Therapeutic use of classic psychedelics to treat cancer-related psychiatric distress

Ross frames the review around the clinical use of classic serotoninergic psychedelics (notably psilocybin and LSD) to treat psychiatric and existential distress in patients with cancer. Earlier clinical work from the 1960s and early 1970s produced promising early‑phase signals, particularly for cancer‑related psychological and existential distress, but research was interrupted by regulatory changes and only resumed in earnest in the early 1990s and 2000s. The author emphasises that contemporary trials are still relatively small and early‑phase, so while findings are encouraging they are not yet definitive with respect to establishing treatment efficacy. This paper sets out to systematically review clinical trials from the historical period and the recent resurgence of research, focusing on trials that treated seriously ill or terminal patients with classical psychedelics. Ross intends to describe the prevalence and impact of psychiatric and existential distress in cancer patients, review the historical and contemporary clinical trial literature on serotoninergic psychedelics for these indications, and discuss implications for future research and clinical availability of psychedelic‑assisted therapy in this vulnerable population.

Ross reports a systematic literature search of clinical trials examining classical psychedelics in patients with advanced or terminal illness, with an explicit focus on cancer‑related psychiatric distress. The authors state the search adhered to PRISMA guidelines and queried multiple electronic databases (PubMed, Cochrane, Embase, Google Scholar). The review aimed to capture peer‑reviewed clinical trial publications in which patients with serious medical illness were treated with a classical psychedelic (examples given: LSD, psilocybin, dipropyltryptamine/DPT). The extracted text contains an ambiguity in exact search dates: one statement extends the search until 1 February 2018, while another phrase indicates searching from 1 January 1960 to 31 January 2017; this inconsistency is present in the source and cannot be resolved from the extraction. Eligibility criteria were trials of psychedelic administration in patients with advanced or terminal illness; the review excluded non‑clinical reports. From this systematic search the authors identified 10 clinical trials comprising a total of 445 participants. They categorised these as six open‑label trials published between 1964 and 1980 (n = 341) and four randomised controlled trials (RCTs) published between 2011 and 2016 (n = 104). Across the identified trials, the serotonergic agents studied were predominantly LSD (reported n = 323), psilocybin (n = 92), and DPT (n = 30).

The review divides findings into the historical early‑phase literature and more recent randomised trials. Historical open‑label work (1960s–1970s) included the initial comparative and open studies led by Eric Kast and the Spring Grove programme. Kast's early comparative trial (LSD 100 mcg orally versus opioid comparators) in a medically ill sample reported acute analgesic effects of LSD lasting several hours and noted apparent reductions in fear of death. Subsequent larger open‑label series by Kast reported diminished pain perception extending up to two weeks, reductions in depressed mood, improved morale, reduced fear of cancer and death, improved sleep, and reports of mystical‑type experiences. The Spring Grove studies (total n = 83) used a treatment model paying attention to set, setting, and preparatory/integrative psychotherapy; of 31 participants analysed longitudinally, the authors reported statistically significant pre–post improvements in anxiety, depression, fear of death and isolation, and a global index indicating 71% of participants were assessed as dramatically or moderately improved. Two of these trials reported positive correlations between occurrence of a ‘mystical experience’ and clinical improvements. All historical studies were open‑label. Contemporary trials represent methodological improvements and include four RCTs. A small randomised, double‑blind, active placebo‑controlled, crossover LSD trial in Switzerland (n = 12) compared LSD 200 mcg with LSD 20 mcg and incorporated preparatory and integrative psychotherapy. Prior to the crossover, the high‑dose group showed significant short‑term reductions in state and trait anxiety (STAI‑state d = 1.1, p = .033; STAI‑trait d = 1.2, p = .021). A 12‑month follow‑up reported sustained anxiety reductions, improved quality‑of‑life, and no serious adverse events (SAEs) attributable to LSD in this cohort. Three US Phase II RCTs tested psilocybin‑assisted psychotherapy at academic centres (UCLA, Johns Hopkins University [JHU], NYU Langone). All three were double‑blind, randomised, used active placebo controls, provided psychotherapeutic preparation and integration, and screened to exclude psychotic spectrum illnesses. The UCLA crossover pilot (n = 12; psilocybin 0.2 mg/kg vs niacin) documented large subjective differences on altered‑states measures but failed to show statistically significant between‑group reductions in anxiety and depression prior to crossover; significant pre–post improvements were observed at later time points but attribution is limited by the crossover design and small sample size. The JHU trial (n = 51) compared a single high dose of psilocybin (0.31 mg/kg) with a very low psilocybin dose (1–3 mg/70 kg) in a crossover design with a 5‑week primary endpoint. Primary clinician‑rated outcomes were GRID‑HAM‑D‑17 and HAM‑A. Prior to crossover, high‑dose psilocybin produced large, sustained improvements up to 5 weeks post‑dose: 92% antidepressant response (≥50% improvement on GRID‑HAM‑D‑17) in the high‑dose‑first group versus 32% in the low‑dose‑first group at 5 weeks, and 76% anxiolytic response in the high‑dose‑first group versus 24% in the low‑dose‑first group. At 6‑month follow‑up (collapsed across sequences) overall response rates were 83% for anxiety and 78% for depression; remission rates were 57% for anxiety and 65% for depression. Participants commonly rated the experience among the most personally meaningful of their lives, and mystical‑type experiences both correlated with and partially mediated the therapeutic effects. No SAEs attributable to psilocybin were reported. The NYU trial (n = 29) tested psilocybin 0.3 mg/kg versus niacin 250 mg in a crossover design (7‑week primary endpoint) and reported rapid, large, and sustained reductions in anxiety and depressive symptoms prior to crossover. At 7 weeks post‑dose‑1, 58% of the psilocybin‑first group met criteria for anxiolytic response (HADS‑Anxiety) versus 14% in the niacin‑first group, and 83% met criteria for antidepressant response (BDI) versus 14% in the niacin‑first group. At final follow‑up (6.5 months), anxiolytic/antidepressant response rates were reported in the region of 60–80%. Complementary outcomes showed improvements in hopelessness, demoralisation, quality‑of‑life and spiritual well‑being; again, mystical‑type experiences correlated with and partially mediated clinical benefit. Across the recent trials, when rigorous screening and attention to set and setting were used, investigators reported no psilocybin‑ or LSD‑related SAEs attributable to the interventions.

Ross interprets the assembled evidence as indicating a promising therapeutic signal for classic serotonergic psychedelics, particularly psilocybin, in treating cancer‑related psychiatric and existential distress. The recent Phase II RCTs are emphasised as producing rapid, robust, and in many cases sustained improvements in anxiety and depression associated with life‑threatening cancer, with complementary improvements in existential outcomes and quality‑of‑life. The author highlights that mystical‑type experiences occasioned by psilocybin correlated with and partially mediated clinical benefit, echoing earlier open‑label findings. At the same time, the paper notes important limitations. Historical studies were open‑label and lacked rigorous controls; contemporary trials, while methodologically improved, remain relatively small and in early phases, and cross‑over designs complicate attribution of long‑term effects after the crossover point. The extracted text also makes clear that safety findings depend on careful screening (notably excluding psychotic spectrum disorders), controlled clinical settings, and structured psychotherapeutic support; these elements were integral to the absence of SAEs reported in the trials reviewed. Ross acknowledges speculative points in the discussion (for example, possible effects of treating psychiatric distress on cancer survival) and states that such ideas require further study. Looking ahead, the author outlines practical and regulatory implications discussed in the paper: planned Phase III trials (sponsored by Usona and others), potential re‑scheduling of psilocybin if advanced‑phase trials demonstrate clear efficacy, and the likely need for delivery via specially certified psychedelic‑assisted therapy clinics with trained therapists and strict protocols for patient safety and drug accountability. Ross also identifies research priorities such as validating the durability of single‑dose effects, evaluating booster or multi‑dose models, and establishing therapist training and regulatory frameworks before broad clinical implementation could be considered. Overall, the paper positions psychedelic‑assisted therapy as a promising but still investigational approach for cancer‑related psychiatric and existential distress.