Abstract
Therapeutic deficiencies with monoaminergic antidepressants invites the need to identify and develop novel rapid-acting antidepressants. Hitherto, ketamine and esketamine are identified as safe, well-tolerated rapid-acting antidepressants in adults with treatment-resistant depression, and also mitigate measures of suicidality. Psilocybin is a naturally occurring psychoactive alkaloid and non-selective agonist at many serotonin receptors, especially at serotonin 5-HT2A receptors, and is found in the Psilocybe genus of mushrooms. Preliminary studies with psilocybin have shown therapeutic promise across diverse populations including major depressive disorder. The pharmacodynamic mechanisms mediating the antidepressant and psychedelic effects of psilocybin are currently unknown but are thought to involve the modulation of the serotonergic system, primarily through agonism at the 5-HT2A receptors and downstream changes in gene expression. It is also established that indirect effects on dopaminergic and glutamatergic systems are contributory, as well as effects at other lower affinity targets. Along with the direct effects on neurochemical systems, psilocybin alters neural circuitry and key brain regions previously implicated in depression, including the default mode network and amygdala. The aim of this review is to synthesize the current understanding of the receptor pharmacology and neuronal mechanisms underlying the psychedelic and putative antidepressant properties of psilocybin.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Psilocybin is a psychoactive alkaloid with psychedelic and putative antidepressant effects. Its actions are proposed to be primarily mediated by agonism at serotonin 5-HT2A receptors and downstream changes in gene expression. |
Psilocybin modulates the serotonergic system and indirectly affects the dopaminergic and glutamatergic systems. |
Psilocybin alters neural circuitry between areas such as the default mode network and amygdala, which may mediate antidepressant effects. |
1 Introduction
Major depressive disorder (MDD) is a prevalent multifactorial mood disorder and a leading cause of long-term disability worldwide [1]. Much of the socioeconomic burden associated with MDD is attributable to treatment-resistant depression (TRD), characterized by failure to achieve full remission following treatment with two conventional antidepressants [2, 3]. In 2013, TRD was reportedly responsible for a 40–50% increase in direct and indirect medical care costs when compared with treatment-responsive depression [4]. Conventional first-line antidepressants, including selective serotonin reuptake inhibitors (SSRIs), norepinephrine reuptake inhibitors (NRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs), often exhibit a therapeutic delay of at least 2 weeks [5], and are associated with treatment-limiting adverse effects (e.g., sexual dysfunction) [6, 7]. In recognition of the inadequacy of conventional first-line antidepressants and the unmet needs of individuals with TRD, along with the recent US Food and Drug Administration and European Medicines Agency approval of esketamine [8], there is a growing interest in rapid-acting antidepressants (RAADs), characterized by therapeutic efficacy following one or few doses [5]. Although there is no well-characterized time frame of therapeutic action for RAADs, these treatments show therapeutic efficacy within a few days to a week [9]. For example, ketamine, a RAAD, was shown to alleviate depressive symptoms within hours of administration, which stands in contrast to monoamine-based antidepressants that require at least 4 weeks before therapeutic benefits are exhibited [10,11,12].
Although the pathophysiology and neurobiology of depression are not completely understood, the traditional ‘serotonin hypothesis’ of MDD asserts that a deficit of central serotonin subserves depressive symptoms [13]. Recent studies have suggested additional mechanisms wherein factors associated with depression such as chronic stress can result in increased levels of extracellular glutamate and overactivity of N-methyl-d-aspartate (NMDA) receptors. This imbalance in glutamatergic neurotransmission ultimately results in excitotoxic effects and subsequent neuronal atrophy in brain regions associated with depression, including, but not limited to, the prefrontal cortex (PFC) and hippocampus [14,15,16,17,18,19,20,21,22]. It is important to note, however, that these recent studies stand in contrast to the widely accepted theory of glutamatergic activity, in which neuronal atrophy in the brain reward circuitry results in decreased glutamatergic synaptic excitation [19]. The foregoing findings are proffered as explanatory for the antidepressant properties of ketamine, an NMDA antagonist proven effective for the rapid-onset treatment of TRD and MDD with suicidality [8]. However, the non-enduring efficacy of ketamine in many patients who are acute responders, as well as the absence of sufficient remission in most patients taking ketamine, invites the need for identifying and developing alternative RAADs [23, 24]. As such, there is a renewed interest in the potential role of classical psychedelics for the treatment of TRD.
Classical psychedelics include three distinct groups of hallucinogens: tryptamines, including psilocybin; lysergamides such as lysergic acid diethylamide (LSD), and phenethylamines such as mescaline [25]. Of these, psilocybin has generated the most interest because of its proposed similarity to the rapid-acting properties of ketamine as well as its low physiological toxicity and abuse liability [26]. In addition, psilocybin has a short acute window of 2–6 h, which contributes to more manageable and inexpensive clinical trials, differing greatly from mescaline and LSD with acute windows of 6–8 h and 8–20 h, respectively [27, 28]. Although preliminary studies have supported the efficacy of psilocybin [29,30,31], a recent phase II clinical trial comparing the relative antidepressant effects of psilocybin with the SSRI escitalopram found no significant differences in antidepressant effects between these two agents. In the aforementioned study, patients in the psilocybin group received two separate 25 mg doses of psilocybin 2 weeks apart plus 6 weeks of daily placebo. Those in the escitalopram group received two separate 1 mg doses of psilocybin 3 weeks apart plus 6 weeks of daily oral escitalopram. In addition, both the psilocybin and escitalopram groups received psychotherapy. Subsequently, the psilocybin group reported a mean change of −8.0 ± 1.0 points in 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR-16) scores from baseline, whereas the escitalopram group reported a mean change of −6.0 ± 1.0 points (p = 0.17). The foregoing results provide important insights regarding the efficacy of psilocybin, specifically, that psilocybin did not perform better than a conventional monoaminergic antidepressant. However, due to the nature of the study design and limitations in the analytic methodology employed (e.g., analyses of secondary outcomes were not corrected for multiple comparisons), the relative antidepressant efficacy of psilocybin remains incompletely understood [32].
Psilocybin is a naturally occurring psychedelic found in the Psilocybe genus of mushrooms [30]. It exists as a prodrug that is dephosphorylated upon administration in the stomach, intestines, kidneys, and blood through the action of alkaline phosphatases and esterases into its active form, psilocin [33]. Psilocybin and other tryptamines are structurally similar to serotonin. Notably, the indole ring at the fourth position of the tryptamine structure of psilocin is reportedly responsible for the hallucinogenic effects associated with the drug [26]. In the liver, further metabolism of psilocin through demethylation and oxidative deamination by monoamine oxidase (MAO) or aldehyde dehydrogenase reduces the hallucinogenic effects [33]. Although numerous studies have positioned psilocybin as an emerging RAAD, the exact mechanisms responsible for its putative antidepressant and anxiolytic effects remain incompletely characterized. In addition, the role of the psychedelic experience in mediating antidepressant effects is unknown [34, 35].
Herein, the aim of this review is to present the current understanding of the putative antidepressant mechanisms of psilocybin. This review is not intended to synthesize the extant evidence regarding the efficacy of psilocybin for the treatment of depression and other mental disorders (reviewed elsewhere) [36], but rather to outline key mechanistic properties that may mediate its RAAD activity and psychedelic effects. The overarching aim is to provide a synthesis of the pharmacology, creating an important scaffold for identifying derivatives for future drug discovery and development.
2 Receptor Pharmacology
2.1 5-HT2A Receptor Agonism and Downstream Effects
The psychedelic effects of all classical psychedelics are mediated by full or partial agonism at serotonergic 5-hydroxytryptamine 2A (5-HT2A) receptors (5-HT2ARs) [25, 37]. The actions of psilocybin on the 5-HT2ARs and the possible involvement of these receptors in mediating the hallucinogenic effects of psilocybin were first reported by Glennon et al. in 1984, who noted a significant correlation between the binding affinities for 5-HT2 receptors and the dose that produced 50% of the maximal effect (ED50) [38].
5-HT2ARs are highly expressed in the visual cortex, thus, receptor activity in visual cortical neurons may be sufficient to mediate psychedelic effects, specifically the propensity for visual hallucinations associated with psilocybin [25]. Increased expression of 5-HT2ARs may also underlie disease states associated with visual hallucinations, including, but not limited to, schizophrenia and Parkinson’s disease [39]. Accordingly, overactivity in cortical 5-HT2ARs is likely contributory to the characteristic visual hallucinations associated with psilocybin. When compared to ketamine employed as a dissociative anesthetic, psilocybin elicits significant visual hallucinatory effects but lacks strong negative effects associated with the psychedelic experience (e.g., loss of physical integrity, pronounced anxiety, emotional withdrawal) [40, 41].
Multiple 5-HT2AR knockout and receptor antagonism experiments support the role of these serotonin receptors in mediating the psychedelic effects of psilocybin. Administration of the 5-HT2AR antagonist, ketanserin, to healthy humans attenuated hallucinatory effects following psilocybin administration. In comparison, antagonism at other 5-HT2 receptors, such as the 5-HT2C receptors, did not completely attenuate psilocybin-induced hallucinatory effects [42, 43]. Likewise, administration of psilocybin to 5-HT2AR knockout mice resulted in no head-twitch response, likely corresponding to attenuated hallucinatory effects. In addition, re-expression of 5-HT2ARs in cortical pyramidal neurons was able to successfully restore hallucinogen-induced head twitching [44, 45]. The results of these mice studies strongly suggest that the hallucinatory effects of psilocybin are mediated by 5-HT2ARs; however, other factors characteristic of a psychedelic experience (e.g., locomotor responses, anxiolytic effects, alterations in time perception) were not investigated [46].
Downstream effects at the 5-HT2ARs are mediated by secondary messenger signaling and alterations in gene expression [25]. Multiple studies have suggested that hallucinogenic 5-HT2AR agonists elicit different downstream mechanisms when compared with non-hallucinogenic 5-HT2AR agonists [47]. It is important to note that binding to other 5-HT2 and non-5-HT2 receptors also contributes a role in mediating the psychopharmacological actions of psilocybin. Experiments conducted by González-Maeso et al. determined that activation of phospholipase C-β is elicited by both 5-HT2AR hallucinogens (e.g., LSD) and non-hallucinogens; however, activation of phospholipase C-β through coactivation of heterotrimeric Gq/11 and pertussis toxin-sensitive Gi/o proteins is unique to hallucinogens, including psilocybin. In addition, co-activation of Gi/o requires Gβγ subunit-mediated activation of Src [48]. These Gi/o proteins are further coupled to metabotropic glutamate receptor 2 (mGlu2) receptors, ultimately forming a co-expressed 5-HT2A/mGlu2 complex [47]. Formation of the 5-HT2A/mGlu2 complex has been shown to be a key component in the hallucinatory effects of certain 5-HT2AR agonists.
In mGlu2-knockout mice, administration of the serotonergic hallucinogens 4-iodo-2,5-dimethoxyphenyl-isopropylamine (DOI) and LSD did not induce head-twitch behavior [49]. Additionally, administration of DOI in mGlu2-knockout mice over-expressing a chimeric mGlu2 construct which cannot be complexed with 5-HT2ARs in the frontal cortex did not restore head-twitch behavior [50, 51]. Binding of hallucinogens to the foregoing complex ultimately resulted in downstream G protein signal transduction and unique gene effects. In contrast, non-hallucinogenic 5-HT2AR agonists induced the foregoing events through a different signal transduction cascade. This difference in G protein activation and specific signaling pathways between 5-HT2AR hallucinogens and non-hallucinogens is referred to as the ‘agonist trafficking of receptor signaling theory’ [52].
Administration of LSD to several 5-HT2AR-expressing brain regions is associated with increased expression of early growth response genes; egr-1 and egr-2, as well as c-fos, jun-B, period-1, gpcr-26, fra-1, N-10, and I-κBα, and decreased expression of sty-kinase [41]. Alterations in the expression profiles of egr-1 and egr-2 are unique to 5-HT2AR hallucinogens, whereas increased c-fos expression occurs upon administration of both hallucinogenic and non-hallucinogenic 5-HT2AR agonists (e.g., R-lisuride). The foregoing gene expression findings may present key mediators in 5-HT2AR agonist-induced hallucination, such that egr-1 and egr-2 expression may be necessary for the induction of hallucinogenic effects, whereas c-fos expression corresponds only to neuronal activity at the 5-HT2ARs and is not sufficient to modify downstream pathways that produce hallucinatory effects [41, 48]. Expression of egr-1 has previously been implicated in neuronal plasticity [53]. Electrical stimulation of the perforant pathway and subsequent induction of long-term potentiation (LTP) resulted in increased expression of egr-1 in the ipsilateral granule cell neurons. As such, egr-1 expression occurs in conditions conducive to synaptic enhancement (e.g., LTP), suggesting that psilocybin may activate key neuroplastic pathways underlying its putative antidepressant effects [53, 54].
Hallucinogenic 5-HT2AR agonists also show differences in signaling cascades, when compared with non-hallucinogenic 5-HT2AR agonists, through varied β-arrestin-2 expression and subsequent β-arrestin-2-dependent mechanisms. Multiple studies conducted by Schmid et al. have demonstrated that serotonin-induced head twitching in mice is normally partially mediated through β-arrestin-2 interactions. In comparison, the hallucinogenic 5-HT 2AR agonist DOI induces head twitching independent of β-arrestin-2 interactions [55, 56]. Taken together, the foregoing findings present important differences in signaling cascades between hallucinogenic and non-hallucinogenic 5-HT2AR agonists.
Although the visual hallucinatory effects of psilocybin are largely associated with increased activity in 5-HT2ARs of the visual cortex, previous studies have suggested that overexpression of 5-HT2ARs is present in patients with MDD, with expression correlating positively to the severity and duration of depression [39]. As a result, downregulation of 5-HT2ARs may be associated with the putative antidepressant and anxiolytic properties of psilocybin [36]. However, the mechanism of 5-HT2AR overexpression in depressed patients is not well characterized. In accordance with the foregoing observation, re-expression of 5-HT2ARs in the PFC in 5-HT2AR knockout models (i.e., rescue experiments) restored anxiety symptoms [57]. Collectively, these findings suggest a possible role for 5-HT2AR downregulation and desensitization in mitigating depressive and anxious symptoms [58].
The downregulation of 5-HT2ARs by psilocybin may be mediated via brain-derived neurotrophic factor (BDNF). A mouse model experiment conducted by Trajkovska et al. noted a decrease in 5-HT2ARs in mice over-expressing BDNF. The preceding result suggests possible downstream expression of BDNF following the binding of psilocybin, ultimately leading to downregulation of 5-HT2ARs [59]. This relationship is further supported by findings that glutamatergic modulation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and NMDA receptors on cortical pyramidal cells subsequent to 5-HT2AR agonism has been shown to increase expression of neurotrophins, including BDNF [36]. Glutamatergic modulation of NMDA receptors and increased BDNF are the predominant proposed antidepressant mechanisms of ketamine, thus suggesting the parallel involvement of this mechanism in mediating antidepressant effects of psilocybin [60].
An inflammatory state characterized by a preponderance of pro-inflammatory cytokines, most notably tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6), has also been implicated in the pathogenesis of depression and measures of anhedonia [61,62,63,64,65,66]. Such findings correlate with the accepted mechanism of TNF-α in inducing IL-6 synthesis through phosphorylation of NFκB and activation of the mitogen-activated protein kinase (MAPK) pathway via phosphorylation of p38 MAPK [67, 68]. Multiple studies have shown that treatment with proinflammatory cytokines, including TNF-α and IL-6, induce depression-like behavior assessed via forced swim tests [69, 70]. In addition, other studies have indicated a positive correlation between TNF-α and IL-6 levels and depressive scores [71, 72]. Moreover, IL-6 and TNF-α antagonists have previously been proven efficacious in treating depressive symptoms [73]. Murine studies have shown that agonism at the 5-HT2AR by DOI results in downstream inhibition of TNF-α and subsequent inhibition of IL-6 release [74]. Furthermore, agonism at the 5-HT2AR by psychedelics including LSD, N,N-dimethyltryptamine, and psilocybin has demonstrated similar results [75,76,77]. Another study conducted by Nkadimeng et al., which investigated properties of the comorbidity of heart failure and MDD, demonstrated decreased damage to cardiomyocytes by TNF-α upon administration of psilocybin [78]. Taken together, these results suggest that 5-HT2AR agonism by psilocybin and other psychedelics mediates antidepressant effects via inhibition of TNF-α and IL-6 release (see Fig. 1).
Proposed mechanism of action for psilocybin in the treatment of major depressive disorder. A The proposed sequence of molecular mechanisms of psilocybin. Psilocybin is a prodrug that is dephosphorylated to the active compound, psilocin. Psilocin then binds to 5-hydroxytryptamine 2A (5-HT2A) receptors, eliciting downstream effects including downregulation of 5-HT2A receptors. B Other proposed downstream effects of psilocybin 5-HT2A receptor agonism do not occur in a specified sequence. These effects include glutamatergic modulation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptors, increased brain-derived neurotrophic factor (BDNF) expression and dopaminergic activity, as well as inhibition of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) release [120].
2.2 Other Receptors and Modulation of Serotonergic, Dopaminergic, and Glutamatergic Systems
Psilocin also has moderate affinity (Psilocin dissociation constant [Ki] <10,000 nM) for non-5-HT2 receptors including, but not limited to, 5-HT1A/B/D/E, 5-HT5, 5-HT6, 5-HT7, alpha2A/B, and dopamine D3 (D3) receptors (see Table 1). It also has weak affinity for other 5-HT receptors, including 5-HT3/5/6/7 and imidazoline 1 receptors [41, 79]. Although it has previously been proposed that psilocybin also has low affinity for dopamine D2 (D2) receptors, it has subsequently been noted that 5-HT2AR agonism leads to increased dopamine levels in the ventral striatum resulting in hallucinogenic-like symptoms including depersonalization and euphoria [80]. Interestingly, pre-treatment with the D2 receptor antagonist haloperidol followed by psilocybin administration produced only a 30% reduction in euphoria, derealization, and depolarization, with no reduction in visual hallucinations [43, 44]. In contrast, addition of a mixed 5-HT2A/CR and D2 receptor antagonist, risperidone, reduced psilocybin-induced psychotic effects [41]. These findings may suggest an indirect role of the dopaminergic system in eliciting hallucinations, as interactions between serotonergic and dopaminergic systems have been established [33]. Other studies have implicated the necessity of D2 antagonism for reducing psychotic effects independently of 5-HT2AR activity [41]. As such, the exact mechanism of dopaminergic modulation in mediating psychosis remains unclear.
Modulation of the serotonergic and glutamatergic systems by psilocybin has also been reported. The actions of psilocybin on the serotonergic system are similar to those of SSRIs, occurring via inhibition of the sodium-dependent serotonin transporter (SERT). The foregoing mechanism leads to decreased serotonin reuptake, elevated serotonin levels in the synaptic cleft, and subsequent increases in serotonergic neurotransmission [79]. Agonism at 5-HT2ARs may also result in activation of glutamatergic systems. 5-HT2AR activity subsequently increases the activity of pyramidal neurons in layer V of the PFC [81, 82]. Studies attribute the increase in activity to a glutamate-dependent interaction; early studies have implicated activation of presynaptic 5-HT2ARs on glutamatergic thalamocortical afferents projecting to the PFC [83]. Recent studies suggest a different mechanism whereby activation of postsynaptic 5-HT2ARs on pyramidal neurons may lead to increased glutamatergic action [44]. Although contrasting views have been proposed, it can be surmised that alterations in glutamate release contribute to the putative rapid antidepressant effects associated with psilocybin.
Other RAADs such as ketamine also exhibit similar modulatory effects on the glutamatergic system, including but not limited to, mGlu2/3 antagonism [84]. The effects on the mGlu2/3 receptors are paralleled by the action of psilocybin on 5-HT2A/mGlu2. Binding of psilocybin to this complex likely results in inhibition of mGlu2 activity. For example, administration of the mGlu2/3 agonist LY354740 counteracts excitatory effects in cortical pyramidal neurons. Similarly, administration of DOI in the presence of LY354740 was not able to restore head-twitch behavior in mice whereas administration of DOI with the mGlu2/3 antagonist LY341495 increased head-twitch behavior [85, 86].
Psilocybin also acts as a partial agonist with moderate binding affinity for the 5-HT1A receptor (Ki = 49.0 nM), specifically at 5-HT1A autoreceptors in the dorsal raphe nucleus (DRN) and median raphe nucleus [87, 88]. Accordingly, activity at the 5-HT1A receptor may lead to increased levels of serotonin and serotonergic modulation [88]. Decreased DRN size has been associated with MDD as the DRN is the largest serotonergic nucleus and a significant contributor to the serotoninergic innervation of the forebrain [89]. Alterations in the DRN may result in changes to normal neural communication and functional connectivity, ultimately allowing new connections and signals to be relayed [88]. Interestingly, psilocybin lessens 5-HT1A activity through partial agonism; however, in comparison to downregulation of 5-HT2ARs upon binding, this does not occur with 5-HT1A receptors. Rather than contributing to the antidepressant effects of psilocybin, dampening of 5-HT1A activity may conduce its hallucinatory effects. This has been supported by studies demonstrating that antagonism at 5-HT1A receptors (as well as 5-HT2A/C and dopamine D2 receptors) restored normal electroencephalographic changes that occurred upon psilocybin administration [79, 90].
3 Alterations in Neural Circuitry
Currently accepted neural models of MDD are characterized by overactivity of the amygdala due to altered connectivity in the default mode network (DMN), particularly in the medial prefrontal cortex (mPFC) [45, 91, 92]. Numerous functional magnetic resonance imaging studies have presented findings consistent with these models and suggest psilocybin induces decreased activity in brain regions and networks associated with MDD, including the amygdala and DMN, which may ultimately underlie its therapeutic effects. A study conducted by Carhart-Harris et al. reported that psilocybin decreased cerebral blood flow and venous oxygenation to the ventral medial prefrontal cortex (vmPFC), thalamus, as well as anterior and posterior cingulate cortices (ACC and PCC, respectively) immediately following intravenous infusion (i.e., during the psychedelic state) [93]. Decreased blood flow in the aforementioned regions is correlated with decreased activity and as such implies decreased functional connectivity. In addition, cerebral blood flow to the thalamus and ACC was found to be positively correlated with the intensity of the psychedelic experience. Collectively, these findings suggest that psilocybin can normalize activity in the default mode network and restore normal neural connectivity in patients with MDD. Activation of 5-HT2ARs within the thalamus and mPFC may also decrease thalamic activity, leading to decreased consciousness, alertness, and sensory signals, which contribute to the psychedelic experience [94].
Previous studies have demonstrated the occurrence of overactivity in the amygdala in response to negative stimuli in patients with MDD [95,96,97]. Using evaluation of affective pictures (i.e., facial expression) conducted in patients with MDD post-psilocybin administration, multiple studies have demonstrated attenuated right amygdala responses to negative stimuli and associated induction of positive affective states [25, 26]. However, an open-label study on patients with TRD reported contrasting findings, revealing that psilocybin increased right amygdala activity in response to fearful and happy faces at 1 day post-treatment [98]. A separate study presented findings consistent with prior models wherein decreased functional connectivity between the vmPFC and right amygdala was observed, resulting in antidepressant effects such as lowered rumination at 1-week post-psilocybin administration. The decreased connectivity, however, was associated with the occurrence of increased activity in the amygdala in response to fearful and neutral faces [37]. Inconsistent findings reported in the literature may correspond to an alternative mechanism for the antidepressant effects of psychedelics compared with conventional antidepressants; however, further research is required.
Widely accepted models of MDD have reported alterations in neuroplasticity, including reduced or maladaptive neuroplasticity due to neuronal atrophy, specifically in the PFC [99]. In vitro and in vivo studies have also demonstrated increased neuritogenesis and spinogenesis in the PFC upon 5-HT2AR agonism [100]. Conventional antidepressants may work to restore and enhance neuroplasticity [101,102,103]. It has been proposed that 5-HT2AR activation increases cortical neural plasticity [100, 104]. These models are consistent with the downstream alterations in gene expression occurring upon 5-HT2AR agonism, most notably upregulation of BDNF. The role of BDNF and other neurotrophins in the pathogenesis of MDD is well understood, although their role in neuroplasticity remains heavily debated. Current models suggest that BDNF increases neuroplasticity by promoting neuronal proliferation and survival [105]. More specifically, studies have suggested that BDNF contributes an essential role in LTP; it is required for late LTP in hippocampal neurons, mediated by binding to its receptor, tropomyosin receptor kinase B (TrkB) [100, 105,106,107]. Activation of the BDNF-TrkB signaling pathway results in downstream activation of other signaling cascades, including the Ras/MAPK and phosphoinositide 3 kinase (PI3K) pathways. In addition, upon binding, TrkB recruits phospholipase Cγ, leading to activation of the calcium/calmodulin kinase pathway. Activation of the Ras/MAPK and PI3K signal transduction cascades ultimately increases intracellular calcium levels, resulting in further activation of important transcription factors involved in mediating changes to synaptic gene expression, such as cAMP response element binding protein (CREB) [105, 107]. Several BDNF-TrkB knockout mice experiments have supported the role of the BDNF-TrkB signaling pathway in mediating LTP. Notably, BDNF mutant and TrkB knockout mice were shown to have impaired LTP in the hippocampal CA3–CA1 region [108,109,110,111,112]. A study by Zhang et al. demonstrated that lipopolysaccharide-induced inflammation in mice resulted in a depression-like phenotype due to alterations in the BDNF-TrkB signaling pathway within the CA3 and dentate gyrus regions of the hippocampus as well as in the PFC and nucleus accumbens [113]. Taken together, the foregoing findings highlight a possible role of the BDNF-TrkB signaling pathway in mediating the antidepressant effects of psilocybin upon 5-HT2AR agonism.
4 Conclusions
In consideration of the molecular mechanisms presented herein, administration of psilocybin may be a potentially efficacious treatment for MDD and TRD. The mechanisms discussed may underlie diverse physiological and behavioral outcomes of psilocybin exhibited in human molecular studies comprising healthy subjects and/or patients with MDD (see Table 2). Notwithstanding, large clinical trials further demonstrating robust efficacy and safety are required to justify widespread implementation. In addition, further mechanistic studies are warranted to establish a model of the neural modulatory effects of psilocybin in order to understand the mechanisms of psychedelics and associated psychedelic experience.
Currently, the most widely accepted molecular model of the antidepressant and psychedelic effects of psilocybin can be attributed to its activity on various 5-HT receptors, notably, agonism at 5-HT2ARs, instigating downstream changes in neuronal gene expression as well as an overall decrease in functional connectivity between brain regions implicated in MDD, such as the DMN. Ultimately, complex alterations in connectivity between neural networks occur, allowing new connections in the brain to be formed; this phenomenon has been referred to as a ‘pharmaco-physiological interaction’ [93].
In light of the association between 5-HT2AR agonism and antidepressant effects, it may be useful to consider the potential of other 5-HT2AR agonists for the treatment of MDD. Pimavanserin (Nuplazid), an antipsychotic drug used in the treatment of Parkinson’s disease psychosis, has shown promise for the treatment of MDD [114]. In contrast to typical antipsychotics, pimavanserin is not a dopamine receptor antagonist but rather a combined 5-HT2AR inverse agonist and antagonist [115]. Other 5-HT2AR agonists such as mescaline, LSD, N, N-dimethyltryptamine, and ayahuasca have also demonstrated potential for the treatment of depression and anxiety. For example, a randomized, double-blind, placebo-controlled study reported antidepressant and anxiolytic effects upon administration of LSD in patients with life-threatening diseases [116]. Similarly, an open-label trial reported a significant reduction in depressive symptoms with a single dose of ayahuasca; however, antidepressant effects of ayahuasca cannot be attributed to 5-HT2AR agonism alone as it also inhibits MAO activity [116, 117]. Other studies examining 5-HT2AR psychedelics (e.g., mescaline, N,N-dimethyltryptamine) should provide additional insights regarding the pharmacodynamics of psychedelics to inform future drug discovery.
References
WHO. Depression. https://www.who.int/news-room/fact-sheets/detail/depression. Accessed 1 Jun 2021.
McIntyre RS, et al. Treatment-resistant depression: definitions, review of the evidence, and algorithmic approach. J Affect Disord. 2014;156:1–7.
Zhdanava M, et al. The prevalence and national burden of treatment-resistant depression and major depressive disorder in the United States. J Clin Psychiatry. 2021;82(2):20m13699.
Rizvi SJ, et al. Treatment-resistant depression in primary care across Canada. Can J Psychiatry. 2014;59(7):349–57.
Witkin JM, Martin AE, Golani LK, Xu NZ, Smith JL. Rapid-acting antidepressants. Adv Pharmacol. 2019;86:47–96.
Patacchini A, Cosci F. Exposure to serotonin selective reuptake inhibitors or serotonin noradrenaline reuptake inhibitors and sexual dysfunction: results from an online survey. Int J Risk Saf Med. 2021;32(3):229–42.
Dodd S, et al. A clinical approach to treatment resistance in depressed patients: what to do when the usual treatments don’t work well enough? World J Biol Psychiatry. 2021;22(7):483–94.
McIntyre RS, et al. Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: an international expert opinion on the available evidence and implementation. Am J Psychiatry. 2021;178(5):383–99.
Gould TD, Zarate CA Jr, Thompson SM. Molecular pharmacology and neurobiology of rapid-acting antidepressants. Annu Rev Pharmacol Toxicol. 2019;59(1):213–36.
Pham TH, Gardier AM. Fast-acting antidepressant activity of ketamine: highlights on brain serotonin, glutamate, and GABA neurotransmission in preclinical studies. Pharmacol Ther. 2019;199:58–90.
Duman RS. Ketamine and rapid-acting antidepressants: a new era in the battle against depression and suicide. F1000Res. 2018;7:659.
Hillhouse TM, Porter JH. A brief history of the development of antidepressant drugs: from monoamines to glutamate. Exp Clin Psychopharmacol. 2015;23(1):1–21.
Albert PR, Benkelfat C, Descarries L. The neurobiology of depression: revisiting the serotonin hypothesis. I. Cellular and molecular mechanisms. Philos Trans R Soc Lond B Biol Sci. 2012;367(1601):2378–81.
Serafini G, Pompili M, Innamorati M, Dwivedi Y, Brahmachari G, Girardi P. Pharmacological properties of glutamatergic drugs targeting NMDA receptors and their application in major depression. Curr Pharm Des. 2013;19(10):1898–922.
Rubio-Casillas A, Fernández-Guasti A. The dose makes the poison: from glutamate-mediated neurogenesis to neuronal atrophy and depression. Rev Neurosci. 2016;27(6):599–622.
Pochwat B, Nowak G, Szewczyk B. An update on NMDA antagonists in depression. Expert Rev Neurother. 2019;19(11):1055–67.
Ates-Alagoz Z, Adejare A. NMDA receptor antagonists for treatment of depression. Pharmaceuticals. 2013;6(4):480–99.
Müller N, Myint A-M, Schwarz MJ. The impact of neuroimmune dysregulation on neuroprotection and neurotoxicity in psychiatric disorders: relation to drug treatment. Dialogues Clin Neurosci. 2009;11(3):319–32.
Duman RS, Sanacora G, Krystal JH. Altered connectivity in depression: GABA and glutamate neurotransmitter deficits and reversal by novel treatments. Neuron. 2019;102(1):75–90.
Campbell S, MacQueen G. An update on regional brain volume differences associated with mood disorders. Curr Opin Psychiatry. 2006;19(1):25–33.
Serafini G, Amore M, Rihmer Z. The role of glutamate excitotoxicity and neuroinflammation in depression and suicidal behavior: focus on microglia cells. Neuroimmunol Neuroinflamm. 2015;2(3):127.
Haroon E, Miller AH, Sanacora G. Inflammation, glutamate, and glia: a trio of trouble in mood disorders. Neuropsychopharmacology. 2017;42(1):193–215.
Kishimoto T, et al. Single-dose infusion ketamine and non-ketamine N-methyl-d-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories. Psychol Med. 2016;46(7):1459–72.
Salloum NC, et al. Time to relapse after a single administration of intravenous ketamine augmentation in unipolar treatment-resistant depression. J Affect Disord. 2020;260:131–9.
Mahapatra A, Gupta R. Role of psilocybin in the treatment of depression. Ther Adv Psychopharmacol. 2017;7(1):54–6.
Patra S. Return of the psychedelics: psilocybin for treatment resistant depression. Asian J Psychiatr. 2016;24:51–2.
Halberstadt AL. Recent advances in the neuropsychopharmacology of serotonergic hallucinogens. Behav Brain Res. 2015;277:99–120.
Passie T, Seifert J, Schneider U, Emrich HM. The pharmacology of psilocybin. Addict Biol. 2002;7(4):357–64.
Ross S, et al. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol. 2016;30(12):1165–80.
Carhart-Harris RL, et al. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry. 2016;3(7):619–27.
Goldberg SB, Pace BT, Nicholas CR, Raison CL, Hutson PR. The experimental effects of psilocybin on symptoms of anxiety and depression: a meta-analysis. Psychiatry Res. 2020;284:112749.
Carhart-Harris R, et al. Trial of psilocybin versus escitalopram for depression. N Engl J Med. 2021;384(15):1402–11.
Dinis-Oliveira RJ. Metabolism of psilocybin and psilocin: clinical and forensic toxicological relevance. Drug Metab Rev. 2017;49(1):84–91.
Hibicke M, Landry AN, Kramer HM, Talman ZK, Nichols CD. Psychedelics, but not ketamine, produce persistent antidepressant-like effects in a rodent experimental system for the study of depression. ACS Chem Neurosci. 2020;11(6):864–71.
Hesselgrave N, Troppoli TA, Wulff AB, Cole AB, Thompson SM. Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice. Proc Natl Acad Sci USA. 2021;118(17):e2022489118.
Gill H, et al. The emerging role of psilocybin and MDMA in the treatment of mental illness. Expert Rev Neurother. 2020;20(12):1263–73.
Mertens LJ, Wall MB, Roseman L, Demetriou L, Nutt DJ, Carhart-Harris RL. Therapeutic mechanisms of psilocybin: changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression. J Psychopharmacol. 2020;34(2):167–80.
Glennon RA, Titeler M, McKenney JD. Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sci. 1984;35(25):2505–11.
Kometer M, Schmidt A, Jäncke L, Vollenweider FX. Activation of serotonin 2A receptors underlies the psilocybin-induced effects on α oscillations, N170 visual-evoked potentials, and visual hallucinations. J Neurosci. 2013;33(25):10544–51.
Vollenweider FX, Geyer MA. A systems model of altered consciousness: integrating natural and drug-induced psychoses. Brain Res Bull. 2001;56(5):495–507.
Tylš F, Páleníček T, Horáček J. Psilocybin: summary of knowledge and new perspectives. Eur Neuropsychopharmacol. 2014;24(3):342–56.
Quednow BB, Kometer M, Geyer MA, Vollenweider FX. Psilocybin-induced deficits in automatic and controlled inhibition are attenuated by ketanserin in healthy human volunteers. Neuropsychopharmacology. 2012;37(3):630–40.
Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Bäbler A, Vogel H, Hell D. Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. NeuroReport. 1998;9(17):3897–902.
Vollenweider FX, Kometer M. The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nat Rev Neurosci. 2010;11(9):642–51.
Lee H-M, Roth BL. Hallucinogen actions on human brain revealed. Proc Natl Acad Sci USA. 2012;109(6):1820–1.
Hanks JB, González-Maeso J. Animal models of serotonergic psychedelics. ACS Chem Neurosci. 2013;4(1):33–42.
López-Giménez JF, González-Maeso J. Hallucinogens and serotonin 5-HT2A receptor-mediated signaling pathways. Curr Top Behav Neurosci. 2018;36:45–73.
González-Maeso J, et al. Hallucinogens recruit specific cortical 5-HT2A receptor-mediated signaling pathways to affect behavior. Neuron. 2007;53(3):439–52.
Moreno JL, Holloway T, Albizu L, Sealfon SC, González-Maeso J. Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists. Neurosci Lett. 2011;493(3):76–9.
González-Maeso J, et al. Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature. 2008;452(7183):93–7.
Moreno JL, et al. Identification of three residues essential for 5-hydroxytryptamine 2A-metabotropic glutamate 2 (5-HT2A·mGlu2) receptor heteromerization and its psychoactive behavioral function. J Biol Chem. 2012;287(53):44301–19.
González-Maeso J, et al. Transcriptome fingerprints distinguish hallucinogenic and nonhallucinogenic 5-hydroxytryptamine 2A receptor agonist effects in mouse somatosensory cortex. J Neurosci. 2003;23(26):8836–43.
Duclot F, Kabbaj M. The role of early growth response 1 (EGR1) in brain plasticity and neuropsychiatric disorders. Front Behav Neurosci. 2017;11:35.
Cole AJ, Saffen DW, Baraban JM, Worley PF. Rapid increase of an immediate early gene messenger RNA in hippocampal neurons by synaptic NMDA receptor activation. Nature. 1989;340(6233):474–6.
Schmid CL, Bohn LM. Serotonin, but not N-methyltryptamines, activates the serotonin 2A receptor via a ß-arrestin2/Src/Akt signaling complex in vivo. J Neurosci. 2010;30(40):13513–24.
Schmid CL, Raehal KM, Bohn LM. Agonist-directed signaling of the serotonin 2A receptor depends on β-arrestin-2 interactions in vivo. Proc Natl Acad Sci USA. 2008;105(3):1079–84.
Weisstaub NV, et al. Cortical 5-HT2A receptor signaling modulates anxiety-like behaviors in mice. Science. 2006;313(5786):536–40.
Van Oekelen D, Luyten WHML, Leysen JE. 5-HT2A and 5-HT2C receptors and their atypical regulation properties. Life Sci. 2003;72(22):2429.
Trajkovska V, et al. BDNF downregulates 5-HT2A receptor protein levels in hippocampal cultures. Neurochem Int. 2009;55(7):697–702.
Björkholm C, Monteggia LM. BDNF: a key transducer of antidepressant effects. Neuropharmacology. 2016;102:72–9.
Rosenblat JD, Cha DS, Mansur RB, McIntyre RS. Inflamed moods: a review of the interactions between inflammation and mood disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2014;53:23–34.
Dowlati Y, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010;67(5):446–57.
Berthold-Losleben M, Himmerich H. The TNF-alpha system: functional aspects in depression, narcolepsy and psychopharmacology. Curr Neuropharmacol. 2008;6(3):193–202.
Ting EY-C, Yang AC, Tsai S-J. Role of interleukin-6 in depressive disorder. Int J Mol Sci. 2020;21(6):2194.
Bob P, et al. Depression, traumatic stress and interleukin-6. J Affect Disord. 2010;120(1–3):231–4.
Lee Y, et al. Peripheral inflammatory biomarkers define biotypes of bipolar depression. Mol Psychiatry. 2021;89:S156.
Tanabe K, Matsushima-Nishiwaki R, Yamaguchi S, Iida H, Dohi S, Kozawa O. Mechanisms of tumor necrosis factor-α-induced interleukin-6 synthesis in glioma cells. J Neuroinflammation. 2010;7(1):1–8.
De Cesaris P, Starace D, Riccioli A, Padula F, Filippini A, Ziparo E. Tumor necrosis factor-alpha induces interleukin-6 production and integrin ligand expression by distinct transduction pathways. J Biol Chem. 1998;273(13):7566–71.
Dunn AJ, Swiergiel AH. Effects of interleukin-1 and endotoxin in the forced swim and tail suspension tests in mice. Pharmacol Biochem Behav. 2005;81(3):688–93.
Dantzer R. Cytokine, sickness behavior, and depression. Immunol Allergy Clin N Am. 2009;29(2):247–64.
Fan N, Luo Y, Ou Y, He H. Altered serum levels of TNF-α, IL-6, and IL-18 in depressive disorder patients. Hum Psychopharmacol. 2017;32(4):e2588.
Luo Y, He H, Zhang M, Huang X, Fan N. Altered serum levels of TNF-α, IL-6 and IL-18 in manic, depressive, mixed state of bipolar disorder patients. Psychiatry Res. 2016;244:19–23.
Kappelmann N, Lewis G, Dantzer R, Jones PB, Khandaker GM. Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions. Mol Psychiatry. 2016;23(2):335–43.
Nau F, Yu B, Martin D, Nichols CD. Serotonin 5-HT2A receptor activation blocks TNF-α mediated inflammation in vivo. PLoS ONE. 2013;8(10):e75426.
House RV, Thomas PT, Bhargava HN. Immunological consequences of in vitro exposure to lysergic acid diethylamide (LSD). Immunopharmacol Immunotoxicol. 1994;16(1):23–40.
Szabo A, Kovacs A, Frecska E, Rajnavolgyi E, Psychedelic N. N-dimethyltryptamine and 5-methoxy-N, N-dimethyltryptamine modulate innate and adaptive inflammatory responses through the sigma-1 receptor of human monocyte-derived dendritic cells. PLoS ONE. 2014;9(8):e106533.
Dos Santos RG, Osório FL, Crippa JAS, Riba J, Zuardi AW, Hallak JEC. Antidepressive, anxiolytic, and antiaddictive effects of ayahuasca, psilocybin and lysergic acid diethylamide (LSD): a systematic review of clinical trials published in the last 25 years. Ther Adv Psychopharmacol. 2016;6(3):193–213.
Nkadimeng SM, Steinmann CML, Eloff JN. Effects and safety of Psilocybe cubensis and Panaeolus cyanescens magic mushroom extracts on endothelin-1-induced hypertrophy and cell injury in cardiomyocytes. Sci Rep. 2020;10(1):22314.
Halberstadt AL, Geyer MA. Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens. Neuropharmacology. 2011;61(3):364–81.
Vollenweider F. 5-HT modulation of dopamine release in basal ganglia in psilocybin-induced psychosis in man: a PET study with [11C]raclopride. Neuropsychopharmacology. 1999;20(5):424–33.
Puig MV, Celada P, Díaz-Mataix L, Artigas F. In vivo modulation of the activity of pyramidal neurons in the rat medial prefrontal cortex by 5-HT2A receptors: relationship to thalamocortical afferents. Cereb Cortex. 2003;13(8):870–82.
Béïque J-C, Imad M, Mladenovic L, Gingrich JA, Andrade R. Mechanism of the 5-hydroxytryptamine 2A receptor-mediated facilitation of synaptic activity in prefrontal cortex. Proc Natl Acad Sci USA. 2007;104(23):9870–5.
Marek GJ, Wright RA, Gewirtz JC, Schoepp DD. A major role for thalamocortical afferents in serotonergic hallucinogen receptor function in the rat neocortex. Neuroscience. 2001;105(2):379–92.
Pałucha-Poniewiera A. The role of glutamatergic modulation in the mechanism of action of ketamine, a prototype rapid-acting antidepressant drug. Pharmacol Rep. 2018;70(5):837–46.
Marek GJ, Salek AA. Extending the specificity of DRL 72-s behavior for screening antidepressant-like effects of glutamatergic clinically validated anxiolytic or antidepressant drugs in rats. J Pharmacol Exp Ther. 2020;374(1):200–10.
Gewirtz JC, Marek GJ. Behavioral evidence for interactions between a hallucinogenic drug and group II metabotropic glutamate receptors. Neuropsychopharmacology. 2000;23(5):569–76.
Aghajanian GK, Hailgler HJ. Hallucinogenic indoleamines: preferential action upon presynaptic serotonin receptors. Psychopharmacol Commun. 1975;1(6):619–29.
Geiger HA, Wurst MG, Daniels RN. DARK classics in chemical neuroscience: psilocybin. ACS Chem Neurosci. 2018;9(10):2438–47.
Michelsen KA, Prickaerts J, Steinbusch HWM. The dorsal raphe nucleus and serotonin: implications for neuroplasticity linked to major depression and Alzheimer’s disease. Prog Brain Res. 2008;172:233–64.
Pokorny T, Preller KH, Kometer M, Dziobek I, Vollenweider FX. Effect of psilocybin on empathy and moral decision-making. Int J Neuropsychopharmacol. 2017;20(9):747–57.
Berman MG, Peltier S, Nee DE, Kross E, Deldin PJ, Jonides J. Depression, rumination and the default network. Soc Cogn Affect Neurosci. 2011;6(5):548–55.
Coutinho JF, Fernandesl SV, Soares JM, Maia L, Gonçalves ÓF, Sampaio A. Default mode network dissociation in depressive and anxiety states. Brain Imaging Behav. 2016;10(1):147–57.
Carhart-Harris RL, et al. Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proc Natl Acad Sci USA. 2012;109(6):2138–43.
Daniel J, Haberman M. Clinical potential of psilocybin as a treatment for mental health conditions. Ment Health Clin. 2017;7(1):24–8.
Hamilton JP, Etkin A, Furman DJ, Lemus MG, Johnson RF, Gotlib IH. Functional neuroimaging of major depressive disorder: a meta-analysis and new integration of base line activation and neural response data. Am J Psychiatry. 2012;169(7):693–703.
Tang S, et al. Abnormal amygdala resting-state functional connectivity in adults and adolescents with major depressive disorder: a comparative meta-analysis. EBioMedicine. 2018;36:436–45.
Ferri J, Eisendrath SJ, Fryer SL, Gillung E, Roach BJ, Mathalon DH. Blunted amygdala activity is associated with depression severity in treatment-resistant depression. Cogn Affect Behav Neurosci. 2017;17(6):1221–31.
Roseman L, Nutt DJ, Carhart-Harris RL. Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression. Front Pharmacol. 2017;8:974.
Christoffel DJ, Golden SA, Russo SJ. Structural and synaptic plasticity in stress-related disorders. Rev Neurosci. 2011;22(5):535–49.
Ly C, et al. Psychedelics promote structural and functional neural plasticity. Cell Rep. 2018;23(11):3170–82.
Pittenger C, Duman RS. Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology. 2008;33(1):88–109.
Castrén E, Hen R. Neuronal plasticity and antidepressant actions. Trends Neurosci. 2013;36(5):259–67.
Rief W, et al. Rethinking psychopharmacotherapy: the role of treatment context and brain plasticity in antidepressant and antipsychotic interventions. Neurosci Biobehav Rev. 2016;60:51–64.
Zhang G, Stackman RW Jr. The role of serotonin 5-HT2A receptors in memory and cognition. Front Pharmacol. 2015;6:225.
Yang T, et al. The role of BDNF on neural plasticity in depression. Front Cell Neurosci. 2020;14:82.
Zhang J-C, Yao W, Hashimoto K. Brain-derived neurotrophic factor (BDNF)-TrkB signaling in inflammation-related depression and potential therapeutic targets. Curr Neuropharmacol. 2016;14(7):721–31.
Minichiello L, Calella AM, Medina DL, Bonhoeffer T, Klein R, Korte M. Mechanism of TrkB-mediated hippocampal long-term potentiation. Neuron. 2002;36(1):121–37.
Minichiello L, et al. Essential role for TrkB receptors in hippocampus-mediated learning. Neuron. 1999;24(2):401–14.
Korte M, Carroll P, Wolf E, Brem G, Thoenen H, Bonhoeffer T. Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc Natl Acad Sci USA. 1995;92(19):8856–60.
Korte M, Kang H, Bonhoeffer T, Schuman E. A role for BDNF in the late-phase of hippocampal long-term potentiation. Neuropharmacology. 1998;37(4–5):553–9.
Gruart A, Sciarretta C, Valenzuela-Harrington M, Delgado-García JM, Minichiello L. Mutation at the TrkB PLC{gamma}-docking site affects hippocampal LTP and associative learning in conscious mice. Learn Mem. 2007;14(1):54–62.
Patterson SL, Abel T, Deuel TA, Martin KC, Rose JC, Kandel ER. Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron. 1996;16(6):1137–45.
Zhang J-C, et al. Antidepressant effects of TrkB ligands on depression-like behavior and dendritic changes in mice after inflammation. Int J Neuropsychopharmacol. 2014;18(4):pyu077.
Fava M, et al. A phase 2, randomized, double-blind, placebo-controlled study of adjunctive pimavanserin in patients with major depressive disorder and an inadequate response to therapy (CLARITY). J Clin Psychiatry. 2019;80(6):19m12928.
Cruz MP. Pimavanserin (Nuplazid): a treatment for hallucinations and delusions associated with Parkinson’s disease. P T. 2017;42(6):368–71.
Muttoni S, Ardissino M, John C. Classical psychedelics for the treatment of depression and anxiety: a systematic review. J Affect Disord. 2019;258:11–24.
Malcolm BJ, Lee KC. Ayahuasca: an ancient sacrament for treatment of contemporary psychiatric illness? Ment Health Clin. 2017;7(1):39–45.
Psilocybin PDSP database—UNC. https://pdsp.unc.edu/databases/pdsp.php?recDDRadio=recDDRadio&receptorDD=&receptor=&speciesDDRadio=speciesDDRadio&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=psilocybin&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query. Accessed 20 Sep 2021.
Psilocin PDSP database—UNC. https://pdsp.unc.edu/databases/pdsp.php?recDDRadio=recDDRadio&receptorDD=&receptor=&speciesDDRadio=speciesDDRadio&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=psilocin&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query. Accessed 20 Sep 2021.
BioRender. https://biorender.com/. Accessed 10 Jun 2021.
Mason NL, et al. Me, myself, bye: regional alterations in glutamate and the experience of ego dissolution with psilocybin. Neuropsychopharmacology. 2020;45(12):2003–11.
Gouzoulis-Mayfrank E, et al. Effects of the hallucinogen psilocybin on habituation and prepulse inhibition of the startle reflex in humans. Behav Pharmacol. 1998;9(7):561–6.
Carhart-Harris RL, et al. Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Sci Rep. 2017;7(1):13187.
Carter OL, Burr DC, Pettigrew JD, Wallis GM, Hasler F, Vollenweider FX. Using psilocybin to investigate the relationship between attention, working memory, and the serotonin 1A and 2A receptors. J Cogn Neurosci. 2005;17(10):1497–508.
Varley TF, Carhart-Harris R, Roseman L, Menon DK, Stamatakis EA. Serotonergic psychedelics LSD & psilocybin increase the fractal dimension of cortical brain activity in spatial and temporal domains. Neuroimage. 2020;220:117049.
Kometer M, Schmidt A, Bachmann R, Studerus E, Seifritz E, Vollenweider FX. Psilocybin biases facial recognition, goal-directed behavior, and mood state toward positive relative to negative emotions through different serotonergic subreceptors. Biol Psychiatry. 2012;72(11):898–906.
Bernasconi F, Schmidt A, Pokorny T, Kometer M, Seifritz E, Vollenweider FX. Spatiotemporal brain dynamics of emotional face processing modulations induced by the serotonin 1A/2A receptor agonist psilocybin. Cereb Cortex. 2014;24(12):3221–31.
Wackermann J, Wittmann M, Hasler F, Vollenweider FX. Effects of varied doses of psilocybin on time interval reproduction in human subjects. Neurosci Lett. 2008;435(1):51–5.
Wittmann M, et al. Effects of psilocybin on time perception and temporal control of behaviour in humans. J Psychopharmacol. 2007;21(1):50–64.
Vollenweider FX, Csomor PA, Knappe B, Geyer MA, Quednow BB. The effects of the preferential 5-HT2A agonist psilocybin on prepulse inhibition of startle in healthy human volunteers depend on interstimulus interval. Neuropsychopharmacology. 2007;32(9):1876–87.
Carter OL, et al. Modulating the rate and rhythmicity of perceptual rivalry alternations with the mixed 5-HT2A and 5-HT1A agonist psilocybin. Neuropsychopharmacology. 2005;30(6):1154–62.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Funding
This paper was not funded.
Conflicts of interest
Dr. Roger McIntyre has received research grant support from CIHR/GACD/Chinese National Natural Research Foundation; speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Abbvie. Dr. Roger McIntyre is a CEO of Braxia Scientific Corp. Dr. Joshua D. Rosenblat is the medical director of the Braxia Health (formally known as the Canadian Rapid Treatment Center of Excellence and is a fully owned subsidiary of Braxia Scientific Corp) which provides ketamine and esketamine treatment for depression; he has received research grant support from the American Psychiatric Association, the American Society of Psychopharmacology, the Canadian Cancer Society, the Canadian Psychiatric Association, the Joseph M. West Family Memorial Fund, the Timeposters Fellowship, the University Health Network Centre for Mental Health, and the University of Toronto and speaking, consultation, or research fees from Allergan, COMPASS, Janssen, Lundbeck, and Sunovion. Dr. Yena Lee is an employee of Braxia Scientific Corp. Leanna M.W. Lui has received: personal fees from Braxia Scientific Corp and honoraria Medscape. Kayla M. Teopiz has received personal fees from Braxia Scientific Corp. All other authors declare no conflicts of interest and/or financial disclosures.
Ethics approval
Not applicable.
Consent to participate
Not applicable.
Consent for publication
Not applicable.
Availability of data and material
Not applicable.
Code availability
Not applicable.
Author contributions
SL, FC, and RSM drafted the manuscript. All authors provided critical feedback and revisions, approved the final manuscript, and agreed to be accountable for the work.
Rights and permissions
About this article
Cite this article
Ling, S., Ceban, F., Lui, L.M.W. et al. Molecular Mechanisms of Psilocybin and Implications for the Treatment of Depression. CNS Drugs 36, 17–30 (2022). https://doi.org/10.1007/s40263-021-00877-y
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40263-021-00877-y