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

This review (2021) presents a framework to understand the basis for using psilocybin to treat individuals with suicidal behaviours. The positive effects psilocybin has on suicidal behaviours are discussed, specifically its role as a 5-HT2A receptor agonist and its ability to increase neuroplasticity and suppress inflammation.


“The available interventions for people who are at risk of suicide have limited efficacy. Recently, research on new mental health treatments has started to consider psychedelic compounds, particularly psilocybin, a molecule with a few thousand years of history of use in human societies. The possible effects of psilocybin on suicidal ideation and behaviors have not been specifically studied yet; however, the current knowledge on the suicidal process and the available data on es/ketamine suggest that psilocybin could be used to modulate the thoughts and behavioral patterns in individuals who are at risk of suicidal behaviors. Here, we summarize the available evidence on the possible mechanisms underlying psilocybin positive effects on suicide risk. Major pathways related to suicidal behaviors that might be modulated by psilocybin include serotonin receptors. Specifically, psilocybin directly stimulates the serotonin 2A receptor (5HT2A), targeting the inflammatory and oxidative stress pathways and leading to a rapid increase in brain plasticity and inflammation suppression and increases in cognitive flexibility, spirituality, and empathy. We also present preliminary epidemiological data and provide a rationale for studying psilocybin in individuals with suicidal ideation or who are at risk of suicidal behaviors. This review presents a framework to understand the basis for psilocybin use in individuals who are at risk of suicidal behaviors and calls for clinical studies.”

Authors: Robertas Strumila, Bénédicte Nobile, Laura Korsakova, Aiste Lengvenyte, Emilie Olie, Jorge Lopez-Castroman, Sébastien Guillaume & Philippe Courtet



The available interventions for people who are at risk of suicide have limited efficacy. Recent research has started to consider psilocybin as a potential treatment, and preliminary epidemiological data suggest that psilocybin may have positive effects on suicidal ideation and behaviors.

  1. Introduction

Research on psilocybin has focused on treatment-resistant depression, addiction, eating disorders, and end-of-life anxiety in patients with cancer. However, psilocybin may also be useful to prevent suicidal behaviors and decrease suicidal ideation.

Despite its entry in the 5th edition of the Diagnostic and Statistical Manual (DSM5) as a putative disorder, suicidal behavior is generally considered as a symptom or a consequence of a concomitant psychiatric disorder, most frequently major depressive disorder. Antidepressants and psychotherapy remain the two main strategies to prevent suicidal behavior and to reduce suicidal impulses. SB and SI are major public health problems. Psilocybin, a new drug, may be an interesting alternative because it acts on mechanisms implicated in SB and SI physiopathology, produces results with just one administration, and does not require co-therapy with a classic antidepressant after intake.

Psilocybin and other psychedelic compounds have been linked to lower odds of past SI and SA in a large American epidemiological study. A recent systematic review found that psychedelics used in nonclinical (e.g., recreational, mystical) and clinical contexts have contradictory effects on suicidality. However, recent clinical trials showed that psilocybin can reduce suicidality in patients with SB. Psilocybin decreases SI in patients with major depressive disorder and treatment-resistant depression, and in old long-term AIDS survivors. It also decreases SI in patients with advanced cancer and in patients with major depressive episode. Although psilocybin has never been specifically studied for suicidality, preliminary data suggests that it may be useful to prevent suicide.

Psilocybin has pharmacological effects on the serotonin system, neurotrophic factors, and inflammatory and oxidative systems, which may explain its anti-suicidal effects.

  1. Suicidal Behaviors Need Specific Therapeutics

Despite the fact that suicidal patients are almost systematically excluded from clinical trials, it is now possible to conduct a safe protocol within this patient population. Furthermore, growing evidence suggests that suicidal behavior has its own physiopathology, which must be studied independently and in addition to depression.

Several recent studies suggest that patients with depression and SB/SI may represent a different group from patients without SB/SI. The course of the depressive symptoms is different in suicidal patients with depression compared to non-suicidal patients with depression. Laboratory/imaging parameters are different between suicidal and non-suicidal patients. Suicidal patients present lower serotonin transporter binding in the midbrain and lower basal cortisol levels and interleukin-2 levels than depressed patients without history of SA.

  1. Psilocybin Pharmacological Properties

Psilocybin, an indoleamine, is the main psychoactive compound of Psilocybe mushrooms and was first synthesized in 1958. It was marketed as a promising agent for psychiatric disorders.

3.1. Pharmacokinetics

Psilocybin cannot freely cross the blood – brain barrier, so it should be considered as a pro-drug and psilocin as the active metabolite. Psilocin is detected in the plasma 20 – 40 min after oral administration, and the plasma concentration reaches a peak at 80 – 105 min post-administration.

Psilocybin was not found in plasma or urine in 12 healthy adults after sequential, escalating oral doses of 0.3, 0.45, and 0.6 mg/kg. No serious side effects were reported in the month following administration.

Psilocin is excreted mainly in the urine, followed by bile and feces. Up to 20% are retained for longer, and significant quantities are still found in urine at day 7 post-administration.

3.2. Pharmacodynamics

Classic psychedelics differ between each other in terms of receptor binding specificity, and exert their hallucinogenic effects through serotonin receptor activation in the cortical and subcortical structures.

Psilocybin interacts with the serotonergic system, especially with the 5-HT2A receptor, and is linked to increased memory formation, learning, and contraction of the bronchial and gastric smooth muscles, as well as the cardiovascular and gastrointestinal anti-inflammatory effects and the release of certain hormones.

Although the binding to 5-HT2A receptors explains most of the effects of psilocybin, interactions with other pre- and post-synaptic 5-HT subtypes might also contribute. Furthermore, increased dopamine levels in the mesoaccumbens pathway might help to ameliorate reward deficits in suicidal patients.

  1. Neuroplastic Changes in Neurons and Synapses

Psilocybin increases the extracellular glutamate levels in the pre-frontal cortex (PFC) by stimulating the 5-HT2A receptors on large glutamatergic pyramidal cells in the deep cortical layers (V and VI) projecting to the layer V pyramidal neurons, resulting in increased PFC neuroplasticity via BDNF increase and other mechanisms. Psilocybin increases the density and strength of neuronal connections in the medial frontal cortex and promotes neuritogenesis, which increases dendritic arbor complexity. This effect is blocked by treatment with rapamycin, an mTOR inhibitor. Psilocybin intake leads to a global decrease in functional network integrity but higher connectivity between networks, which could stimulate the creation of new behavioral and thought patterns.

Psilocybin could be beneficial in patients who are at a high risk of suicide because SB have been associated with neuroplasticity dysfunction (e.g., low BDNF levels) and with decreased cortical thickness, a decreased number of dendritic spines, and the atrophy of neurons in the PFC.

  1. Anti-Inflammatory Effects of Psilocybin

Psilocybe mushrooms have an anti-inflammatory effect by mimicking the action of serotonin on 5-HT2A receptors. This action is exerted by inhibiting the production of the pro-inflammatory cytokines tumor necrosis factor and IL-1 in human U937 macrophage cells and decreasing the concentration of IL-6 and cyclooxygenase 2 in cardiomyocytes.

Indirect evidence has shown that single-nucleotide genetic polymorphisms in the 5-HT2A receptor gene are associated with rheumatoid arthritis, and that mirtazapine, a potent 5-HT2A antagonist, increases TNF- levels.

Mirtazapine is among the least effective antidepressants for the prevention of SA and death by suicide in patients with major depressive disorder. This may be because it impairs neuronal plasticity and does not induce serotonin toxicity.

Studies on psilocybin and LSD found significant acute effects on circulating steroids, especially glucocorticoids. As glucocorticoids have major anti-inflammatory properties, their rapid increase might immediately suppress inflammation, reducing chronic inflammation, as commonly observed in patients with depression.

Some studies suggest that the therapeutic effects of 5-HT2A receptor activation are generated upon the central or peripheral activation of the 5-HT2A receptors, but it is not clear whether a psilocybin-like molecule that does not cross the BBB and do not have subjective psychedelic effects may still be effective.

Psilocybin has anti-inflammatory effects and may be useful in suicidal behaviours, as patients with history of SA and SI have increased levels of inflammatory markers. Moreover, psilocybin induces 5-HT2A receptor downregulation rapidly, which may explain the rapid antidepressant effect observed in the clinical studies.

  1. Antioxidant Effects of Psilocybin

Indole ring-containing molecules, including psilocybin, have antioxidant effects. Studies on similar molecules, such as dimethyltryptamine (DMT), support this putative antioxidant effect, and these effects might be implicated in the anti-suicidal effects of these molecules.

Similar to inflammation, oxidative stress has been associated with SB. Classic antidepressants may reduce oxidative stress and improve antioxidant function.

  1. Neuropsychological Aspects

Psilocybin might enhance cognitive flexibility, which might mediate the switch from avoidance to acceptance thought and behavioral patterns. This change might be maintained for a long time after psilocybin intake.

Psilocybin administration has been associated with increased empathy, a decreased sense of social exclusion, and an increased sense of connectedness with the surrounding environment and people. This effect may be important in patients at risk of suicide.

SB has been associated with reduced specific autobiographical memories, and psilocybin has been shown to enhance autobiographical recollection by stimulating the recall/re-experiencing of autobiographical memories and by accentuating the vividness of memories during its acute effects. Recent studies have shown that emotional breakthrough (EB) also contributes to the increased well-being after psilocybin intake. EB could be useful in suicidal patients who often have history of childhood trauma, other negative life events, and/or biased memories. Psilocybin administration has been associated with “mystical” or “quantum change” experiences, which may lead to sustained behavioral changes. Moreover, previous therapeutic trials found a positive association between the magnitude of mystical experiences and sustained positive outcomes.

  1. Risks

Psilocybin has a favorable physiological safety profile and no cardiovascular events or deaths have been recorded following psilocybin administration. There may be yet unknown risks from psilocybin acting in peripheral tissues.

Psilocybin can cause reality-altering effects and can also bring up various traumatic memories, inducing a fear response. It is important to be psychoeducated about the reality-altering effects of this drug and to consider the theoretical possibility of hallucinogen persisting perception disorder.

Clinicians and researchers may be afraid to test psilocybin in suicidal patients because they think that it could be stressful. However, safe clinical trials can be conducted using an adapted protocol.

  1. Conclusions

Psilocybin, a naturally occurring compound, may act by binding to the 5-HT2A receptors and promoting neuroplasticity, which might explain its putative anti-suicidal effects.

We propose to compare the effects of psilocybin and ketamine in patients some days after a suicidal crisis, regardless of the associated psychiatric disorder. Patients who are at risk must be excluded, and psychotherapy must be offered after psilocybin intake under strict medical supervision.

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