within the accepted scope of modern psychiatry," said Dr Nutt.

The commentators generally praised the studies, variously calling them "well-designed" and "methodologically rigorous." They agreed that this is an exciting new era of psychedelic psychopharmacology. Several noted that the systematic replication of the main outcomes across two sites contributes to the confidence in the robustness of the findings.

However, some commentators pointed out that although the studies tried to blind participants and personnel to the treatment assignment, it is unclear how effective the blinding procedures were.

"Placebo responsiveness and expectations are of course complex issues to isolate," writes Paul Summergrad, MD, Tufts University School of Medicine, Boston, Massachusetts, in his commentary.

"This is especially true in studies that included a significant percentage of participants with prior psychedelic use and who were facing serious medical and existential issues. Nevertheless, the rate and speed of response to an active drug, its intensity and duration are decidedly more substantial than one sees in placebo responses in moderately depressed patients, even with higher committed and engaged research groups."

John D. McCorvy, PhD, and colleagues from the Division of Chemical Biology and Medicinal Chemistry, Department of Pharmacology, University of North Carolina at Chapel Hill, and the Psychoactive Drug Screening Program, National Institute of Mental Health, noted that the placebo effect is "a major confound in the development of novel antidepressant drugs as placebo can produce antidepressant effects in 30%-40% of individuals."

In their commentary, Richard C. Shelton, MD, Department of Psychiatry and Behavioral Neurobiology, and Peter S. Hendricks, PhD, Department of Health Behavior, School of Public Health, University of Alabama at Birmingham, pointed out that the studies did not use a direct assessment of the integrity of the blinding procedures.

"[N]either directly asked participants to estimate treatment assignment. It would be prudent to collect this information in future studies."

However, they noted that the "salience" of psilocybin's effects may render complete blinding infeasible, as is often the case with studies of psychoactive drugs and behavioral interventions.

David Spiegel, MD, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, in California, pointed out that in the study by Dr Griffiths and colleagues, only 10% of those initially screened took part in the study, mostly because of not meeting inclusion criteria. "[S]o to begin with these were people inclined to believe that a psychedelic drug might help them at this time of their life."

Commentators flagged the crossover design of the studies as a limitation in that it restricts interpretation after the crossover; only outcomes before the crossover can reliably be regarded as resulting from taking the drug.

In the study by Dr Griffiths and coworkers, the low dose might have had some activity and therefore could have affected the double-blind assessment of the efficacy of the higher dose, according to Craig D. Blinderman, MD, Adult Palliative Care Service, Department of Medicine, Columbia University Medical Center/New York Presbyterian Hospital, New York City. In the study by Dr Ross and colleagues, he said, the use of a control with limited blinding could have contributed to some bias of the results.

Findings Generalizable?

According to Dr Blinderman, the psychiatric exclusion criteria limit the findings to those patients with depression and anxiety disorders but not those with a family history or patient history of other psychiatric disorders, such as schizophrenia and bipolar disorder.

"Additionally, the relatively small sample size, made up of a largely white, educated population, precludes generalizability."

Using subjective measures in the studies is understandable but is "a particular weakness of any study where blinding is inadequate," noted Guy M. Goodwin, MD, Department of Psychiatry, University of Oxford Warneford Hospital, United Kingdom.

"Any cue that makes participants in an experimental study aware of what the experimenter expects to find or how participants are expected to behave is called a demand characteristic. These studies have demand characteristics in spades."

Assessing the value of treatment on the basis of symptoms alone is also a limitation, said Dr Goodwin.

"More objective measures of activity, simply motor or economic, the costs of their cancer care, and so on should also be part of the future picture for research in this area."

Dr Goodwin also believes that it would be "helpful" to consider studies of hallucinogens as psychological treatment studies rather than drug studies.

"If patients experience lasting improvement because of insights or reframing of their view of life lived with terminal illness, the approach really does represent psychotherapy, albeit drug assisted."

As for the mystical experiences that some patients reported, it is not clear whether these are "a cause, consequence or corollary of the anxiolytic effect or unconstrained cognition," commented Benjamin Kelmendi, MD, Clinical Neuroscience Division, National Center for PTSD, West Haven, Connecticut, and colleagues.

"The association between a psychedelic-induced mystical experience and therapeutic outcome requires further exploration, as when induced under optimal conditions and in a controlled setting, it could provide a valuable therapeutic intervention for disorders that are otherwise difficult to treat," they write.

Unclear Mechanism

The lack of understanding about how psilocybin produces an altered state of consciousness with spiritual qualities is of great concern, according to Jeffrey A. Lieberman, MD, Department of Psychiatry, Columbia University, New York City, and colleague Daniel Shalev, MD.

"[W]e cannot tell if the anxiolytic and antidepressant effects of the drugs are direct results of their serotonergic effects or secondary to the mystical altered state of consciousness that they produce. Since other serotonergic agonists (eg, lisuride) do not produce this psychedelic experience it has been suggested that psychedelic drugs must bind to the 5-HT2A receptors in a special way or exhibit functional selectivity or receptor bias."

Some of the commentators wondered whether the observed benefits would be sustained when applied under "real-life" conditions outside the tightly controlled conditions of these two studies.

Despite these various caveats, commentators generally concluded that the new results support moving forward with phase 3 clinical trials. If confirmed in large, powered studies in a diverse population, the current classification of psilocybin as a Schedule I drug "should be challenged," writes Dr Blinderman, "for this would represent a treatment modality unlike anything in psychiatry."

Dr Ross pointed out that many of the commentators represent "organizational psychiatry" – the same type of leaders in the field who helped ban psychedelics in 1970. "So organizational psychiatry is embracing this again."

He cautioned that these new results should not send a message to patients that illicit magic mushrooms will help them.

"Psilocybin should be restricted to hospital settings," said Dr Ross. "This should not encourage recreational use; this should encourage more research in carefully controlled laboratory settings."

Both Dr Ross's study and Dr Griffiths' study were principally funded by the Heffter Research Institute, a nonprofit organization founded by scientists in the 1990s to review and fund research with psilocybin and other psychedelics.

Exceeded Expectation

George Greer, MD, a psychiatrist and medical director of the Heffter Research Institute, told Medscape Medical News that he was "delighted" by the new results, which are "better than what we hoped."

The Heffter Research Institute has funded pilot studies involving psilocybin, and these new clinical trials are the largest that have been carried out to date, he said.

"What's important is that it's a new model for treatment of anxiety and depression where the therapy is a single dose of the drug and the benefits are profound and last for months.

"So it's a new paradigm in psychiatry. There's just nothing like it in psychiatry at all."

The Heffter Research Institute is supporting research into the use of psilocybin in addiction. There are two large clinical trials involving smoking (at Johns Hopkins) and alcohol (at NYU), and a pilot study at the University of Alabama at Birmingham is investigating the use of psilocybin for cocaine dependence, said Dr Greer.

The institute is also considering proposals for use of psilocybin in the treatment of resistant depression, obsessive compulsive disorder, and possibly eating disorders, he said.

"Psilocybin is so unique compared to all approved drugs. It's a tool that has potential for a lot of things, and we want to explore those potentials."

The Heffter Research Institute is also supporting animal research into the impact of a drug similar to psilocybin on inflammation. Studies in mice found that tiny doses of the drug reduced inflammation and opened airways. "We are excited" about the possible implications for asthma and atherosclerosis, "but it's very early," said Dr Greer.

Dr Griffiths is on the board of directors of the Heffter Research Institute. Dr Summergrad receives personal fees from CME Outfitters, Pharmasquire, and universities and associations for nonpromotional speaking; royalties from Harvard University Press, Springer, and American Psychiatric Press; and consulting fees from Owl, Inc, and Quartet Health Inc, all of which are outside the submitted work. Dr Goodwin is an National Institute for Health Research (NIHR) senior investigator; the views expressed are his own and not necessarily those of the National Health Sservice, the NIHR, or the Department of Health. He holds a grant from Wellcome Trust, holds shares in PIVital, and has in the past 3 years served as consultant, advisor, or CME speaker for AstraZeneca, Merck, Cephalon/Teva, Eli Lilly, Lundbeck, Medscape, Otsuka, PIVital, Pfizer, Servier, Sunovion and Takeda. The other authors have disclosed no relevant financial relationships.

J Psychopharmacol. Published online December 1, 2016. Ross et al, Full text; Griffiths et al, Full text

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Cite this: Psilocybin May Be a Psychiatry Game Changer - Medscape - Dec 01, 2016.