Introduction
In their recent article entitled “Psychedelic Psychiatry's Brave New World,” Nutt
et al. (1) wrote that new research on psychedelic drugs, especially psilocybin, has
highlighted their potential for psychiatric disorder management. In the past decade,
many studies focused on psilocybin effects on mood disorders (2) showing that it can
significantly improve depressive symptomatology for weeks and even for years in some
people (1). However, Nutt et al. (1) focused on depression and addiction, without
mentioning the potential interest of psilocybin to prevent suicidal behavior (SB;
i.e., completed suicide and suicide attempts) and to decrease suicidal ideation (SI).
Unfortunately, SB and SI are often considered a symptom or a consequence of depression,
although growing evidences indicate that SB does not overlap with depression and deserves
specific attention (3). As SB is a major public health problem (more than 800,000
deaths by suicide/year worldwide, and 20 to 30 times more suicide attempts), still
without specific and efficient treatments, it is urgent to find effective therapeutics.
Here, we propose that besides its antidepressant effect, psilocybin antisuicidal properties
should be tested. Indeed, in a large American epidemiological study (190,000 subjects),
the use of psilocybin and other psychedelic drugs (e.g., LSD) was linked to a decrease
of SB and SI, while other illicit drugs were associated with increased suicidal risk
(4). In a recent open-label study, psilocybin intake was associated with a significant
SI decrease at 1 and 2 weeks (5). We hypothesize that psilocybin biological effects
might counteract the pathophysiological abnormalities observed in SB.
Biological Pathways Implicated in SB on which Psilocybin Acts
Several studies reported alterations of the serotoninergic (e.g., serotonin depletion),
glutamatergic (e.g., alteration of the kynurenine pathway), and inflammatory systems
(e.g., increased levels of proinflammatory cytokines), as well as neuroplasticity
[e.g., low levels of brain-derived neurotrophic factor (BDNF)] in SB (6). Psilocybin
is rapidly metabolized into its active metabolite psilocin that is a serotoninergic
agonist with high affinity for 5-HT2A receptors (5-HT2AR) (1). Psilocybin intake results
in a rapid increase in 5-HT2AR activity that might lead to higher BDNF expression
and consequently to major synaptic changes (7) and might promote neuroplasticity.
Postmortem studies showed that 5-HT2AR availability is increased in the brain of suicide
victims, possibly due to genetic variations or compensatory mechanisms (6). Therefore,
psilocybin-positive effect on neuroplasticity and the serotoninergic system could
contribute to compensate SB-related impairment of these systems. Second, similarly
to ketamine, which reduces SI (6), psilocybin is a modulator of glutamatergic activity
in prefrontal circuits. A common mechanism of action through modulation of glutamatergic
transmission (leading to neuroplastic adaptations) could underlie the antisuicidal
action of psilocybin and ketamine (2). Third, psilocybin intake might induce a decrease
of inflammation because 5-HT2AR are also localized in immune system cells. Indeed,
psilocybin might affect cell signaling within the immune system by stimulating anti-inflammatory
pathways (7).
Neuropsychological Pathways Implicated in SB on which Psilocybin Acts
In neuroimaging studies, psilocybin intake has been associated with disruption of
the default mode network connectivity. This might enhance cognitive flexibility (2)
and promote changes from avoidance (i.e., the tendency to avoid unpleasant thoughts
or emotions) to acceptance by patients. It is assumed that in psychedelic therapy,
cognitive flexibility, and promotion of acceptance increase in response to psilocybin
intake, reinforced by the slogan: “trust, let go, and be open,” but could also continue
for a long time after the treatment (8). This effect might be particularly relevant
for suicidal patients who are characterized by altered decision-making, reduced cognitive
flexibility, and poor problem-solving ability (6). Furthermore, SB could be considered
the most extreme expression of experiential avoidance. Thus, similarly to Acceptance
and Commitment Therapy (9), psilocybin might be useful in SB by promoting acceptance.
Moreover, psilocybin increases inner peace, patience and good humor/play, interpersonal
gaze, and compassion (7). This might promote well-being and prevent SB. SB is associated
with reduced specific autobiographical memories (6), whereas psilocybin intake is
accompanied by increased autobiographical memory. This effect is amplified when music
is played during the session because it increases the drug-induced visual imagery
(9). Finally, the response to psilocybin intake correlates with the induction of a
“mystical” or “spiritual” experience. The 30-item Mystical Experience Questionnaire
scores positively predicted psilocybin-related changes in attitudes, behavior, and
well-being (2). This suggests that psilocybin stimulates spirituality, and this might
protect from suicide (10).
Discussion
Psilocybin actions on neurobiological systems involved in SB (e.g., serotoninergic
system, neuroplasticity, cognitive, and psychological functioning) and preliminary
results on its impact on SI should encourage more research on its antisuicidal effects
and related mechanisms of action. Clinicians and researchers might be afraid of testing
this drug in suicidal patients, particularly due to the risk of “bad trips” that may
facilitate suicidal acts. However, suicidal patients should be included in clinical
trials on psilocybin by putting in place an adapted protocol, as already done for
other drugs, such as ketamine (e.g., to stay with the patient throughout the session,
to assess the patient's family and social support, to prepare emergency plans with
patients, to have close clinical monitoring) (3). SI reduction by psilocybin may last
for several months or even years in some patients. Therefore, psilocybin use could
be particularly interesting because SI is often recurrent and persistent and is a
very strong predictor of future death by suicide. Finally, psilocybin has been recently
designated by the U.S. Food and Drug Administration as a “breakthrough therapy” for
treatment-resistant depression (2), stressing its potential for treating serious psychiatric
disorders, such as SB. To conclude, although all mechanisms underlying psilocybin
effects are not understood yet, these elements should encourage setting-up clinical
trials or open label studies to test its efficacy in patients with SB.
Author Contributions
PC supervised the redaction of the paper. BN performed bibliographic research and
wrote the manuscript. EO actively revised and contributed to the redaction of the
manuscript. All authors have contributed to the manuscript and have accepted the final
version of the paper.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.