1 billion views! Why we should be concerned about PR campaign for 2 RCTs of psilocybin for cancer patients

According to the website of an advocacy foundation, coverage of two recent clinical trials published in in Journal of Psychopharmacology evaluating psilocybin for distress among cancer patients garnered over 1 billion views in the social media. To put that in context, the advocacy group claimed that this is one sixth of the attention that the Super Bowl received.

In this blog post I’ll review the second of the two clinical trials. Then, I will discuss some reasons why we should be concerned about the success of this public relations campaign in terms of what it means for both the integrity of scientific publishing, as well as health and science journalism.

The issue is not doubt that cancer patients will find benefit from the ingesting psychedelic mushroom in a safe environment. Nor that sale and ingestion of psilocybin is currently criminalized (Schedule 1, classified same as heroin).

We can appreciate the futility of the war on drugs, and the absurdity of the criminalization of psilocybin, but still object to how, we were strategically and effectively manipulated by this PR campaign.

Even if we approve of a cause, we need to be careful about subordinating the peer-review process and independent press coverage to the intended message of advocates.

Tolerating causes being promoted in this fashion undermines the trustworthiness of peer review and of independent press coverage of scientific papers.

To contradict a line from the 1964 acceptance speech of Republican Presidential Candidate Barry Goldwater, “Extremism in pursuit of virtue is no [a] vice. “

In this PR campaign –

We witnessed the breakdown of expected buffer of checks and balances between:

  • An advocacy group versus reporting of clinical trials in a scientific journal evaluating its claims.
  • Investigators’ exaggerated self-promotional claims versus editorial review and peer commentary.
  • Materials from the publicity campaign versus supposedly independent evaluation by journalists.

What if the next time the object of promotion is pharmaceuticals or medical devices by authors with conflicts of interest? But wait! Isn’t that what we’ve seen in JAMA Network journals on a smaller scale? Such as dubious claims about the wondrous effects of deep brain stimulation in JAMA: Psychiatry by promoters who “disappeared” failed trials? And claims in JAMA itself that suicides were eliminated at a behavioral health organization outside Detroit?

Is this part of a larger trend, where advocacy and marketing shape supposedly peer-reviewed publications in prestigious medical journals?

The public relations campaign for the psilocybin RCTs also left in tatters the credibility of altmetrics as an alternative to journal impact factors. The orchestrating of 1 billion views is a dramatic demonstration how altmetrics can be readily gamed. Articles published in a journal with a modest impact factor scored spectacularly, as seen in these altmetrics graphics the Journal of Psychopharmacology posted.

I reviewed in detail one of the clinical trials in my last blog post and will review the second in this one. They are both mediocre, poorly designed clinical trials that got lavishly praised as being highest quality by an impressive panel of commentators. I’ll suggest that in particular the second trial is best seen as what Barney Caroll has labeled  an experimercial, a clinical trial aimed at generating enthusiasm for a product, rather than a dispassionate evaluation undertaken with some possibility of not been able to reject the null hypothesis. If this sounds harsh, please indulge me and read on and be entertained and I think persuaded that this was not a clinical trial but an elaborate ritual, complete with psychobabble woo that has no place in the discussion of the safety and effectiveness of medicine.

After skeptically scrutinizing the second trial, I’ll consider the commentaries and media coverage of the two trials.

I’ll end with a complaint that this PR effort is only aimed at securing the right of wealthy people with cancer to obtain psilocybin under supervision of a psychiatrist and in the context of woo psychotherapy. The risk of other people in other circumstances ingesting psilocybin is deliberately exaggerated. If psilocybin is as safe and beneficial as claimed by these articles, why should use remain criminalized for persons who don’t have cancer or don’t want to get a phony diagnosis from a psychiatrist or don’t want to submit to woo psychotherapy?

The normally pay walled Journal of Psychopharmacology granted free access to the two articles, along with most but not all of the commentaries. However, extensive uncritical coverage in Medscape Medical News provides a fairly accurate summary, complete with direct quotes of lavish self-praise distributed by the advocacy-affiliated investigators and echoed in seemingly tightly coordinated commentaries.

The praise one of the two senior authors heaped upon their two studies as captured in Medscape Medical News and echoed elsewhere:

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:

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

The Hopkins Study

Griffiths RR, Johnson MW, Carducci MA, Umbricht A, Richards WA, Richards BD, Cosimano MP, Klinedinst MA. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. Journal of Psychopharmacology. 2016 Dec 1;30(12):1181-97.

The trial’s available registration is at ClinicalTrial.gov is available here.

The trial’s website is rather drab and typical for clinical trials. It contrasts sharply with the slick PR of the website for the NYU trial . The latter includes a gushy, emotional  video from a clinical psychologist participating as a patient in the study.  She delivers a passionate pitch for the “wonderful ritual” of the transformative experimental session. You can also get a sense of how session monitor structured the session and cultivated positive expectations. You also get a sense of the psilocybin experience being slickly marketed to appeal to the same well-heeled patients who pay out-of-pocket for complementary and alternative medicine at integrative medicine centers.

Conflict of interest

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Roland Griffiths is on the Board of Directors of the Heffter Research Institute.

Heffter Research Institute is listed as one of the funders of the study.

The introduction.

 The Hopkins study starts with some familiar claims from psycho-oncology ] that portray cancer as a mental health issue. The exaggerated estimates of 40% of cancer patients experiencing a mood disorder is arrived at by lumping adjustment reactions with a smaller proportion of diagnoses of generalized anxiety and major depression.

The introduction contradicts a large body of literature that suggests that the prevalence of mental disorder in cancer patients is no greater than other chronic health conditions  and may approximate what is found in primary care waiting rooms . There is also a fundamental confusion of psychological distress associated with diagnosis of cancer with psychiatric disorder in need of treatment. Much of the initial psychological distress in cancer patients resolves in a short time, making it difficult to demonstrate benefits of treatment beyond this natural trajectory of decline. Prescription of an antidepressant would be ineffective and inappropriate.

The introduction ends with a strong claim to the rigor and experimental control exercised in the clinical trial:

The present study provides the most rigorous evaluation to date of the efficacy of a classic hallucinogen for treatment of depressed mood and anxiety in psychologically distressed cancer patients. The study evaluated a range of clinically relevant measures using a double-blind cross-over design to compare a very low psilocybin dose (intended as a placebo) to a moderately high psilocybin dose in 51 patients under conditions that minimized expectancy effects.

The methods and results

In a nutshell: Despite claims to the contrary, this study cannot be considered a blinded study. At the six month follow-up, which is the outcome assessment point of greatest interest, it could no longer meaningfully considered a randomized trial. All benefits of randomization were lost. In addition, the effects of psilocybin were confounded with a woo psychotherapy in which positive expectations and support were provided and reinforced in a way that likely influenced assessments of outcome. Outcomes at six months also reflected changes in distress which would’ve occurred in the absence of treatment. The sample is inappropriate for generalizations about the treatment of major depression and generalized anxiety. The characterization of patients as facing impending death is inaccurate.

 The study involved a crossover design, which provides a lower level of evidence than a placebo controlled comparison study. The study compared a high psilocybin dose (22 or 30 mg/70 kg) with a low dose (1 or 3 mg/70 kg) administered in identically appearing capsules. While the low dose might not be homeopathic, it can be readily distinguished soon after administration from the larger dosage. The second drug administration occurred approximately 5 weeks later. Not surprisingly, with the high difference in dosage, session monitors who were supposedly blinded readily identified the group to which the participant they were observing had been assigned.

Within a cross over design, the six month follow-up data basically attributed any naturalistic decline in distress to the drug treatments. As David Colquhoun would argue, any estimate of the effects of the drug was inflated by including regression to the mean and get-better anyway effects. Furthermore, the focus on outcomes at six months meant patients assigned to either group in the crossover design had received high dosage psilocybin by at least five weeks into the study. Any benefits of randomization were lost.

Like the NYU study, the study Johns Hopkins involves selecting a small, unrepresentative sample of a larger group responding to a mixed recruitment strategy utilizing flyers, the internet, and physician referral.

  • Less than 10% of the cancer patients calling in were randomized.
  • Almost half of the final sample were currently using marijuana and, similarly, almost half had used hallucinogens in the past.
  • The sample is relatively young for cancer patients and well educated. More than half had postgraduate education, almost all were white, but there were two black people.
  • The sample is quite heterogeneous with respect to psychiatric diagnoses, with almost half having an adjustment disorder, and the rest anxiety and mood disorders.
  • In terms of cancer diagnoses and staging, it was also a select and heterogeneous group with only about a quarter having recurrent/metastatic disease with less than two years of expected survival. This suggests the odd “life-threatening” in the title is misleading.

Any mental health effects of psilocybin as a drug are inseparable from the effects of accompanying psychotherapy designed by a clinical psychologist “with extensive experience in studies of classic hallucinogens.” Participants met with that “session monitor” several times before the session in which the psilocybin was ingested in the monitor guided and aided in the interpretation of the drug experience. Aside from providing therapy, the session monitor instructed the patient to have positive expectations before the ingestion of the drug and work to maintain these expectations throughout the experience.

I found this psychotherapeutic aspect of the trial strikingly similar to one that was included in a trial of homeopathy in Germany that I accepted for publication in PLOS One. [See here for my rationale for accepting the trial and the ensuing controversy.] Trials of alternative therapies notoriously have such an imbalance of nonspecific placebo factors favoring the intervention group.

The clinical trial registration indicates that the primary outcome was the Pahnke-Richards Mystical Experience Questionnaire. This measure is included among 20 participant questionnaires listed in the Table 3 in the article as completed seven hours after administration of psilocybin. Although I haven’t reviewed all of these measures, I’m skeptical about their psychometric development, intercorrelation, and validation beyond face validity. What possibly could be learned from administering such a battery?

The authors make unsubstantiated assumptions in suggesting that these measures either individually or collectively capture mediation of later response assessed by mental health measures. A commentary echoed this:

Mediation analysis indicates that the mystical experience was a significant mediator of the effects of psilocybin dose on therapeutic outcomes.

But one of the authors of the commentary later walked that back with a statement to Medscape Medical News:

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.”

Clinical outcomes at six months are discussed in terms of multiple measures derived from the unblinded, clinician-rated Hamilton scales. However, there are repeated references to box scores of the number of significant findings from at least 17 clinical measures (for instance, significant effects for 11 of the 17 measures), in addition to other subjective patient and significant-other measures. It is unclear why the authors would choose to administer so many measures that are highly likely intercorrelated.

There were no adverse events attributed to administration of psilocybin, and while there were a number of adverse psychological effects during the session with the psilocybin, none were deemed serious.

My summary evaluation

The clinical trial registration indicates broad inclusion criteria which may suggest the authors anticipated difficulty in recruiting patients that had significant psychiatric disorder for which psychotropic medication would be appropriate, as well as difficulty obtaining cancer patients that actually had poorer prognoses. Regardless, descriptions of the study is focusing on anxiety and depression and on “life-threatening” cancer seem to be marketing. You typically do not see a mixed sample with a large proportion of adjustment reaction characterized in the title of a psychiatric journal as treatment of “anxiety” and “depression”. You typically do not see a the adjective “life-threatening” in the title of an oncology article with such a mixed sample of cancer patients.

The authors could readily have anticipated that at the six-month assessment point of interest that they no longer had a comparison they could have been described as a rigorous double-blind, randomized trial. They should have thought through exactly what was being controlled by a control comparison group of a minimal dose of psilocybin. They should have been clearer that they were not simply evaluating psilocybin, but psilocybin administered in the context of a psychotherapy and an induction of strong positive expectations and promise of psychological support.

The finding of a lack of adverse events is consistent with a large literature, but is contradicted in the way the study is described to the media.

The accompanying editorial and commentary

Medscape Medical News reports the numerous commentaries accompanies these two clinical trials were hastily assembled. Many of the commentaries read that way, with the authors uncritically passing on the psilocybin authors’ lavish self praise of their work, after a lot of redundant recounts of the chemical nature of psilocybin and its history in psychiatry. When I repeatedly encountered claims that these trials represented rigorous, double blinded clinical trials or suggestions that the cancer was in a terminal phase, I assumed that the authors had not read the studies, only the publicity material, or simply had suspended all commitment to truth.

harmsI have great admiration for David Nutt  and respect his intellectual courage in campaigning for the decriminalization of recreational drugs, even when he knew that it would lead to his dismissal as chairman of the UK’s Advisory Council on the Misuse of Drugs (ACMD). He has repeatedly countered irrationality and prejudice with solid evidence. His graph depicting the harms of various substances to the uses and others deserves the wide distribution that it has received.

He ends his editorial with praise for the two trials as “the most rigorous double-blind placebo-controlled trials of a psychedelic drug in the past 50 years.” I’ll give him a break and assume that that reflects his dismal assessment of the quality of the other trials. I applaud his declaration, available nowhere else in the commentaries that:

There was no evidence of psilocybin being harmful enough to be controlled when it was banned, and since then, it has continued to be used safely by millions of young people worldwide with a very low incidence of problems. In a number of countries, it has remained legal, for example in Mexico where all plant products are legal, and in Holland where the underground bodies of the mushrooms (so-called truffles) were exempted from control.

His description of the other commentaries accompanying the two trials is apt:

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. They include two past presidents of the American Psychiatric Association (Lieberman and Summergrad) and the past-president of the European College of Neuropsychopharmacology (Goodwin), a previous deputy director of the Office of USA National Drug Control Policy (Kleber) and a previous head of the UK Medicines and Healthcare Regulatory Authority (Breckenridge). In addition, we have input from experienced psychiatric clinical trialists, leading pharmacologists and cancer-care specialists. They all essentially say the same thing..

The other commentaries. I do not find many of the commentaries worthy of further comment. However, one by Guy M Goodwin, Psilocybin: Psychotherapy or drug? Is unusual in offering even mild skepticism about the way the investigators are marketing their claims:

The authors consider this mediating effect as ‘mystical’, and show that treatment effects correlate with a subjective scale to measure such experience. The Oxford English Dictionary defines mysticism as ‘belief that union with or absorption into the Deity or the absolute, or the spiritual apprehension of knowledge inaccessible to the intellect, may be attained through contemplation and self-surrender’. Perhaps a scale really can measure a relevant kind of experience, but it raises the caution that the investigation of hallucinogens as treatments may be endangered by grandiose descriptions of their effects and unquestioning acceptance of their value.

The commentary by former president of the American Psychiatric Association Paul Summergrad, Psilocybin in end of life care: Implications for further research shamelessly echoes the psychobabble and self-promotion of the authors of the trials:

The experiences of salience, meaningfulness, and healing that accompanied these powerful spiritual experiences and that were found to be mediators of clinical response in both of these carefully performed studies are also important to understand in their own right and are worthy of further study and contemplation. None of us are immune from the transitory nature of human life, which can bring fear and apprehension or conversely a real sense of meaning and preciousness if we carefully number our days. Understanding where these experiences fit in healing, well-being, and our understanding of consciousness may challenge many aspects of how we think about mental health or other matters, but these well-designed studies build upon a recent body of work that confronts us squarely with that task.

Coverage in of the two studies in the media

The website for Heffter Research Institute  provides a handy set of links to some of the press coverage of the studies have received. There’s remarkable sameness to the portrayal of the study in the media, suggesting that journalists stayed closely to the press releases, except occasionally supplementing these with direct quotes from the authors. The appearance of a solicitation of independent evaluation of the trial almost entirely dependent on the commentaries published with the two articles.

There’s a lot of slick marketing by the two studies’ authors. In addition to what I wrote noted earlier in the blog, there are recurring unscientific statements marketing the psilocybin experience:

“They are defined by a sense of oneness – people feel that their separation between the personal ego and the outside world is sort of dissolved and they feel that they are part of some continuous energy or consciousness in the universe. Patients can feel sort of transported to a different dimension of reality, sort of like a waking dream.

There are also recurring distinct efforts to keep the psilocybin experience under the control of psychiatrists and woo clinical psychologists:

The new studies, however, suggest psilocybin be used only in a medical setting, said Dr. George Greer, co-founder, medical director and secretary at the Heffter Research Institute in Santa Fe, New Mexico, which funded both studies.

“Our focus is scientific, and we’re focused on medical use by medical doctors,” Greer said at the news conference. “This is a special type of treatment, a special type of medicine. Its use can be highly controlled in clinics with specially trained people.”

He added he doubts the drug would ever be distributed to patients to take home.

There are only rare admissions from an author of one of the studies that:

The results were similar to those they had found in earlier studies in healthy volunteers. “In spite of their unique vulnerability and the mood disruption that the illness and contemplation of their death has prompted, these participants have the same kind of experiences, that are deeply meaningful, spiritually significant and producing enduring positive changes in life and mood and behaviour,” he said.

If psilocybin is so safe and pleasant to ingest…

I think the motion of these studies puts ingestion of psilocybin on the path to being allowed in nicely furnished integrative cancer centers. In that sense psilocybin could become a gateway drug to quack services such as acupuncture, reiki, and energy-therapy therapeutic touch.

I’m not sure that demand would be great except among previous users of psychedelics and current users of cannabis.

But should psilocybin remain criminalized outside of cancer centers where wealthy patients can purchase a diagnosis of adjustment reaction from a psychiatrist? Cancer is not especially traumatic and PTSD is almost as common in the waiting rooms of primary care physicians. Why not extend to primary care physicians the option of prescribing psilocybin to their patients? What would be accomplished is that the purity could be assured. But why should psilocybin use being limited to mental health conditions, once we accept that a diagnosis of adjustment reaction is such a distorted extension of the term? Should we exclude patients who are atheists and only wants a satisfying experience, not a spiritual one?

Experience in other countries suggests that psilocybin can safely be ingested in a supportive, psychologically safe environment. Why not allow cancer patients and others to obtain psilocybin with assured purity and dosage? They could then ingest it in the comfort of friends and intimate partners who have been briefed on how the experience needs to be managed. The patients in the studies were mostly not facing immediate death from terminal cancer. But should we require that persons need to be dying in order to have a psilocybin experience without the risk of criminal penalties? Why not allow psilocybin to be ingested in the presence of pastoral counselors or priests whose religious beliefs are more congruent with the persons seeking such experiences than are New York City psychiatrists?

 

 

 

 

 

Psilocybin as a treatment for cancer patients who are not depressed: the NYU study

psilocybinThe well orchestrated promotion of a modest and misrepresented pair of studies of using psilocybin with cancer patients raises lots of issues and should leave lots of people embarrassed.

A breakdown in peer review allowed unmoderated and misleading statements about the studies to appear in commentaries from an impressive array of leading psychiatrists. They embarrassed themselves by claiming the studies were well-designed trials and that the patients were clinically depressed.

There was a breakdown in the press’s evaluation of press releases from the studies, with journalists embarrassing themselves by passing on outrageously self-congratulatory statements by the authors without independently checking them. Journalists covering the story almost exclusively drew on a rich set of promotional materials from the authors’ institutions and added little else.

A lot of commentators in the social media, especially Twitter, embarrassed themselves by tweeting and liking others’ tweets with unbridled, uncritical enthusiasm for the claims of the authors. They obviously did not read the papers or read them carefully.

From the 1960s, the United States has had an irrational policy of criminalizing use of psilocybin. The articles and publicity campaign do not directly challenge this policy or call for decriminalization. Rather, they propose establishing a loophole by which people of means can obtain a diagnosis of adjustment disorder from a psychiatrist, receive a prescription for psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine), and purchase an elaborate ceremony with lots of pseudoscientific trappings and mystical explanations. Use by others outside of this context will remain criminalized.

The publicity campaign can be seen as a larger effort by psychiatry to define dying as a mental health issue, routinely requiring their specialty expertise and services.

The articles’ justification for the trials runs roughshod over the existing literature, exaggerating psychiatric aspects of cancer, and minimizing the needs and preferences of cancer patients.

Hopefully, by the end of this blog and the next, I will convince readers that my assessments are more reasonable than they first appear.

Although published in a pay wall journal, both articles were made freely available, along with some of the laudatory comments, mostly from psychiatrists.

The first article is

Ross S, Bossis A, Guss J, Agin-Liebes G, Malone T, Cohen B, Mennenga SE, Belser A, Kalliontzi K, Babb J, Su Z. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. Journal of Psychopharmacology. 2016 Dec 1;30(12):1165-80.

The trial’s freely available registration at ClinicalTrial.gov is available here.

In this first of two blog posts, I will center on this study. However, a forthcoming blog post will focus on the second article, comparing and contrasting it to another study in methods and interpretation :

Griffiths RR, Johnson MW, Carducci MA, Umbricht A, Richards WA, Richards BD, Cosimano MP, Klinedinst MA. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. Journal of Psychopharmacology. 2016 Dec 1;30(12):1181-97.

The trial’s available registration is at ClinicalTrial.gov is available here. https://clinicaltrials.gov/ct2/show/NCT00465595

Distortions in coverage of the literature in the introduction to Ross et al study at NYU

 The introduction states:

Enduring clinically significant anxiety and/or depressive symptoms are common in patients with cancer, present in 30–40% of patients in hospital settings (Mitchell et al., 2011).

I debated Alex Mitchell, the author of this review to a packed audience at the International Association for Psycho-oncology meeting in Rotterdam.  Here are my slides.

I pointed out that these estimates are of self-reported symptoms, not clinical diagnoses, which is substantially lower. Although there is a modest elevation in self-reported symptoms immediately after diagnosis, there is a trajectory of rapid decline. Only about 12% of patients have heightened distress at six months, and is likely that many of those that do, had pre-existing psychological disorders or past histories. After the initial stress of a diagnosis, rates of distress among patients in an oncology waiting room approximate the rates of patients in primary care waiting rooms.

These symptoms are associated with a variety of poor outcomes, including medication non-adherence, increased health care utilization, adverse medical outcomes, decreased quality of life, decreased social function, increased disability, hopelessness, increased pain, increased desire for hastened death, increased rates of suicide, and decreased survival rates (Arrieta et al., 2013; Brown et al., 2003; Jaiswal et al., 2014).

These correlations are not established as causal, and mostly come from cross-sectional studies. Residual confounding and reverse causality are highly likely. Patients with more debilitating physical symptoms inadequately controlled pain register more distress. There is no evidence that treating depression increases survival rates or slows progression.

The introduction goes on to mention that effects of antidepressants have a slow onset and they are incompletely effective. The author should have noted that antidepressant treatment would be inappropriate for the patients with adjustment disorders that dominated their study sample.

…With a growing body of evidence linking higher levels of existential/spiritual wellbeing (in cancer patients) with improved quality of life and decreased depression/hopelessness/suicidality (Breitbart et al., 2000; McClain et al., 2003; Nelson et al., 2002), the need to develop effective therapeutic approaches to mitigate this domain of distress has become increasingly recognized within the disciplines of palliative care and psycho-oncology.

Hold on! The authors are introducing some pretty shabby research that psychiatrists should be addressing existential/spiritual well-being.Since when are existential/spiritual well-being issues psychiatric?

A number of manualized “existentially oriented psychotherapies” for cancer patients have been developed to address these existential/spiritual issues, with some empirical support from clinical trials (Lemay and Wilson, 2008), and several of these approaches were integrated into the therapy platform developed for this study.

I will pick up on this discussion in my next blog post. But in a previous blog post, I examined the largest trial (with 441 palliative care patients) for one of these “existential/spiritual” therapies.

That study found no differences in 22 different measures of distress (!) between a mental health professional delivering an existential/spiritual “dignity therapy” over standard palliative care or a client centered care delivered by a nurse. Nonetheless, in New York, you can find expensive continued education courses offered by psychiatrist for this dignity therapy.Having been evaluated in a large clinical trial does not necessarily make a treatment “evidence-based,” particularly when it only achieved no findings.

One of the problems acknowledged in that trial is that only a small proportion of palliative care patients had clinically significant anxiety and depression scales. This study is a particularly interesting comparison compared to the study of psilocybin for cancer patients. Palliative care patients in the larger study are arguably more confronting of an impending death than the patients in the psilocybin study. Yet the authors of the psilocybin study make a broad assumption that end-of-life is a time of considerable distress and a mental health issue.

Methods and results of the Ross et al study at NYU

Patients in the NYU Psilocybin Cancer Anxiety Study begin their hallucinatory experience wearing eyeshades and headphones as doctors encourage them to bear witness to an inner world - Photo and description provided by NYU Alumni News
Patients in the NYU Psilocybin Cancer Anxiety Study begin their hallucinatory experience wearing eyeshades and headphones as doctors encourage them to bear witness to an inner world – Photo and description provided by NYU Alumni News

Representing only about a third of the patients screened for the study, 29 patients were randomized to either psilocybin or niacin (vitamin B3) in a cross over design. The randomized patients were highly educated and almost half had a history of use of hallucinogens. Almost all patients (93%) indicated “white” as their race. No patients endorsed black, Hispanic, Asian, or Native American. All but five patients had diagnoses of adjustment disorder, and these other five had diagnoses of general anxiety disorder. Although about two thirds of the patients had stage III or stage IV cancer, the rest had stage I or stage II. is not clear why they allow such heterogeneity of patients expected survival time in their study. I suspect they had trouble recruiting patients.

Regardless, my immediate observation is that this is a highly unrepresentative sample. For psychiatry journal, it would usually be considered a misrepresentation to use “anxiety “ and “depression” in a title when we’re sample did predominantly not have diagnoses of major depression in clinical anxiety disorders. When did you last see “life-threatening” in the title of a paper in an oncology or even psycho-oncology journal? With the title, we already are seeing a bit of dramatization in the service of attracting more attention than a more accurate and conventional title.

Any sense of a double blinded study is undone by the use of niacin as a comparison/control. Patients would shortly discover whether they had been given vitamin B3 or a hallucinogenic drug in any research assistants would notice the difference.

The abstract mentions that the psilocybin and the vitamin B3 were administered after a preparatory psychotherapy session. The therapy was then delivered at during both the psilocybin and vitamin B3 treatments. Thus, that this is not simply treatment with psilocybin, but with a psilocybin/psychotherapy combination. There is not even minimal description of this psychological treatment in the article.

However,  if you go to the NYU Alumni Magazine, you’ll find an extensive interview and photos of some of the investigators. You’ll learn that both psilocybin and vitamin B3 are administered with a special ceramic chalice. Description of the psychotherapy is certainly what you would not expect for a manualized therapy. But the following section of the article is enlightening:

The NYU Psilocybin Cancer Anxiety Study is conducted in a serene space that seems more like someone’s living room than part of a bustling research clinic. There’s a couch strewn with ethnic-printed pillows, shelves stocked with oversize books of Tibetan art, framed landscape photographs, warm pools of lamplight, Buddha figurines, and, on dosing days, fresh fruit and flowers.

Notwithstanding the lovely room, psilocybin does present risks. Although it is not known to induce addiction, overdose, or withdrawal symptoms, some research has suggested it can bring about prolonged psychosis in people with a personal or family history of major mental illness, so such patients are carefully screened out of the study. In the session itself, there may be some physical side effects, such as nausea, dizziness, and tremors, but the more pronounced hazards are psychological. Periods of transient anxiety can occur as patients navigate the challenging psychological material related to cancer. More extreme reactions, such as paranoia and panic, can occur, but are rare and safeguarded against through careful preparation and a highly structured therapy session, much of which is influenced by the rituals of indigenous cultures that utilize psychedelic medicines.

Subjects start with a series of meetings with a male-female therapist dyad to build trust, establish familiarity, and set intentions. On the dosing day—there is one for placebo and one for the real thing, set seven weeks apart—a small container of psilocybin synthesized in a government-monitored laboratory and weighed daily according to strict DEA regulations is taken from an 800-pound safe. Twenty milligrams of powder, an amount precisely judged to increase the likelihood of a mystical experience, are measured and pressed into a pill, which subjects swallow from a ceramic chalice.

The drug starts to take hold after about half an hour and the subjects are encouraged to put on eyeshades and headphones, lie down, and ride the waves of music on a carefully curated playlist. The therapists sit quietly nearby. There’s often sobbing and sometimes laughter. After a few hours, subjects usually remove their eyeshades and start bearing witness to the inner world they’ve traversed.

This investigator’s New Age depiction of mechanism falls short of conventional scientific standards”

“People come out with an acceptance of the cycles of life,” Bossis says. “We’re born, we live, we find meaning, we love, we die, and it’s all part of something perfect and fine. The emergent themes are love, and transcending the body and this existence. In oncology, we’re pretty good at advancing life and targeting chemotherapies, but we’re not so good at addressing deep emotional distress about mortality. So to see someone cultivate a sense of acceptance and meaning, something that we all hope to cultivate over a 90-year life, in six hours? It’s profound.”

This study evaluated as a clinical trial

This study is grossly underpowered study, involving an unrepresentative sample of 29 patients whose only diagnosis was an adjustment disorder, with the exception of a few patients with generalized anxiety. Diagnoses of adjustment disorders are not validated nor have they received extensive study. If a patient has some distress with recent onset and they want to see a mental health professional, they can be given a diagnosis of adjustment disorder to justify treatment. For a while, that was a common practice in the Netherlands, but treatments billed for adjustment reactions are no longer allowed.

I’m sure where I got this phrase, but I sometimes refer to adjustment disorder as an acute compensatory reaction of psychiatrists seeking to bill for services.

The idea that this is a blinded trial is ridiculous. Very soon after administration of the drug,  patients and clinical and research staff knew whether the patients had received psilocybin or vitamin B3.

chalice used in studyA chalice was used to administer both psilocybin and vitamin B3. Once patients became unblinded by noticing any effects of the drug they had been given, the chalice added to the sense of this supposed to be a mystical experience. There is more than a little hokum in play.

We’re told little about the psychotherapy, but enough to reveal that it has strong nonspecific factors and should induce strong positive expectations.

Crossover designs provide weak evidence, particularly ones that are readily unblinded and if we are interested in any effects of the first treatment after the crossover. Patients immediately realized in the first session whether they were assigned to psilocybin or vitamin B3. Awareness of their first treatment assignment further unblinded them to the next phase of the trial. Patients who received psilocybin in the first session (and clinical and research staff assigned to them) knew that they were going to get. Because psilocybin was expected to have lasting effects, it would be predicted that patients assigned to the vitamin B3 in the second session would nonetheless exhibit the lowered self-reported symptoms, due to the effects of earlier psilocybin. So what was the point?

The crossover design means that any expected natural decline in distress will be folded into effect of treatment. That is, it’s well-known that the distress of cancer patients has a strong natural declining trajectory. That natural decline in distress will be interpreted as part of the effects of the treatment.

For each of the six primary outcome measures (HADS T, HADS A, HADS D, BDI, STAI S, STAI T), there were significant differences between the experimental and control groups (prior to the crossover at 7 weeks post-dose 1) with the psilocybin group (compared to the active control) demonstrating immediate, substantial, and sustained (up to 7 weeks post-dosing) clinical benefits in terms of reduction of anxiety and depression symptoms. The magnitude of differences between the psilocybin and control groups (Cohen’s d effect sizes) was large across the primary outcome measures, assessed at 1 day/2 weeks/6 weeks/7 weeks post-dose 1.

And:

Compared to the control, psilocybin produced mystical-type experiences, consistent with prior trials of psilocybin administration in normal volunteers (Griffiths et al., 2006, 2008, 2011).

Conflict of interest

 The authors declared no conflict of interest. However they indicate that a private foundation advocating use of psilocybin funded the study and professionals associated with this foundation provided preliminary review of the manuscript before it was published.

The foundation’s involvement in the funding study in vetting of the manuscript does not necessarily invalidate results reported in the manuscript, but readers have the right to be informed of this potential conflict of interest.

Coming up next: the Johns Hopkins study and integrated discussion

 Undoubtedly, ingesting psilocybin in a setting in which expectations are well structured can be a positive experience. I can say that from experience. Yet it is criminalized in the United States to sell, purchase, or ingest psilocybin. The study seems clearly aimed at creating a loophole for cancer patients who engaged psychiatrists. What’s wrong with that? What’s wrong with anybody being able to obtain psilocybin of assured purity and consume it in a pleasant safe environment with a knowledgeable guide whom they trust?

Suppose the cancer patient was a skeptic like myself and did not want to submit to the mumble jumble psychotherapy offered in this trial. Particularly if they were experienced taking psychedelics, as almost half of the patients were in the study, shouldn’t they be able to go to a primary care physician and get a prescription for psilocybin of known doses and purity, and go home and take it with a trusted friend or two? What if someone did not have cancer, but like many patients in primary care waiting rooms, had distress elevated to the degree that participants in the study did. Should they be allowed to self-administer psilocybin?

It’s a wise idea to take psilocybin with a knowledgeable friend in a context conducive to a good experience. Why should somebody have to involve a psychiatrist? People experience was psilocybin are aware in someone else’s experience is becoming anxiety provoking, and can usually appropriately distract them away and into a more pleasant experience.

It’s a wise idea not to go scuba diving alone, but to be accompanied by a knowledgeable friend. Should scuba divers also be required to take their psychiatrists along?

Okay, you as a reader may personally have no interest in taking psilocybin out of the presence of a psychiatrist anymore than having any interest in scuba diving, with or without a psychiatrist. You may even object to people doing so and considerate it foolish. But should the people, whether suffering from cancer or not, taking psilocybin at home with friends be subject to steep fines and jail time

We will next discuss the other study of psilocybin administered to cancer patients. We will also examine the larger issues of the commentaries that accompanied this set of articles and the press coverage that they were given.

In the meantime and afterwards, I certainly welcome back talk in comments on this blog.