1. Simoneaux, Richard

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With the technological advances that have been made in diagnostics for cancer, more disease is being detected at an earlier stage. Although this generally improves the patient's chances for survival, a diagnosis of cancer can often provoke significant psychological distress in patients. A significant number of cancer patients will ultimately be affected by conditions such as anxiety and depressive disorders.

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These cancer patients often exhibit existential distress, the term often applied to the mental stress observed in patients who are facing end-of-life issues. This condition is often associated with hopelessness, demoralization, loss of purpose or meaning, and a loss of dignity, which often leads to patient isolation.


All too often, medical care providers are focused only on treating their patient's malignancy, instead of treating the whole patient. Consequently, the clinically significant depression and anxiety which often accompany a cancer diagnosis are frequently neglected or inadequately addressed. This often results in negative patient outcomes such as: increased desire for death and rates of suicidality, lower survival rates, diminished quality of life and therapy adherence.


The use of psychotropic substances to treat patients with cancer-related distress has become somewhat commonplace despite the relative scarcity of data supporting the efficacy of such therapies in this patient population. As a result, studies have begun to explore the use of less traditional therapies, including the use of psilocybin, a naturally occurring tryptamine analog which is the active component of psychedelic mushrooms.


One recent placebo controlled, randomized, blinded, crossover clinical study (NCT00957359) evaluated the use of a single dosing session of psilocybin (0.3 mg/kg) versus a single dosing session of the active control niacin (250 mg) in conjunction with psychotherapy as a treatment for clinically significant anxiety or depression in patients diagnosed with life-threatening cancer (J Psychopharmacol 2016; 30: 1165-1180).


The principal investigator on this study was Stephen Ross, MD, Associate Professor in the Department of Psychiatry at New York University School of Medicine. In a recent publication, Ross and colleagues presented an analysis of the long-term follow-up for 15 of the 16 surviving patients included in their 2016 clinical study (J Psychopharmacol 2020; 34: 155-166).


"The findings of this long-term follow-up study give the first suggestion of persistent and long-term effects for psilocybin-assisted psychotherapy in patients with cancer-related distress," he noted.


Study Details

In the 2016 crossover study, a total of 29 patients were randomized to one of two dosing regimens: psilocybin (3 mg/kg) followed by niacin (250 mg) or niacin (250 mg) followed by psilocybin (3 mg/kg). Patient randomization was not stratified according to any particular demographic (e.g., race, gender, or religious or spiritual affiliation) or clinical characteristic (e.g., cancer disease stage or prior hallucinogen use).


The treatment regimen was as follows: baseline assessments, followed by administration of dose 1 (psilocybin or control) 2-4 weeks (a mean of 18 days) later; crossover occurred 7 weeks (a mean of 52 days) after dose 1; at that point dose 2 (psilocybin or control) was administered. Assessments were performed at the following time points: baseline (2-4 weeks before dose 1), 1 day before dose 1, the day of dose 1 (at 7 hours post-dose), 1 day after dose 1, 2 weeks after dose 1, 6 weeks after dose 1, 7 weeks after dose 1 (1 day before dose 2), the day of dose 2 (7 hours post-dose), 1 day after dose 2, 6 weeks after dose 2, and 26 weeks after dose 2. The total length of the study was roughly 9 months.


Prior to taking dose 1 of the investigational compound, the patients received 3 2-hour counseling sessions over a period of 2 to 4 weeks. If sufficient rapport had not been reached between the researcher and the patient, that patient was removed from the study. During dosing, the researcher remained with the patient until both agreed that the patient was no longer impaired by the investigational compound. In the first 6 weeks following dose 1 and dose 2, the patients had a minimum of 3 2-hour counseling sessions with Ross to integrate their psychedelic experiences. In the 6 months following dose 2, patients had a minimum of monthly meetings either via telephone or in-person with the researcher.


The primary study outcomes were anxiety and depression, which were assessed prior to the crossover occurred. The secondary study outcomes, which were measured both before and after the crossover, included assessments of the following: existential distress, quality of life, and spirituality, and surrogates for the immediate and prolonged effects of psilocybin dosing (e.g., subjective or mystical experiences, cognition, affect, spirituality, and behavior).


"Prior to the crossover portion of the study," Ross noted, "psilocybin elicited an immediate, substantial, and prolonged improvements in anxiety and depression, which led to decreases in cancer-related demoralization and hopelessness, improved spiritual well-being, and in general, increased quality of life.


"At the six-and-a-half month follow-up, psilocybin was associated with durable anxiolytic and anti-depressant effects, with nearly 60-80 percent of the patients continuing with clinically significant reductions in anxiety and/or depression, sustained benefits in existential distress, quality of life, and improved attitudes towards death and end of life," he added. "The psilocybin-induced mystical experience appeared to have an association with the magnitude of the therapeutic effect of psilocybin on anxiety and depression, although further studies will need to be performed to sort out these relationships."


Long-Term Follow-Up Analysis

The participants in the long-term follow-up study had previously completed treatment in the parent study (NCT00957359). "Of the original 29 participants, we contacted the 16 surviving participants at the time of long-term follow-up," Ross explained.


While all 16 surviving participants agreed to be contacted about future research opportunities, only 15 agreed to participate in the long-term follow-up study and completed measures via a secure online portal. In the interim between completion of the first long-term follow-up (which included 15 participants) and completion of the second long-term follow-up, one participant died as a result of cancer-related complications, thus leaving 14 patients for the second long-term follow-up. The first long-term follow-up occurred at an average of 3.2 years (range: 2.3-4.5 years), while the second long-term follow-up occurred on average of 4.5 years (range: 3.5-5.5 years) following the patients' psilocybin dosing date, respectively.



In noting the positive results obtained for their follow-up analyses, Ross stated, "Psilocybin appears to work rather rapidly to reduce depression and anxiety in these patients with cancer that are facing end-of-life issues. In addition, these positive effects are noted when the patients are taking only one or two doses of psilocybin, which means that there is the potential for fewer dosing-related toxicities associated with its administration. Importantly, there are no medications that are currently approved for the treatment of patients exhibiting existential distress.


"Patients often described their dosing experience as 'epiphanous' or 'transformative,' while approximately three-fourths of the participants felt that their psychedelic experience was the most spiritual experience of their life," he explained.


When asked about some of the more surprising results obtained in their study, Ross replied, "What is amazing about these results is that patients will take only 1 or 2 doses of psilocybin and have durable responses to their existential distress, often lasting many years."


On potential limitations of their study, Ross noted, "One major limitation to this study was that this was a cross-over study and not a parallel study. Another clear limitation, was the relatively small number of patients included in the study.


"Clearly we are hoping that a loosening of the restrictions imposed on psilocybin occurs, as that would make it considerably easier to perform larger studies with this potentially important drug," he added.


When queried about next steps for exploring psilocybin use in cancer patients, Ross stated, "We would like to perform larger studies to assess the efficacy of this potentially transformative therapy; I have written proposals for performing one such study with up to as many as 150 patients. It would be very important for us to replicate the very positive results obtained in the earlier study that included much fewer patients."


Richard Simoneaux is a contributing writer.