**4. Discussion**

Psilocybin is a molecule with structural similarities to serotonin, an endogenous neurotransmitter. It can be found in some mushrooms and has been widely used to induce hallucinations and altered states of consciousness. Its laboratory synthesis was performed by Albert Hofmann while working at Sandoz Laboratories and it was marketed later under the commercial name Indocybin® for basic psychopharmacology and clinical research [25].

Nonetheless, it was withdrawn in the early 1970s and was classified as a Schedule I drug due to its use outside of medical research and in association with emerging counterculture. Despite withdrawal and criminalization, its potential therapeutic value led many scientists to study the effects and mechanisms of action of the drug. There is preliminary evidence that psilocybin may be useful in the treatment of anxiety and depression in life-threatening diseases, depression, obsessive-compulsive disorder, alcoholism and nicotine addiction, cluster headaches and autism [25]. Although further research is needed to assess the efficacy and safety in the treatment of these conditions, it should be noted that psilocybin is illegal in most countries. Therefore, the illegal status of psilocybin adds complexity and some costs to clinical trials involving its administration to human subjects.

The mechanism of action of psilocybin in depression is still unknown. However, some research suggests that its therapeutic effects in depression may reflect the deactivation of the medial prefrontal cortex (mPFC) that is usually hyperactive in depressed patients [26].

The deactivation of mPFC by psilocybin is detected using functional magnetic resonance imaging (fMRI) and it is correlated with the subjective effects induced by the drug. Other studies with fMRI support that psilocybin attenuates amygdala activation on response to threat-related visual stimuli [27]. This may be one of the mechanisms underlying the therapeutic effectiveness of psilocybin in depression and anxiety, given that the amygdala is extremely important in perception and generation of emotions and amygdala hyperactivity in response to negative stimuli is correlated to negative mood states in depressed patients [28]. Furthermore, the mechanism of action of psilocybin, an agonist of 5-HT(2A) receptors, indicates other evidence of its action in depression, since cortical 5-HT(2A) receptor expression is usually increased in postmortem samples of depressed and suicidal patients [29].

Patients with a potentially life-threatening disease often experience considerable anxiety and psychological distress, depression, anger, loss of perceived self-worth, social isolation, hopelessness, and helplessness [30]. There is no FDA approved pharmacotherapy for psychological distress related with life-threatening diseases and conventional therapy often shows limited efficacy to address symptoms of anxiety and depression. The obtained results in the present work emphasize the importance of psilocybin translational research, when used in the correct environment and with trained professionals and may give clues to future clinical trials.

Psilocybin produces sustained reduction in symptoms of both depression and anxiety. However, a recommendation for its use could only be given under rigorous definition of the conditions and precautions. The efficacy of psychedelic therapy may, unlike conventional pharmacotherapy, be linked to an experiential and meaningful process, responsible for the long-term effects and positive effects in cognition, affect, behavior and spirituality [31]. After psilocybin administration, patients report alleviation from anxiety, reconciliation with death, emotional uncoupling from cancer, spiritual or religious phenomena, reconnection to life and greater confidence [32]. The activation of serotonin receptors 5-HT(2A) mediates perception, attention, and emotional regulation, influencing the waking consciousness, sensory experiences, affectivity, experience of self and dream-like visual imagery [31]. Psilocybin is, therefore, responsible for inducing a profound shift in consciousness, with intensification of affective responses, enhanced ability for introspection, regression to primitive and childlike thinking and activation of vivid memory traces with pronounced emotional processes [33].

The persistence in time of the positive effects of psilocybin suggests that the acute destabilization of brain networks induced by the drug modifies activity in a long-lasting way [34]. Psilocybin may alter acutely brain network activity, decreasing connectivity within the default mode network (DMN) [26]. DMN has a role in consciousness and high-level constructs, such as the self, being essential for the maintenance of cognitive integration and constraint under normal conditions [35].

The increases of both SBP and DBP and heart rate are consistent with the sympathetic effects of psilocybin reported in the literature [36]. The sympathetic effects may also be noticeable through the induction of pupil dilatation [37]. Psilocybin, however, is not likely to cause changes on electrocardiograph or body temperature nor to affect the ionic balance, blood glucose or cholesterol [31].

There were not reported serious adverse effects following psilocybin administration. Besides transient moderate increases in SBD, DBP and heart rate, there are some references to nausea, both physical and psychological discomfort, transient episodes of psychological distress and anxiety. There are, however, no cases of hallucinogen persisting perception disorder (HPPD) neither prolonged psychosis, although literature points these effects to be quite dangerous and life-impairing following hallucinogen consumption [38]. This may occur because in all studies included in the present meta-analysis, patients were carefully monitored in a calm and relaxed environment and had been previously informed about the effects that the drug might have in their bodies and mind. This is known as "set and setting" and it is designed to facilitate a mystical experience and to increase the probability of a positive outcome after the administration of any hallucinogen [25]. In fact, many drug-related and not drug-related variables may influence the adverse effects experienced by patients, namely, age, gender, education, experimental setting, and drug dose [39].

According to the literature, besides the mentioned adverse effects, psilocybin may also cause somatic symptoms such as dizziness, weakness, tremor, drowsiness, yawning, paresthesia, blurred vision, and increased tendon reflexes [40]. Although not applicable to the studies included in this meta-analysis, psilocybin is very likely to induce nausea when consumed through psilocybin-containing mushrooms [41].

Classical hallucinogens are not likely to cause addiction, as it is mainly linked to the dopaminergic system, while classical hallucinogens act mostly on the serotoninergic system. Furthermore, these drugs lead to tachyphylaxis, the rapid decrease in the effect of a drug in consecutive doses, related to their mechanism of action. Thus, the development of addiction by patients after treatment with psilocybin is not of concern. However, authors suggest that if a psilocybin-containing medicines is approved, it should be included in the Schedule IV of Controlled Substance Schedules [42].
