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
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.
A 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 (Figure 3). 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 (Figure 3).
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.