Compassionate use of psychedelics

Psychedelics—here focused on psilocybin and MDMA—are psychoactive substances that produce marked changes in perception, affect and cognition. After decades of prohibition following mid‑20th century research, recent clinical studies have rekindled interest in therapeutic applications, with psilocybin and MDMA attracting attention for cancer‑related distress, depression, addiction and post‑traumatic stress disorder (PTSD). Both substances remain investigational and have been granted breakthrough therapy designations, but are not yet approved medicines; nevertheless, regulatory mechanisms such as compassionate use / expanded access allow seriously ill patients who have exhausted proven options to request investigational therapies outside clinical trials. Greif and Šurkala set out to consider whether compassionate psychedelic therapy (PT) can be ethically permissible. Rather than addressing all procedural issues of conducting PT, the paper focuses on a fundamental question: can compassionate PT ever be ethical? To answer this, the authors review available evidence on safety and efficacy for psilocybin and MDMA, advance a beneficence‑based defence of compassionate use, and respond to a specific philosophical objection—that PT causes epistemic harm by foisting metaphysical delusions—arguing that the objection is unsubstantiated given current evidence and conceptual issues.

This paper is a philosophical and ethical analysis supported by a narrative review of clinical and safety literature on psilocybin and MDMA. Rather than reporting a systematic search strategy, the authors draw on prominent clinical trials, pooled phase II analyses, historical data, and selected safety reports cited in the text (for example, early‑21st‑century psilocybin studies in cancer patients and pooled MDMA phase II PTSD trials). The extracted text does not provide information about databases searched, search dates, or formal inclusion/exclusion criteria, so the review should be understood as selective rather than systematic. Methodologically, the study combines empirical summary and normative argumentation. Empirical material on pharmacology, therapeutic outcomes and adverse events is used to assess the risk–benefit ratio of compassionate PT. Normative work proceeds in two strands: a beneficence defence that evaluates expected value comparisons between compassionate PT and alternatives (routine care, palliative care or no care), and a conceptual critique of an epistemic harm objection advanced by Letheby. The authors examine the premises of Letheby’s argument, consider evidential and conceptual shortcomings, and discuss regulation‑dependent objections (such as effects on clinical‑trial enrolment) while explicitly focusing their normative conclusions on regulation‑independent considerations.

On psilocybin, the authors report that its pharmacodynamic profile resembles LSD but with a shorter clinical duration (approximately 6 hours), and that single administrations can produce long‑lasting therapeutic effects, plausibly via changes to dysfunctional neuronal circuitry and increased global cortical connectivity. Clinical findings summarised include a 2011 study of 12 advanced‑cancer patients given a medium dose (0.2 mg/kg) versus niacin, which showed continual and significant reductions in depression and anxiety over 6 months. A 2016 trial in 51 cancer patients comparing very low (0.01–0.004 mg/kg) and very high (0.31–0.43 mg/kg) doses reported that 60% of high‑dose participants lost depressive/anxiety symptoms. A further study in cancer‑related adjustment and generalised anxiety disorder similarly found about 60% complete remission following high‑dose psilocybin; a British 2016 study reported significant antidepressant effects in treatment‑resistant depression. Safety data indicate very low toxicity: no documented human deaths directly attributable to psilocybin in the cited data, typical trial doses around 0.4 mg/kg, and animal LD50 values reported as 285 mg/kg (mice) and 12.5 mg/kg (rabbits). Common acute effects include pupil dilation, modest cardiovascular changes, nausea and transient perceptual alterations; panic reactions and prolonged unpleasant experiences (“bad trips”) have occurred. Psychotic reactions are rare but documented: historical data cited show 5 cases per 5,000 general‑population exposures and 37 cases per 4,300 psychiatric‑patient exposures (figures the authors translate to roughly 4 per 1,000 administrations in psychiatric patients, or one per 1,338 administrations). Post‑hallucinogen perceptual disorder (HPPD) is estimated at about 1%, with substantial unpleasantness in many affected individuals. Some studies also report personality shifts (increased openness, decreased neuroticism) following psychedelic experiences. Regarding MDMA, the paper describes it as an empathogen/entactogen with a different mechanism than classical psychedelics, typically dosed at 60–125 mg, and noted for increasing serotonin, noradrenaline, dopamine and oxytocin and modulating amygdala–hippocampus connectivity. The authors cite a pooled analysis of six phase II PTSD trials (2004–2017) showing that after two months 54.2% of MDMA‑assisted participants no longer met PTSD criteria versus 22.6% in control groups, and that 66.2% were in remission at one year. Trials administered MDMA on one or two occasions alongside psychotherapy and reported improvements in sleep, emotional regulation and coping. Safety findings from phase II trials list transient adverse effects such as insomnia, nausea, bruxism, impaired concentration, dry mouth and thirst; anxiety, headache and appetite loss affected 40–60% of participants but were usually short‑lived. Clinical monitoring recorded temporary blood‑pressure elevations (occasionally above 140/90 mmHg) and modest increases in body temperature (1–1.5 °C), prompting exclusion of patients with cardiovascular risk. Neurotoxicity concerns derive primarily from high‑dose animal studies; the authors report no clinical‑trial evidence of neurotoxicity when MDMA is administered in controlled settings and note only minimal abuse potential observed in trials. Isolated serious events in the cited phase II programme included pre‑existing suicidal behaviour prior to MDMA exposure in one case and supraventricular extrasystoles in another. On the broader question of risk–benefit and the rationality of compassionate use, the authors present empirical and probabilistic considerations used to evaluate expected value. They acknowledge general drug‑development attrition—cited estimates include an overall 11.83% chance of approval for drugs in clinical testing, with 20.5% of attrition due to safety and 35.3% due to efficacy concerns, and an estimate that 54% of late‑stage candidates fail (57% for efficacy, 17% for safety). Despite these sobering rates, the authors argue that (1) the existing PT literature shows a relatively favourable safety and efficacy record compared with many investigational drugs and (2) for severely ill patients who have exhausted options, the expected benefit of PT may exceed the expected value of alternatives. They also note regulation‑dependent objections (such as potential undermining of trial enrolment) but avoid jurisdiction‑specific policy prescriptions in this paper. Finally, the authors present a critical review of the epistemic harm argument (Letheby): they reconstruct it as premises P1–P4 (mystical experience as mechanism, naturalism true, mystical experience foists delusions, therapeutic foisting of delusions is impermissible) and offer empirical and conceptual rebuttals. Key counterpoints include that the epistemic‑harm claim applies to classical psychedelics but not MDMA; that mystical experience is not definitively shown to compel non‑naturalistic beliefs; that mystical‑type experience is not the sole or necessary therapeutic mechanism; and that philosophical naturalism is not a settled empirical truth that could ground an epistemic‑harm verdict. The authors further argue that diagnosing metaphysical beliefs as delusions is problematic and that proposed remedial steps (for example, “philosophical therapy” to correct metaphysics) would be ethically dubious.

Greif and Šurkala interpret the reviewed empirical literature and conceptual analysis to conclude that compassionate psychedelic therapy can be morally permissible on beneficence grounds for at least some patients. They maintain that, although psilocybin and MDMA are investigational and outcome uncertainty exists, expected‑value calculations can justify compassionate use when the likely benefit outweighs risks and when patients have exhausted proven options. The paper positions these conclusions with respect to earlier research by noting the encouraging single‑ or limited‑dose effects reported in modern trials and the relatively favourable safety profiles observed under controlled, therapeutic conditions. When addressing objections, the authors treat regulation‑dependent concerns—such as potential impacts on clinical‑trial enrolment and public‑health considerations—as context‑sensitive and therefore outside the primary focus of their regulation‑independent ethical argument. A novel epistemic‑harm objection is examined in detail; the authors find it unsubstantiated because its key premises lack empirical support or rest on contestable metaphysical claims. They emphasise that the epistemic‑harm argument applies mainly to classical psychedelics (psilocybin/LSD), not to MDMA. Limitations acknowledged by the authors include the inherent uncertainty of investigational treatments and the possibility of suboptimal or problematic uses of psychedelics, including undesirable personality changes. They also recognise practical ethical concerns raised earlier in the paper—difficulties in obtaining informed consent for ineffable experiences, maintaining clear sexual and professional boundaries in therapy, and managing suggestion and expectation—but explicitly limited their main inquiry to permissibility rather than procedural implementation. The authors call for further scientific investigation to clarify long‑term effects, mechanisms of therapeutic benefit, and the ethical implications that will follow improved empirical knowledge.

The paper concludes that, based on a review of safety and efficacy literature and on normative analysis, compassionate psilocybin‑ and MDMA‑assisted therapies can be rational for some patients and therefore morally permissible under a beneficence rationale. The authors reiterate their responses to two primary regulation‑independent objections: first, that outcome uncertainty does not render compassionate PT irrational because expected‑value reasoning can favour PT for severely ill patients; second, that concerns about epistemic harm are not substantiated given the lack of evidence that mystical experiences compel metaphysical delusions and given the contested status of metaphysical claims in medicine. They nonetheless caution that problematic uses and unwanted personality changes are possible and call for continued scientific and ethical reflection as understanding advances.