Rediscovering Psilocybin as an Antidepressive Treatment Strategy
Rene Zeiss, Maximilian Gahr and Heiko Graf
Pharmaceuticals, 2021, 14, 985, 1-14.
doi : 10.3390/ph14100985
Abstract : There has recently been a renewal of interest in psychedelic research on the use of psilocybin in psychiatric treatment and, in particular, for the treatment of major depressive disorder (MDD). Several state-of-the-art studies have provided new insight into the mechanisms of action of psilocybin and its therapeutic potential. Nevertheless, many questions remain unanswered. With this review, we provide an overview of the current state of research on the potential mechanisms of psilocybin, its antidepressant potential, and the associated risks and adverse effects, to provide an update on a controversial topic discussed in psychopharmacology. A database search was conducted in Medline including articles on psilocybin over the period of the last 20 years. Despite the promising progress in understanding the mechanisms of psilocybin, the exact antidepressive mechanism and the role of the psychedelic experience remain elusive. The studies included in this review found high treatment effect sizes for psilocybin as an antidepressant. However, the results must be regarded as preliminary due to several limitations. Although the current studies observed no severe adverse events, several questions regarding safety and utility remain and must be subject of future research.
Keywords : psilocybin; psilocin; review; depression; antidepressant therapy
Major depressive disorder (MDD) is one of the most commonly diagnosed mental disorders and one of the largest contributors to the global disease burden . Numerous clinical and neuroscientific efforts have been undertaken in recent decades to provide a better understanding of the etiopathology of MDD, yielding important insights into abnor- malities in genes, neurochemical and neuroendocrine systems, functional and structural brain anatomy, inflammatory processes, and cognition [2,3]. The most influential neuro- biological discoveries have probably been neurotransmitter-related abnormalities within the monoaminergic/catecholaminergic system, including the neuromodulators serotonin, noradrenalin, and dopamine. Accordingly, one of the main strategies in the pharmaco- logical treatment of MDD comprises the reuptake-inhibition of monoamines, in partic- ular serotonin and/or noradrenaline. Other antidepressants directly target monoamine (e.g., serotonin receptors by vortioxetine) or other receptors (e.g., melatonin 1 and 2 recep- tors by agomelatine) .
However, despite the efficacy of several pharmacological and non-pharmacological treatment options for MDD, there is still a high rate of treatment-resistant depression [5,6], supporting the need for further and new treatment options for MDD [7–10]. After decades of relative obscurity, scientific research is recently focusing on the use of psychedelics as a potential approach for the treatment of psychiatric disorders [11–14]. In addition to MDMA-assisted therapy as a treatment option for PTSD , there is preliminary evidence for the antidepressant efficacy of psilocybin, presumably due to its serotonergic effects.
Psilocybin is a tryptamine derivate that occurs naturally in numerous mushrooms such as psilocybe mexicana and psilocybe cubensis. Albert Hofmann isolated psilocybin and its main metabolite psilocin from these two species for the first time in the 1950s .
Psilocybin-containing mushrooms have been used in religious rituals for centuries, if not millenia [17,18]. Some of the earliest written records stem from the Spanish friar Bernardino de Sahagún, who noted the sacred mushrooms used in Aztec spiritual acts. They were called teonanacatl or “God’s Flesh” . Psilocybin was first introduced into the modern Western world by Robert Gordon Wasson after attending a Mazatec ritual called “Velada”. In 1957, he shared his experiences in a “Life” article called “Seeking the Magic Mushroom” . During the 1950s and 1960s, there was also an intense period of research on the use of “classical” psychedelics resulting in more than 1000 scientific papers, including data from over 40,000 participants . LSD in particular, among other psychedelics, was used in the treatment of depression, anxiety, or alcohol disorders .
However, this initial wave of research on psychedelics indicating antidepressant effects was followed by a decline in interest. The increasing popularity and recreational use of psychedelics, inter alia among followers of protest movements, the political atmosphere, and incidences such as the “Harvard drug scandal”, cumulated in the illegalization of psilocybin and other psychedelics in the United States in 1968 . Psilocybin was and is still categorized as a Schedule I drug in the “Convention on Psychotropic Substances”, a United Nations treaty designed to establish a control system for psychotropic substances. Accordingly, research became considerably complicated and psilocybin was supposed to create “a serious risk to public health” and was not considered to have a “known therapeutic benefit” . The legal status of psilocybin remains in flux depending on the country or state. Although the possession and sale of psilocybin remains illegal in the US according to federal law, several states (e.g., Colorado and California) partially decriminalized the substance. In Oregon, a ballot was in favor of legalizing psilocybin, including plans to allow its therapeutic use . The legal status of psilocybin also varies across the EU. Although some countries list hallucinogenic mushrooms as a controlled substance, making its cultivation, sale, and possession illegal (e.g., in Germany), others consider cultivation as legal as long as it is not for drug abuse (e.g., Austria) .
After decades of hibernation, psilocybin and other psychedelics have recently received increasing scientific attention as potential therapeutic approaches for various mental disor- ders, e.g., tobacco addiction , alcohol dependence , anxiety in cancer patients [28,29], obsessive compulsive disorder , and depression . In particular, the pivotal role of psilocybin as an antidepressant treatment option has captured media’s attention after the FDA granted a “Breakthrough Therapy Designation” to a psilocybin trial on MDD .
These studies have not only attracted scientific and clinical attention, but also the inter- est of the public, and this topic is increasingly represented in public media. Thus, clinicians will be increasingly engaged with this topic. In this review, we provide an overview of the current literature to provide a better understanding of the non-pharmacological and pharmacological mechanisms of action and caveats associated with the use of psilocybin.
2. Materials and Methods
We conducted a database search in Medline, from 2000 until present (06/2021). The search was performed in June 2021 and abstracts were screened independently for rel- evance by RZ and HG. We used the following terms as the search strategy: “(“Psilocy- bin”[MeSH]) AND ((((((“Depression”[MeSH Terms]) OR (“Depressive Disorder”[MeSH Terms])) OR (“depressive disorder, treatment resistant”[MeSH Terms])) OR (“Dysthymic Disorder”[MeSH Terms])) OR (“depressive disorder, major”[MeSH Terms])))”,
“((“Psilocybin”[Mesh]) AND (“adverse effects”[Mesh])” and (“Psilocybin”[Mesh]) AND “Neuroimaging”[Mesh]).
3.1. Mechanism of Action
3.1.1. Pharmacological, Neurobiological and Neuroimaging Findings
Psilocybin and its main metabolite psilocin act through a variety of mechanisms which are not yet fully understood . Despite its affinity to several serotonin receptors, such as the 5HT2B, 5-HT2C, 5HT5A, 5-HT1A, 5-HT1D, 5-HT1E, 5-HT6, and 5-HT7-receptors [34–38], the most important antidepressant mechanism of action is thought to be the (partial) agonism at the 5-HT2A receptor [11,39], relevant in the pathway implicated in suicidality and depression [40–42]. The pivotal role of the 5-HT2A receptor is further supported by the observation that the psychotomimetic effects of psilocybin can be impeded by the administration of 5-HT2A antagonists, e.g., ketanserin . Further evidence for the pivotal role of the 5-HT2A-receptor for the antidepressive effect stem from a double-blind study with 17 healthy participants. The processing of negative emotional stimuli and mood states was altered by the administration of psilocybin (215 μg/kg) and a previously found diminished recognition of negative facial expression could be blocked by the administration of 50 mg ketanserin . Moreover, in a PET study on eight healthy participants taking doses between 3 and 30 mg of psilocybin, the 5-HT2A occupancies were found to be dose related . The 5-HT2A occupancies were up to 72% and correlated with the subjective intensity and psychedelic effect .
One proposed mechanism for the antidepressant effect of 5-HT2A agonists is the downregulation of the 5-HT2A-receptors . However, this downregulation of 5-HT2A density by psilocybin does not appear to be a lasting effect. In a recent PET study on healthy volunteers, the 5-HT2A binding of psilocybin one week after administration did not differ significantly from that of the baseline . Similar effects were observed in an animal model. A single dose of psilocybin (0.08 mg/kg) led to a reduced 5-HT2A density in the hippocampus and the prefrontal cortex after one day that was not observed after seven days post-injection . Nevertheless, the same study demonstrated a higher hippocampal synaptic vesicle protein 2A density that remained significantly higher 7 days post-treatment, suggesting an increased persistent synaptogenesis .
In addition to modulating monoaminergic levels in the synaptic cleft, there is evidence for considerable effects of psilocybin on neuroplasticity and neurogenesis, relevant in the pathophysiology of mood disorders [49,50]. In a mouse model, several psychedelics including psilocybin promoted an increase in dendritic arbor complexity and dendritic spine growth, and stimulated synapse formation . However, long-term data considering structural alterations in humans by psilocybin are scarce. Recent evidence from animal models suggest that the antidepressant effects of psilocybin apparently cannot be fully explained by 5-HT2A agonism. In a study on the effects of psilocybin on chronically stressed mice, an increase in hedonic responses was found under psilocybin in addition to strengthening of excitatory hippocampal synapses, although the 5-HT2A antagonist ketanserin was administered a priori .
In addition to these pharmacological and animal studies, various neuroimaging stud- ies have investigated the effects of psilocybin on neural network activations to elucidate its antidepressant mechanisms, indicating considerable differences between acute and short-term post-treatment effects. Most of these studies focused on intrinsic neural net- work architecture and, in particular, on the Default Mode Network (DMN) considering an increased and ineffective suppression of functional connectivity in this network in MDD . Carhart-Harris et al.  investigated the acute effect of psilocybin in 15 healthy participants and demonstrated a significant reduction in functional network connectiv- ity within the DMN after intravenous administration of psilocybin compared to placebo. An open-label study by the same research group in depressed patients receiving psilo- cybin, observed a decrease in cerebral blood flow (CBF) within the amygdala, and an increase in DMN integrity, one day after administration of 10 and 25 mg, respectively, of psilocybin . A further analysis also considered the fMRI data of a phase 2 trial on psilo- cybin vs. escitalopram, focusing on neural network modularity. Although this preprinted study is currently still under review and results have to be considered as preliminary, the authors observed a significantly reduced brain network modularity . According to these neuroimaging findings with differential acute and short-term post-treatment effects, one hypothesis regarding the mechanism of psilocybin is that the 5-HT2A-agonism may provoke an “entropic brain state” suggestive for “resetting” brain networks, particularly within DMN .