Sunday, March 7, 2021

JAMES COYNE'S COLUMN

Psilocybin as an Antidepressant for Cancer Patients Who Are Not Depressed

Should psilocybin be provided to patients at the end of life without them having to pay for a dubious diagnosis from a psychiatrist and a new-age ritual?

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A key study of psychedelic-assisted psychotherapy for depressed cancer patients actually included no patients with major depression. Other details of the study have been grossly misrepresented in ways that should influence our assessment of the study’s importance.

Most guests had left what we knew would be John Weakland’s last birthday celebration. John was dying from ALS (Amyotrophic lateral sclerosis, Lou Gehrig’s disease).

His lifework as an originator of family and grief problem-focused therapy had already been honored at a special conference in New Orleans. Weeks before his death, John would complete an article about the future directions of family therapy.

At least on that night, complications from that horrible disease did not seem to dull his spirit or his intellect, although his speech was noticeably slurred.

For what would be our last night together, John shared his cache of Cuban cigars and Bas Armagnac with me. We did not say much, mostly just enjoying the clear cloudless night until we fell asleep on the swath of grassy land that he and his wife, artist Anna Wu, owned in Los Altos. She discretely monitored us from inside their house.

John did not ask permission to smoke the cigars from the physicians who had been at the party.

Possession of the cigars was illegal. I recall the cigars having been smuggled into the US and presented to John as a gift in New Orleans. Fortunately, John knew more about how to savor an expensive cigar than I did, else he might have died instantly with a first deep draw.

Although both of us had experience with psychedelics, we did not think to ingest psilocybin that night. If we had wanted to trip, we would not have asked one of the psychiatrists to bestow a diagnosis of adjustment disorder on us to make it legal.

Why can’t two consenting adults legally ingest a substance that evidence suggests is safer than cigar smoke or Armagnac, particularly when it is the last visit together? Or at any time?

If the campaign for psilocybin-assisted psychotherapy succeeds, it will allow psychiatrists to market an expensive package deal of a psychiatric diagnosis, a couple of capsules of psilocybin delivered in an elaborate ritual, with six months of spiritually-oriented support and therapy thrown in.

Research concerning the role of psychedelics in mental health treatment and its superb publicity campaign depends on millions of dollars raised by venture capitalists. In a podcast series hosted by American entrepreneurinvestorauthor, and podcaster Tim Ferriss, a stream of investor guests expresses a vision of the treatment being provided private spa treatment, as well as psychedelics being used with underperforming athletes and a route to better sex.

At New York University, the ritual involves administering the psychedelic out of a chalice while new age music is played in a candlelit room, intended to create an aura of mysticism.

Before dismissing my skeptical perspective, let’s take a look at one of the key earlier studies cited as the rationale of the recent clinical trial of psilocybin as an antidepressant. The study from NYU is presented as a trial with dramatic results that were obtained when treating depression in terminal cancer patients. None of the patients in that study met the criteria for major depression.

Orchestrating an unprecedented publicity campaign

The article one of two clinical trials of psilocybin with cancer patients that were published with ten commentaries. The other study was from the group at Johns Hopkins that produced the recent randomized trial of psilocybin for major depression in JAMA Psychiatry discussed in my last article. Powerful Placebo in a Psilocybin for Depression Study

Leading the series of commentaries on the study of psilocybin with cancer patients, David Nutt, Editor of Journal of Psychopharmacology remarked:

The honours list of the commentators reads like a ‘who’s who’ of American and European psychiatry and should reassure any waverers that this use of psilocybin is well within the accepted scope of modern psychiatry.

The Heffter Research Institute funded both studies and managed publicity for the special issue. The institute’s website boasted of altmetrics (big data) revealing that the media mentions of the special issue had received over a billion views. The theme of the publicity was a mishmash of claims about mystical experiences, wild speculation about specific areas of the brain that psilocybin affected, and the distinctive religion-without-religion spirituality musings of popular writer Sam Harris.

As part of the publicity campaign, the senior authors of the NYU and Hopkins studies lavishly praised their own work in a long article in Medscape:Psilocybin May Be a Psychiatry Game Changer

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.

And

Professor Roland Griffiths, of the departments of psychiatry and neuroscience who led the study at Johns Hopkins University school of medicine, said he did not expect the findings, which he described as remarkable. “I am bred as a skeptic. I was skeptical at the outset that this drug could produce long-lasting changes,” he said. These were people “facing the deepest existential questions that humans can encounter — what is the nature of life and death, the meaning of life.”

Delving into the details of the NYU study

The title of the article makes three claims:

(1) that anxiety and depression were being treated (2) that rapid and sustained symptom relief was achieved; and (3) that the cancer was life-threatening.

[How many titles of peer-reviewed articles in clinical oncology or psycho-oncology journals highlight that cancer is life-threatening?]

The 29 patients in the study consisted of 26 patients with adjustment disorder and three with a generalized anxiety disorder.

This study included a clinically mixed sample of ten patients with stage I or II cancer and 18 with stage III or IV cancer with a small representation of a broad range of cancer sites. Staging is not a good predictor of individual life expectancy, particularly in a mixed sample. Most patients still maintained some full or part-time employment or student status. Two died in the course of the study and follow-up period.

Most cancers could be characterized as “life-threatening” except for some skin cancers. The term is not particularly informative or precise in the context of a scientific paper, but the term does serve to dramatize the findings.

The trial is described as a double-blind, placebo-controlled, crossover trial with single-dose psilocybin or niacin (Vitamin B3), with both pills administered in the context of psychotherapy. Patients were randomized to get first either the psychedelic or the placebo pill. Patients then received the other pill in a crossover at seven weeks.

Before receiving the psychedelic or placebo pill in the first round, they were coached to expect a mystical experience.

Patients received 3 sessions of 6 hours total duration in which rapport was established, along with expectations for the drug experience ahead.

The therapist/facilitator/monitor was also present in the five-hour or so session in which the drug or placebo was given and then for 3 sessions of post-integration work. The sequence was repeated for the second administration of a capsule of whatever had not been given the first time. Next were 20 weeks of support and integration of the experience with the therapist who has accompanied the patient through the trial.

The authors claimed the psilocybin achieved ‘rapid and sustained relief of symptoms, but this must be understood in the context of 8 months of supportive psychotherapeutic treatment.

Critical commentary on the study

As a clinical trial. The study is described as “double-blinded,” indicating an intent to keep both the patients and the research team in the dark as to whether the patients had received psilocybin versus vitamin B3. Any mystery would only last until a half hour or so after the patient got the pill. At that point, a marked shift in the patient’s mood and perception alerted the patients and their facilitators to the patient had been given the psychedelic.

The study was no longer blinded a half-hour after the pill was administered and patients had no doubt to what condition they had been assigned.

The study is described as a randomized controlled trial (RCT). That should give confidence that results observed in the follow-up period were not simply due to the passage of time. But here is the catch. In a crossover design, patients get both drug and placebo, just at different times. Those patients who did not get the psilocybin the first time got it at seven weeks. From that point until the last follow-up 26 weeks later, all patients had ingested both psilocybin and the placebo. So, everybody had exposure to the drug and there was, therefore, no control for the passage of time. In that sense, the study was no longer an RCT in the crucial follow-up period in which the ‘sustained relief of symptoms’ is observed.

The study was no longer a randomized trial at long term follow up and the sustained relief of symptoms did not control for passage of time.

As a study of the treatment of patients with psychiatric diagnoses. Ninety percent of patients had a diagnosis of adjustment disorder, which meant that a psychiatric diagnosis had been ruled out for which an evidence-based treatment would have been indicated. Any depressive or anxious symptoms were subthreshold.

Clinicians, particularly non-psychiatrist physicians in cancer care, often prescribe an antidepressant to patients with subthreshold symptoms, but there is no evidence that an antidepressant would improve patient outcomes beyond placebo effects.

Adjustment disorders are administrative diagnoses usually made for documentation and billing purposes. Patients receive this diagnosis to justify clinicians taking some action administratively, but patients with such a diagnosis are a mixed group in terms of the source of any symptoms and the presumed mechanism by which the symptoms were produced.

Psychopharmacologists would not expect the patients with adjustment disorder to have any particular biological abnormality in common. So, the presumed action of a drug effective in treating major depression might not be observable in this population because of the lack of the biological abnormality that an antidepressant is theorized to address.

Conventional antidepressants are not happy pills. They do not make persons below a minimal threshold of depression happier than a placebo.

As a study of cancer patients. Responses to the diagnosis and treatment of cancer are quite varied, but cancer does not typically pose the mental health issues that the authors claimed in the peer-reviewed article and their statements to the media.

My team studied a waiting room sample of over 400 consecutive breast cancer patients at a comprehensive cancer center. We found a third scored in the distressed range on a screening instrument, virtually the same as in a primary care waiting room sample that we had also studied. There were few cases of PTSD, all patients with a history of being treated for major depression.

Most distress among cancer patients resolves in three to six months, typically without the patients obtaining formal mental health treatment. As in other studies, we found that approximately 10–14 percent of patients remained distressed at 6 months, despite receiving a variety of formal interventions. The same proportion of unresolved distress probably holds in other medical populations.

Persistent distress can have diverse causes, including current circumstances beyond cancer, conditions created by the treatment of cancer including being devasted financially, and pre-existing psychopathology.

There are crude, psychometrically unsound checklists for assessing the unmet needs associated with distress in cancer care. The items which are endorsed most vary across populations, but typically the most common are practical matters. A need for formal mental health treatment does not get a strong endorsement.

As a study of end-of-life-treatment. The peer-reviewed paper is vague about the nature of therapy and support provided except for noting it draws on a “number of manualized existentially oriented psychotherapies [that] have been developed to address…existential/spiritual issues.”

Dignity therapy is a particular brand of manualized existential therapy for the end of life. Unanticipated and fascinating results were found in a large RCT.

The multisite trial involved over 400 patients. The study compared this manualized psychotherapy delivered by psychiatrists and psychologists to a simple supportive discussion with someone who was not formally trained as a psychotherapist, such as a pastoral counselor, and to remaining in routine cancer care without additional intervention.

No differences were found among the three groups across two dozen outcome measures, including various measures of depressed mood, hopelessness, and despair, as well as psychological, existential, and spiritual distress.

One reason is a floor effect dictated by the low level of mental health symptoms with which patients entered the study. Their symptoms could not fall any lower. That finding alone should shake up some myths about mental health care at the end of life.

The condition treated by psychiatrists in terminally ill medical patients. All but two had an administrative diagnosis with subclinical symptoms. Outside a small group of psychiatrists and psychologists, I do not think there would be much agreement about the validity of a “cancer-related demoralization syndrome.” Or that is necessarily a clinical problem when patients give up at the end of life and desire a hastened death without seeking further hope, meaning, or purpose in prolonged life. At least not a problem that mental health professionals would be the most equipped to address.

A lot of prescriptive moral judgments are being made in this study about how people should live and die. These psychiatrists have a wealth of ideas about the good death which they apparently promote with great passion in the 8 months of support and drug-assisted psychotherapy. As Stanford David Spiegel indicates in the title to his commentary, the NYU research group believes that they are guiding cancer patients on the last trip.

Outside the trial. a lot of cancer patients face death with their own form of spirituality that has served them well over a lifetime. It is perhaps for good reason that so few Christians enrolled in the study.

Many Christians would rather slowly walk with Jesus on their last trip, not fly with these NYU psychiatrists.

That only a couple of Christians enrolled in the study probably avoided some clashes in theology and basic values.

On the other hand, there are people who very much want an experience with psilocybin that this research group advertises. They may have seen NYU’s normal volunteer study with psilocybin. In what sounds like a Trip Advisor review, the paper reports:

Thirty-three percent of the volunteers rated the psilocybin experience as being the single most spiritually significant experience of his or her life, with an additional 38% rating it to be among the top five most spiritually significant experiences.

Some may even think “Too bad I don’t have cancer.”

They would not have to meet the criteria for major depression. They would only need to impress a psychiatrist with subsyndromal symptoms. That could be easily done by a motivated person.

The nondepressed research participant would get to trip. The NYU researchers would get data points for claims about psilocybin as an antidepressant.

But how perverse is it, that psilocybin needs to be accessed through an RCT of a mental health treatment because it is needlessly kept as criminalized heroin?

For more details of the psychotherapy provided in this trial including patient testimonials see the NYU Alumni News.

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James Coynehttp://www.coyneoftherealm.com
James C. Coyne is Professor Emeritus of Psychology in Psychiatry at the University of Pennsylvania where he was Director of Behavioral Oncology at the Abramson Family Cancer Center and Senior Fellow, Leonard Davis Institute of Health Economics. He also was Professor of Health Psychology at the University of Groningen, the Netherlands, and has been on the faculties of University of Michigan School of Medicine and University of California, Berkeley. He received a BA in Psychology from Carnegie Mellon in 1969 and a Ph.D. in Clinical Psychology from Indiana University in 1975. Professor Coyne was the 2015 Carnegie Centenary Visiting Professor at the University of Stirling. He is the author of over 400 articles and chapters and has been designated one of the most influential psychologists of the second half of the twentieth century. His diverse interests have included clinical health psychology, mental health services research, and evaluation of depression screening and suicide prevention programs. As a blogger at Science-Based Medicine and Mind the Brain, Dr. Coyne is known for skeptical appraisals of advice gurus misleading consumers with hype and hokum. His activism with colleagues concerning undisclosed conflicts of interest has yielded dozens of corrections to published papers, a few retractions, and the Bill Silverman Prize from the Cochrane Collaboration.

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JAMES COYNE, PHD

James C. Coyne is Professor Emeritus of Psychology in Psychiatry at University of Pennsylvania where he was Director of Behavioral Oncology at the Abramson Family Cancer Center and Senior Fellow, Leonard Davis Institute of Health Economics. He also was Professor of Health Psychology at University of Groningen, the Netherlands and has been on the faculties of University of Michigan School of Medicine and University of California, Berkeley. He received a BA in Psychology from Carnegie Mellon in 1969 and a PhD in Clinical Psychology from Indiana University in 1975.

Professor Coyne was the 2015 Carnegie Centenary Visiting Professor at the University of Stirling. He is the author of over 400 articles and chapters and has been designated one of the most influential psychologists of the second half of the twentieth century. His diverse interests have included clinical health psychology, mental health services research, and evaluation of depression screening and suicide prevention programs. As a blogger at Science-Based Medicine and Mind the Brain,

Dr. Coyne is known for skeptical appraisals of advice gurus misleading consumers with hype and hokum. His activism with colleagues concerning undisclosed conflicts of interest has yielded dozens of corrections to published papers, a few retractions, and the Bill Sliverman Prize from the Cochrane Collaboration.

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