Serotonergic hallucinogens in the treatment of anxiety and depression in patients suffering from a life-threatening disease: A systematic review

Receiving a diagnosis of a life‑threatening physical illness commonly provokes profound emotional distress, including fear, hopelessness, loss of meaning and higher rates of anxiety and depression. The authors note that these problems—often described as "existential distress"—are associated with poorer quality of life, reduced treatment adherence and higher mortality, and that current pharmacological options specifically targeting existential distress are lacking. Psychotherapeutic approaches that enhance meaning have been developed, but there remains interest in pharmacological adjuncts for patients whose distress is refractory to conventional care. Reiche and colleagues set out to review systematically the clinical evidence for classic serotonergic hallucinogens (primarily LSD and psilocybin, and in one trial DPT) in treating anxiety and depression among patients with life‑threatening disease. The review aims to summarise trials conducted across historical periods, assess methodological quality and safety, and highlight how conceptual approaches (for example the role of "mystical" or peak experiences and the importance of set and setting) have evolved over time.

The investigators conducted a systematic literature review following PRISMA principles, searching MEDLINE (PubMed), Embase, the Cochrane Library and Google Scholar. The Methods text in the extraction is incomplete regarding the precise start date wording, but elsewhere in the paper the search is described as covering studies between 1960 and 2017. The review targeted clinical trials that evaluated serotonergic hallucinogens in patients with life‑threatening diseases and associated anxiety or depressive symptomatology. Screening and selection proceeded in stages: the electronic search produced 1,674 hits; after removing duplicates and screening titles/abstracts, 89 abstracts were reviewed and 33 full texts were assessed. Non‑clinical reports, case reports, duplicate samples, studies with ineligible populations and review articles were excluded, leaving 11 clinical trials (total N = 445) for inclusion. The extracted text does not provide full details of specific inclusion/exclusion criteria, risk‑of‑bias assessment methods or the precise data‑extraction procedures; these details are not clearly reported in the provided Methods fragment. Included trials spanned earlier open‑label and pilot work from the 1960s–1970s through more recent controlled trials (2000–2016). The authors categorised studies by era and approach (analgesia‑focused early trials, psychedelic peak therapy and later randomized controlled designs), and summarised outcomes and adverse events across these studies.

The review identified 11 clinical trials comprising a total of 445 participants. Most studies involved patients with cancer (9 of 11 studies); six trials (N = 341) were published between 1960 and 2000, and five trials (N = 104) were published from 2000 to 2016. Across the included trials, seven investigated LSD, three investigated psilocybin and one investigated dipropyltryptamine (DPT), according to the extracted summaries. Clinical trials from 1960–2000: Early investigations included an LSD analgesia trial in terminal cancer patients (N = 50) that reported greater and longer‑lasting pain relief after LSD than after opioids, though the p‑value reported in the extraction appears ambiguous (text gives "p > 0.001", and the extraction does not clarify this). Subsequent work—particularly at Spring Grove Hospital—adapted substance‑assisted psychotherapy (SAP) methods with preparatory interviews, supportive settings and post‑session therapy. Open‑label pilot studies (combined N = 112 across several reports) tested high LSD doses (200–500 µg) and one trial tested DPT (75–127.5 mg, N = 30). In a high‑dose LSD sample (N = 22) 14 patients showed positive changes on a bespoke Emotional Condition Rating Scale (ECRS), with 6 showing dramatic improvements; peak experiences were associated with pronounced benefit. Another trial (N = 31) reported pronounced improvement in 9 patients and moderate improvement in 13 across multiple psychological domains (ECRS t = 9.8; p = 0.001 as reported). The DPT study (N = 30) found significant improvements on ECRS depression (t = 2.31; p = 0.03) and anxiety (t = 2.71; p = 0.01), and on the Personal Orientation Inventory in 'Time‑Competence' and 'Inner‑Directedness' (t = 2.22; p = 0.03 and t = 2.75; p = 0.01, respectively). Earlier studies that lacked psychological preparation reported high rates of benzodiazepine use for acute panic reactions, whereas those employing preparatory set and setting reported fewer psychiatric adverse events. Clinical trials from 2000–2017: More recent research employed randomization, active placebos and structured psychotherapeutic support. A double‑blind, crossover trial of psilocybin (0.2 mg/kg) versus niacin in 12 patients with advanced cancer‑related anxiety/adjustment disorders found significant reductions in State‑Trait Anxiety Inventory (STAI) scores at one month (t = 4.36; p = 0.001) and three months (t = 2.55; p = 0.03) after the second session; Beck Depression Inventory (BDI) scores decreased by nearly 30% at one month and reached significance at six months (t = 2.71; p = 0.03). An LSD pilot randomised study (N = 12; 8 received 200 µg, 4 received 20 µg as active placebo) embedded in psychotherapy reported significant reductions in STAI‑state (effect size d = 1.1; p = 0.033) and STAI‑trait (d = 1.2; p = 0.021) two months after the second session, with reductions sustained to 12 months; qualitative follow‑up described reduced fear of death and improved quality of life for many survivors. Larger psilocybin trials produced notable response and remission rates. In a randomized crossover study (N = 51) comparing a single high dose (22 or 30 mg/70 kg) with a low dose control, 78% of patients had a clinically significant response on the Hamilton Depression Rating Scale (≥50% decrease) at six months and 65% met remission criteria (≥50% decrease and HAM‑D ≤ 7). Hamilton Anxiety Rating Scale results at six months showed 82.5% response and 56.5% remission. Another crossover trial (N = 29) comparing a relatively high psilocybin dose (0.3 mg/kg) with niacin reported that seven weeks after the first dose, 83% of patients had a ≥50% decrease in BDI and 58% had similar reductions on HADS anxiety scores; at 6.5 months approximately 60–80% of patients exhibited clinically significant anxiolytic or antidepressant responses. Across recent trials, scores on mystical‑experience measures (MEQ30) correlated significantly with positive therapeutic outcomes. Adverse events: Across studies, adverse events were generally transient and manageable in the controlled clinical setting. Reported acute reactions included nausea, vomiting, headaches, tremor and transient increases in blood pressure; one recent trial reported a transient paranoid episode. No serious medical complications, persistent prolonged psychosis or clear cases of Hallucinogen Persisting Perception Disorder (HPPD) were reported in the included clinical trials. Early studies that lacked preparation reported higher rates of acute psychiatric reactions requiring benzodiazepines, whereas trials incorporating set, setting and preparatory support reported fewer such events.

Reiche and colleagues interpret the body of evidence as suggestive that serotonergic hallucinogens, when administered within a structured therapeutic framework, can reduce anxiety and depressive symptoms in patients with life‑threatening disease and may also improve coping and quality of life. The authors divide the literature into three historical groups: early analgesia‑focused trials where psychological effects were incidental; the 1960s–1970s "psychedelic (peak) therapy" studies that intentionally combined high doses with intensive preparation and integration; and recent trials that revive earlier methods while using lower doses (often of psilocybin) and stronger methodological rigour such as randomization and controlled designs. The investigators emphasise that mystical‑type or peak experiences have repeatedly been associated with better outcomes, suggesting a mechanistic role that echoes historical PDT concepts, but they caution that peak experiences are not the sole pathway to benefit—some patients improve without reporting such experiences while others report mystical experiences without lasting change. Methodological limitations are highlighted: inadequate blinding because of obvious psychoactive effects, frequent use of crossover designs that expose control participants to the active treatment, small sample sizes, strict exclusion criteria and a high prevalence of prior hallucinogen use and higher education among participants, all of which limit generalisability and introduce potential bias. Regarding safety, the authors conclude that serotonergic hallucinogens have a reasonable safety profile in controlled settings when appropriate screening, preparatory support and monitoring are used. They acknowledge rare reports of long‑term adverse psychiatric outcomes historically and note that most contemporary trials report only transient adverse reactions. The paper calls for further rigorous trials to determine how these results could be implemented in clinical practice, while also recognising ethical considerations that have influenced study designs (for example, the difficulty of withholding a potentially beneficial treatment in patients with limited life expectancy).

The authors conclude that substance‑assisted psychotherapy with serotonergic hallucinogens shows some evidence of efficacy for anxiety and depression in patients with life‑threatening disease and appears well tolerated in controlled clinical environments. They state that mystical‑type experiences may contribute to symptom reduction and enhanced disease coping, but emphasise that additional trials are required to establish how these findings can be translated safely and effectively into routine clinical practice.