**1. Introduction**

Major depressive disorder (MDD) is characterized by the persistence of negative thoughts and emotions that disrupt mood, cognition, motivation, and behavior [1]. According to the Diagnostic Statistical Manual V (DSM), symptoms, etiologies and pathophysiologies of MDD are heterogeneous

and their subtypes have been already described. Although symptomatic remission increases the probability for recovery in MDD, most patients do not achieve nor sustain a state of full remission [2]. The options for treatment when the patient is resistant to the available standard treatments generally involve combining, augmenting, or switching medications, introducing electroconvulsive therapy (ECT) or other neurostimulation strategies. However, the risk of complications associated with those approaches exists, including increased toxicity with higher medication dosages and combination regimens [1].

Anxiety is a very common psychiatric symptom in terminally ill patients. Factors such as treatment process, disease progression, uncontrolled pain, dying and uncertainty about death have a negative impact on these patients [3]. Anxiety also contributes to poor recovery from medical procedures and lower survival time in terminally-ill patients [4].

Depression and anxiety are independent risk factors of early death in patients with life-threatening diseases, like cancer [5] and most of these individuals develop a chronic syndrome of psychological distress, usually associated with decreased treatment adherence, prolonged hospitalization, decreased quality of life and increased suicidality [6]. Antidepressants and benzodiazepines are used to treat depressed mood and anxiety in patients with life-threatening diseases [7], although there are no Food and Drug Administration (FDA) approved pharmacotherapies for the psychological distress related to those diseases. In addition, the onset of clinical improvement with antidepressants is delayed, relapse rates are high and significant side effects compromise adherence to therapy [8].

Regarding the treatment of severe depression and anxiety, special attention should be paid to the approval of intranasal Spravato® by the FDA in March 2019. Its active compound is esketamine, a ketamine enantiomer, which is a non-competitive *N*-methyl-d-aspartate (NMDA) glutamate receptor antagonist. The effects of ketamine have made it a popular recreational drug, due to its euphoric and dissociative properties [9]. Nonetheless, esketamine appears to provide significant short-term symptom improvement in severe depression and anxiety and it is considered an innovative and promising therapeutic approach. Moreover, molecules such as 3,4-methylenedioxy-methamphetamine (MDMA) and lysergic acid diethylamide (LSD) are also being studied for the treatment of anxiety conditions, namely, post-traumatic stress disorder (PTSD) and generalized anxiety disorder (GAD). Nevertheless, none of these drugs has been approved by the FDA.

In spite of all studies and therapeutic innovations in this area, further research is needed, notably on classic hallucinogens like psilocybin, to provide patients with depression and anxiety associated with life-threatening diseases better chances of recovery and consequently better quality of life.

Recently, Goldberg et al., 2020 [10] published a meta-analysis concerning the use of psilocybin and symptoms of anxiety and depression. The approach used in their meta-analysis is different from the one we present in several aspects, for instance—it does not include data on previous pathologies of the patients receiving psilocybin and did not analyze physiological effects induced by the drug. Also, the authors did not examine psilocybin dose and administration duration as moderators of treatment effects [10].

In this context, this paper aims to perform a systematic review, complying with the Preferred Reported Items for Systematic Reviews and Meta-Analysis (PRISMA) statement, followed by a meta-analysis of clinical trials on the therapeutic potential of psilocybin in anxiety and depression associated with life-threatening diseases.
