Psilocybin as a Novel Pharmacotherapy for Treatment-Refractory Anorexia Nervosa

Rodan and colleagues frame anorexia nervosa (AN) as a severe, treatment‑resistant psychiatric disorder with very high morbidity, mortality and health‑care costs, and with few effective pharmacological options. They note that adult psychotherapies such as cognitive behavioural therapy (CBT) produce modest remission rates (typically ≤ 50%) and high drop‑out and relapse rates, and that an urgent need exists for novel interventions that can address treatment resistance and chronicity in AN. The introduction also summarises a resurgence of clinical interest in classic psychedelics over the past two decades, especially psilocybin, which has shown rapid, durable reductions in anxiety and depression after one or two doses in several preliminary studies; because anxiety and depression are common and prognostically important co‑morbidities in AN, this literature is positioned as clinically relevant. This review sets out to examine the therapeutic rationale for applying psilocybin to treatment‑refractory AN. The authors aim to integrate clinical, preclinical and neurobiological evidence on psilocybin — covering acute effects, safety, mechanisms (serotonergic modulation, network connectivity, neuroplasticity) and outcomes in conditions that commonly co‑occur with AN — to assess whether psilocybin‑assisted therapy warrants clinical investigation in AN and to identify key research questions and limitations for future trials.

This paper is a narrative review. Literature searches used combinations of terms related to classic psychedelics and eating disorders (for example, “psilocybin” AND depression*/anxiety*/substance abuse disorders*/PTSD*/autism spectrum disorder*/neuroplasticity*/safety*/eating disorders*; “anorexia nervosa” AND psychotherapy*/pharmacological treatments*/cognitive flexibility*/serotonin*/co‑morbidities*/treatment‑resistant*). The authors included peer‑reviewed original research, reviews, case reports and animal studies retrieved from databases such as PubMed, ScienceDirect, SpringerLink and Elsevier. The review synthesises evidence from human experimental and clinical studies, open‑label and small controlled trials, population surveys, preclinical models, and neuroimaging and neurobiological investigations. The authors do not report a formal systematic review protocol, pre‑specified inclusion/exclusion criteria, or quantitative meta‑analytic methods within the extracted text; instead, they integrate findings thematically (history and resurgence, acute and long‑term effects of psilocybin, relevance to AN psychopathology and co‑morbidities, neural mechanisms, safety and limitations of existing evidence).

The review summarises several literatures relevant to the potential use of psilocybin in AN. Clinical signal in related disorders: Small open‑label and early controlled trials indicate rapid and sometimes durable therapeutic effects of psilocybin in depression, anxiety associated with life‑threatening illness, obsessive‑compulsive disorder (OCD), and substance use disorders. Reported figures include: in open‑label trials of treatment‑resistant depression (TRD), one study of 12 patients found 67% had clinically significant antidepressant effects at 1 week and 58% met remission criteria; 42% remained in remission at 3 months. Another open‑label TRD study (n=20) reported 47% maintained clinically significant antidepressant responses at 5 weeks. In patients with major depressive disorder, one study reported 67% with clinically significant reductions at 1 week and 58% in remission, with 71% maintaining antidepressant effects at 4 weeks. A randomised trial comparing two doses of psilocybin with a 6‑week course of escitalopram in 57 patients found clinically significant antidepressant effects in 70% of the psilocybin group versus 47% with escitalopram, and remission rates of 57% versus 28%. For anxiety in cancer patients, several small trials reported substantial and sustained anxiolytic responses: one report of 29 individuals found 60–80% met criteria for clinically significant anxiolytic response at 6.5 months; a randomised, double‑blind crossover trial in 51 cancer patients reported 83% maintained clinically significant anxiolytic responses at 6 months and 57% were in remission. In nine patients with refractory OCD, reductions of 23–100% in obsessive‑compulsive symptoms were reported following psilocybin. For substance use disorders, proof‑of‑concept studies reported reductions in drinking for up to 8 months after one or two psilocybin sessions in alcohol dependence, and an 80% smoking abstinence rate at 6 months after two doses in long‑term heavy smokers. Relevance to AN psychopathology: The authors highlight that anxiety (including OCD and social phobia), depression and substance misuse are common co‑morbidities in AN and contribute to treatment resistance. They note that psilocybin induces acute effects that may be therapeutically relevant: increased openness, emotional empathy, insightfulness, cognitive flexibility, and ‘‘emotional breakthrough’’ experiences. These changes are argued to facilitate engagement with psychotherapy, increase motivation to change and reduce emotional avoidance — processes that are commonly impaired and predict poor outcomes in AN. Neurobiological mechanisms: Psilocybin acts primarily via agonism at serotonin 5‑HT2A receptors (and has affinity for 5‑HT2C and 5‑HT1A), with subjective intensity correlating with 5‑HT2A receptor occupancy and plasma psilocin levels. Imaging studies report that psilocybin decreases activity in connector hubs (salience network, executive control network and default mode network) and increases connectivity across brain networks; the authors link this to enhanced cognitive flexibility. Preclinical and in vitro evidence indicates psychedelics can increase neurotrophic factors such as brain‑derived neurotrophic factor (BDNF) and glial cell line‑derived neurotrophic factor (GDNF), suggesting a mechanism for enduring changes in mood and cognition. The review also summarises evidence of serotonergic dysregulation in AN from PET and related studies and reports low BDNF in AN, supporting a biological rationale for targeting serotonergic signalling and plasticity. Safety and adverse effects: The authors report that clinical use of psilocybin in controlled settings has a favourable safety profile: no overdose‑related deaths reported, low potential for dependence, and transient physiological effects (increases in heart rate and blood pressure) that have not reached hazardous levels in trials. Psychological adverse effects reported include transient anxiety, fear, nausea, paranoia and headaches. A survey of nearly 2,000 people who had challenging experiences with psilocybin during illicit use found 11% reported the episode placed themselves or others at risk and 7.6% sought treatment for enduring psychological symptoms a year later; however, at least 84% of that sample reported benefiting from the challenging experience. The authors note exclusion of individuals with current schizophrenia‑spectrum or bipolar disorders in trials to mitigate psychosis risk. Dose ranges discussed include low doses from about 2 mg up to high doses around 28 mg and, in some studies, up to 0.6 mg/kg (~45 mg for a 75 kg person). The review also references a comparison suggesting higher doses produced larger reductions in depressive and anxiety symptoms than low doses at follow‑up (for example, at 5 weeks 92% versus 35% had clinically significant depression improvements in one reported comparison, and 76% versus 24% for anxiety), supporting the view that a full psychedelic experience may yield stronger therapeutic effects than microdosing. Limitations of the existing evidence: The authors consistently emphasise that most clinical data derive from case reports, open‑label feasibility studies and small crossover trials, with few high‑quality double‑blind randomised controlled trials. They note biases related to limited blinding and frequent absence of control groups, and acknowledge that more rigorous replication in larger controlled trials is necessary.

Rodan and colleagues interpret the assembled evidence as providing a plausible therapeutic rationale for investigating psilocybin‑assisted therapy in treatment‑refractory AN. They argue that psilocybin’s rapid and durable anxiolytic and antidepressant effects in other disorders, together with its effects on cognitive flexibility, emotional processing and neuroplasticity, align with key psychopathological features of AN — namely pathological anxiety around food and weight, cognitive rigidity, serotonergic dysregulation and reduced neurotrophic signalling. The authors posit that these mechanisms could increase motivation, reduce emotional avoidance, and create a ‘‘therapeutic window’’ during which psychological interventions might be more effective. They position the review within the current evidence base by acknowledging encouraging preliminary signals across a range of psychiatric conditions but emphasise the paucity of high‑quality RCT data. The authors note that several phase 1 open‑label trials of psilocybin in AN have been approved at Imperial College London, Johns Hopkins University and the University of California (San Diego), but stress these are small, uncontrolled and non‑blinded and thus will provide only preliminary safety and feasibility data. Key methodological challenges for future research discussed by the authors include difficulties in blinding psychedelic interventions and distinguishing drug‑specific effects from expectancy and therapeutic context effects; they call for carefully controlled trials despite these obstacles. The review lists specific unanswered questions to guide future research: whether psilocybin as an adjunct to psychotherapy can increase treatment acceptance and remission, reduce dropout and relapse, reduce AN psychopathology and co‑morbid symptoms, and promote weight gain and recovery. The authors also suggest exploring other classic psychedelics (LSD, DMT, 5‑MeO‑DMT, mescaline) and investigating efficacy across other eating disorders. They conclude that while safety in controlled settings appears acceptable and the biological and behavioural phenotype of AN provides a compelling rationale, rigorous placebo‑controlled and larger trials are required to validate efficacy and inform evidence‑based clinical practice.