Psilocybin, a Naturally Occurring Indoleamine Compound, Could Be Useful to Prevent Suicidal Behaviors

Research interest in psychedelic treatments has resurged over recent decades, with psilocybin emerging as one of the most intensively studied compounds. Earlier clinical work has associated psilocybin with rapid and sometimes sustained remission of depressive symptoms, prompting the United States Food and Drug Administration to designate psilocybin a “breakthrough therapy” for treatment‑resistant depression. Despite this progress, suicidal behaviours (suicide, suicide attempt) and suicidal ideation are generally treated as manifestations of other psychiatric disorders (most often major depressive disorder), and standard prevention strategies rely on antidepressants and psychotherapy. These approaches have limitations in suicidal populations: suicidal patients often respond less well to classic antidepressants, a minority experience treatment‑emergent or worsening suicidal ideation, some continue to have suicidal ideation despite improvement in depressive symptoms, and effective psychotherapy can be slow, costly, and difficult to access in crisis situations. Strumila and colleagues set out to review the evidence linking psilocybin’s pharmacology and psychological effects to pathophysiological systems implicated in suicidal behaviours, and to present a rationale for studying psilocybin as an intervention to reduce suicidal ideation and prevent suicidal acts. The review focuses on psilocybin’s actions on the serotonergic system (notably 5‑HT2A receptors), neuroplasticity (including BDNF and mTOR pathways), inflammatory and oxidative stress processes, and the psychological changes (e.g., cognitive flexibility, connectedness, autobiographical recall, mystical/quantum experiences) that might mediate clinical benefit. The authors also summarise preliminary epidemiological and clinical findings and outline priorities for future clinical trials.

The paper synthesises pharmacokinetic, pharmacodynamic, cellular, behavioural, epidemiological, and clinical evidence relating psilocybin to mechanisms implicated in suicidal behaviours. Pharmacokinetics: Psilocybin (4‑phosphoryloxy‑N,N‑dimethyltryptamine) is described as a prodrug converted rapidly to the active metabolite psilocin after oral administration. Psilocin appears in plasma within 20–40 minutes, with mean peak concentrations reported at 80–105 minutes (mean concentration 8.2 ± 2.8 ng/mL) after oral dosing; estimated oral bioavailability is approximately 50%. Intravenous administration produces faster and higher early plasma peaks (reported mean 12.9 ± 5.6 ng/mL at about 1.9 ± 1.0 minutes). Oral effects typically begin around 40 minutes and last 4–6 hours, whereas intravenous effects onset and offset are much faster. A small open‑label pharmacokinetic study of sequential ascending oral doses (0.3, 0.45, 0.6 mg/kg) in 12 healthy adults found no serious adverse events in the month following dosing. Pharmacodynamics and neurotransmission: Preclinical and human imaging data link most psychedelic effects to activation of serotonin receptors, in particular the 5‑HT2A receptor. Psilocin binds multiple serotonergic receptor subtypes (5‑HT1A, 5‑HT2A, 5‑HT2B, 5‑HT2C). Blockade of 5‑HT2A receptors with antagonists such as ketanserin abrogates many subjective effects, indicating a primary role for 5‑HT2A agonism. Psilocybin administration increases frontal cortical metabolic rates and alters activity in striatal and limbic structures on positron emission tomography. Preclinical data also suggest that 5‑HT2A activation can modulate mesoaccumbens dopamine release, which the authors link to potential amelioration of reward‑processing deficits observed in suicidal individuals. Neuroplasticity: The review summarises evidence that psilocybin stimulates neuroplastic mechanisms: 5‑HT2A activation on deep cortical pyramidal cells increases extracellular glutamate in the prefrontal cortex, activating AMPA and NMDA receptors and raising BDNF expression. Animal studies reported rapid increases in genes associated with plasticity (e.g., c‑Fos) and, in mice, an approximately 10% increase in the density and strength of neuronal connections in medial frontal cortex; dendritic spine growth was observed within 24 hours and persisted up to one month. Psilocybin’s effects on neuritogenesis appear to involve mTOR signalling, and rapamycin (an mTOR inhibitor) blocks these effects in experimental models. The authors note that reduced BDNF, lower mTOR expression, decreased cortical thickness and dendritic spine loss have been reported in suicidality and suicide decedents, and they propose that psilocybin‑induced plasticity could counteract these abnormalities. Anti‑inflammatory and antioxidant effects: Extracts of Psilocybe mushrooms inhibited lipopolysaccharide‑induced production of pro‑inflammatory cytokines (TNF‑α, IL‑1β) and reduced IL‑6 and COX‑2 concentrations in human macrophage cell models; Psilocybe cubensis extracts protected cardiomyocytes from TNF‑α‑induced injury. The authors highlight that 5‑HT2A receptor agonists can block TNF‑α effects in some vascular cell models and that glucocorticoid release observed after psilocybin/LSD administration may exert acute anti‑inflammatory effects. Peripheral and central expression of 5‑HT2A receptors in immune tissues is noted, raising the possibility of both central and peripheral anti‑inflammatory actions. Regarding oxidative stress, the review cites limited direct data but points to antioxidant properties of indole compounds and related findings for DMT and 5‑MeO‑DMT that may be relevant; a recent meta‑analysis associating suicide attempt history with increased nitro‑oxidative stress is also mentioned. Psychological effects and cognition: Psilocybin acutely disrupts default mode network integrity and increases between‑network connectivity, an effect described as acute desynchronisation or enhanced entropy. The authors argue that this acute state, combined with the subsequent neuroplastic window, can permit the formation of new cognitive and behavioural patterns. Clinically relevant psychological changes summarised include rapid increases in cognitive flexibility, acceptance, empathy, connectedness, improved emotional face recognition, reduced feelings of social exclusion, and enhanced vivid autobiographical recall—effects that could counteract cognitive rigidity, poor problem solving, social thwartedness, and overgeneral memory associated with suicidal risk. The review also emphasises that the intensity of mystical or “quantum change” experiences correlates with sustained positive outcomes in prior psilocybin trials. Epidemiological and clinical observations: Large‑scale epidemiological data are cited linking lifetime use of psilocybin and other classic psychedelics with lower odds of past suicidal behaviours and ideation in a sample of about 190,000 people. The authors acknowledge contradictory findings in older, heterogeneous studies but state that recent clinical trials (including open‑label studies and at least one randomised controlled trial) reported rapid reductions in suicidal ideation after psilocybin administration, with some effects persisting up to 6.5 months and no suicide‑related events reported in those trials. Studies of ayahuasca (a serotonergic psychedelic) similarly showed decreases in suicidal ideation in depressed patients. Safety and adverse effects: Physiologically, psilocybin is described as having a favourable safety profile; transient increases in heart rate and blood pressure occur, but cardiovascular events or deaths have not been reported after controlled administration. Psychological risks include challenging or disturbing experiences that can be traumatising for some patients, rare case reports of post‑traumatic stress following difficult sessions, and the theoretical risk of hallucinogen persisting perception disorder. The authors emphasise the importance of careful patient selection (excluding personal or family history of psychosis or active high suicide imminence), psychological preparation, continuous monitoring during sessions, and integration therapy afterwards. They also note practical considerations such as the need for a minimum antidepressant washout period of at least 7 days prior to psilocybin dosing.

Strumila and colleagues interpret the assembled evidence as providing a plausible mechanistic rationale for studying psilocybin as an intervention to reduce suicidal ideation and prevent suicidal behaviours. They argue that 5‑HT2A agonism can rapidly modulate inflammatory and oxidative pathways and trigger neuroplastic processes (via glutamate, AMPA/NMDA, BDNF and mTOR) that, together with acute changes in brain network dynamics and psychological experiences (increased cognitive flexibility, connectedness, and emotional breakthrough), may translate into clinically relevant reductions in suicidal ideation and risk. The review positions these putative mechanisms relative to existing treatments: psilocybin is proposed as complementary to, and potentially faster‑acting than, classic antidepressants and as an alternative or comparator to ketamine and esketamine, which also have rapid anti‑suicidal effects in some patients. The authors acknowledge important limitations and uncertainties in the current evidence base. They note that, to date, psilocybin has not been specifically tested in trials with suicidal behaviour or ideation as the primary outcome, and much of the evidence is indirect (preclinical, mechanistic, small open‑label trials, or epidemiological associations that may be biased). Earlier epidemiological studies produced mixed results and were often limited by confounding (for example, concomitant use of other substances) and small, biased clinical reports. Additionally, psychological harms are possible if psilocybin is used without medical supervision and careful patient selection. The review therefore emphasises that safety and efficacy must be established in controlled trials with adapted protocols for high‑risk populations. On practical implications, the authors recommend a staged clinical research approach. They propose initial trials comparing psilocybin to ketamine in patients a few days (at least 7) after a suicidal crisis (for example following a suicide attempt or hospitalisation for suicidal ideation), regardless of the underlying diagnostic category, with exclusion of patients at high risk of psychosis or imminent suicidal act. Such trials would incorporate strict medical supervision, psychosocial supports, and post‑session psychotherapy (for example mindfulness‑based approaches) to integrate the experience. If safety is demonstrated, subsequent trials should assess psilocybin’s effects on active suicidal ideation and suicidal behaviour as primary outcomes, and determine optimal dosing, clinical setting, and interactions with existing pharmacotherapies and psychotherapies.

The review concludes that psilocybin binds 5‑HT2A receptors and, through downstream actions, may rapidly suppress inflammation and oxidative stress while promoting neuroplasticity. These biological effects, together with acute and enduring psychological changes (greater cognitive flexibility, empathy, connectedness, and episodic recollection), form a coherent rationale for investigating psilocybin’s potential to reduce suicidal ideation and prevent suicidal behaviours. The authors consider psilocybin to have a favourable safety profile in controlled settings, but recommend carefully designed clinical trials—initially comparing psilocybin with ketamine in patients days after a suicidal crisis, excluding those at high psychosis or imminent risk, and pairing the intervention with psychotherapy and strict medical supervision—before studying its use in patients with active suicidal ideation.