Psilocybin can treat depression and other mental health disorders

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Psilocybin mushrooms have been found to have minimal harmful effects and could potentially benefit those with depression.

But they remain illegal even though they offer a groundbreaking alternative to several under-treated psychological conditions.

Nevertheless, psychedelics are currently riding a wave of positive momentum brought on by cannabis, and if psilocybin gets approved as a pharmaceutical drug, production in yeast appears to be the most commercially viable option.

“It’s infeasible and way too expensive to extract psilocybin from magic mushrooms and the best chemical synthesis methods require expensive and difficult to source starting substrates. Thus, there is a need to bring down the cost of production and to provide a more consistent supply chain,” says Nick Milne, former Postdoc at DTU Biosustain and CSO and Co-founder of Octarine Bio.

Bio-based production of psilocybin has gained big interest and researchers have already proved small-scale production in E. coli.

However, production in bacteria comes with a wide range of concerns which can be addressed by using yeast instead.

In yeast, the scientists prove that psilocybin can be produced de novo, which means that you can produce the molecule by simply growing the yeast with sugar and other nutrients, without the need to add any other starting substrates.

Producing psilocybin de novo in E. coli is difficult since a key enzyme in the biosynthetic pathway doesn’t work in bacteria, and so to get around this problem you need to add an expensive starting substrate, making the whole production process too costly.

“Since yeast and Psilocybe mushrooms are quite closely related species, this enzyme works very well in yeast, providing a much more cost-efficient alternative,” says group leader at DTU Biosustain Irina Borodina.

Additionally, yeast also performs better in large-scale fermentation due to its long history in the beer brewing process, and also in the purification process since E. coli produces additional potentially harmful compounds that you would not like to have in your final product.


Psychoplastogens

Psychoplastogens are substances capable of rapid induction of structural and functional neural plasticity with the ultimate modulation of cognitive faculties. This recently defined class [8] includes a growing number of chemically diverse compounds working through common molecular mechanisms.

The concept is based upon similar effects of serotonergic psychedelics, several flavonoids, and ketamine, of which the latter has been recently approved for the treatment of resistant forms of depression [9,10].

Though they target different receptors, in the end, they promote activation of tropomyosin kinase B (TrkB) and mammalian target of rapamycin (mTOR) [8].

Pathomechanisms Relevant to the Action of Psychoplastogens

Monoamine Hypothesis

Monoamine hypothesis started with an accidental observation that reserpine, a drug used to treat high blood pressure, also causes behavioral depression in rodents and humans.

This finding has been adopted as an experimental model of depression [11–13]. On a molecular level, reserpine blocks the transport of monoamines into vesicles and causes their profound depletion in the long term. This is manifested by typical symptoms of depression—anhedonia, anergia, and low mood [12,14].

The subsequent development of drugs targeting the metabolism of monoamines has resulted in the advent of tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs), and other compounds with the combined mechanism of action.

In general, these compounds lead to an increase in synaptic monoamine concentration and are able to induce complete or partial remission of the symptoms. However, the first signs of alleviation come often after several weeks of continuous treatment. Thus, there has been a need for a greater understanding of their mechanism of action [3].

Subsequently, HPA-axis dysregulation and neurogenic theory of depression have been elaborated. These help to explain the delay between the beginning of treatment and the onset of action by SSRIs. It has been shown that chronic SSRI treatment repairs these abnormalities [2,15,16].

Nevertheless, the monoamine hypothesis has withstood the testing and provides a partial explanation of the disease. Substantial evidence has been amassed during the last 50 years of research.

For example, depressed patients have lower 5-hydroxyindoleacetic acid to 5-HT ratio (5-HIAA/5-HT) in cerebrospinal fluid, a sign of decreased serotonergic neurotransmission.

Chronic antidepressant treatment normalizes these changes, along with symptom reduction [17]. Moreover, acute and chronic tryptophan depletion lowers 5-HT reserves, which changes reactivity to affective stimuli and leads to higher aggression or anxiety in humans [18].

Post mortem studies on suicidal patients show marked changes in the 5-HT system in the prefrontal cortex, hippocampus, or amygdala [19]. Similar results come from animal research—chronic unpredictable stress or other models of depression reduce 5-HT concentration in the prefrontal cortex and limbic system. SSRIs are able to compensate for these changes [20,21].

Furthermore, variations in genes involved in monoamine metabolism have been linked to depression [22]. Serotonin signaling is also indispensable in neurogenesis maintenance, which is another principal mechanism involved in the development of depression [16] (see below).

Neurotrophic Hypothesis

Impaired neurogenesis and neuroplasticity are also considered to be an important mechanism involved in the pathogenesis of depression [2]. In order to adapt behaviorally to external stimuli (including stressful ones), animals need to modify the functional connectivity of their brain networks.

In the adult mammalian brain, these changes are driven by two opposite synaptic processes—long term potentiation and long-term depression, LTP and LTD, respectively. LTP is further conceptualized into two partially overlapping phases—early (e-LTP) and late (l-LTP) [23].

The former involves modification (e.g., phosphorylation, nitrosylation) of existing synaptic proteins, while the latter is characterized by expression of new synaptic proteins at both pre- and post-synaptic membranes [24,25].

The extracellular signal initiating the expression of synaptic proteins has been identified to be a brain-derived neurotrophic factor (BDNF). Its secretion is stimulated by the sole activity of neurons (both pre- and post-synaptic) expressed as calcium concentration ([Ca2+]).

Increased [Ca2+] leads to activation of the cascade, including protein kinase C (PKC), mitogen-activated protein kinase (MAPK), and cAMP response-element binding protein (CREB). CREB directly up-regulates the expression of the bdnf gene. After its release into the synaptic cleft, BDNF binds to TrkB receptor at both pre- and post-synaptic membrane.

Its stimulation leads to the activation of MAPK, mTOR, and CREB (forming a positive feedback loop) [26,27]. Activation of these pathways promotes cell survival and proliferation [25]. Besides synaptic protein synthesis, neurons treated with BDNF undergo axonal and dendritic spine sprouting and synaptogenesis.

All of these changes ultimately contribute to the facilitation of synaptic communication between two neurons [25].
Chronic stress or long-term elevation of glucocorticoids are the leading etiological factors in the development of depression [2].

Their direct implication as a cause of marked atrophy of prefrontal cortex (PFC) and hippocampus is well known. On the other hand, the amygdala undergoes hypertrophy in acute depression and atrophy during long-term depression [28]. Correspondingly, chronic stress causes a decrease in BDNF concentration in these regions, along with distinctive changes in dendritic arborization and decreased cell proliferation [29–32].

Opposite effects have been found to unfold in the amygdala, also contributing to higher stress reactivity [33,34]. These changes correspond to the abnormal function of these structures, which is expressed by some symptoms of depression—higher stress reactivity, chronically elevated stress hormones, cognitive deficits, and rumination [28].

Most importantly, patients with depression have been found to have lower levels of circulating BDNF. SSRIs have been able to normalize this decrease [35,36]. Val66Met polymorphism in the bdnf gene leads to lower inducible expression of BDNF.

Furthermore, the Met allele has been linked to increased amygdala reactivity to affective stimuli and higher trait anxiety [37]. Another study found that carriers of Met allele were more prone to anxiety and depression as a function of early life stress.

Moreover, Met allele carriers had lower hippocampal and prefrontal grey matter volume, which predicted a higher risk of depression [38]. There is also some evidence that suicide cases have lower BDNF expression in the prefrontal cortex and hippocampus in comparison to controls [39] and simultaneously lower mTOR expression and proteins under its control [40]. However, there are several inconsistencies, such as differential up- or down-regulation of BDNF outside of the above-mentioned areas [41]. This might suggest that altered neurotrophic signalization is not the direct cause of depression, but rather a link in the pathomechanism.

Natural Psychoplastogens with Potential in Clinical Practice

In the following section, we have summarized the molecular mechanisms and effects on animals and humans of several naturally occurring psychoplastogens, including serotonergic psychedelics and flavones (Figure 1). Serotonergic psychedelics are a broad group, based mostly around the indole ring or phenetylamine backbone.

Among many others, these include psilocybin, produced by several Psilocybe spp., N,N-dimethyltryptamine (DMT), produced by Psychotria viridis, mescaline, produced by several North American cacti, and lysergic acid diethylamide (LSD), a derivate of ergotamine, produced by Claviceps spp. [42]. 7,8-dihydroxyflavone (7,8-DHF) is produced by several plants, including the weed Tridax procumbens and a tree Godmania aesculifolia, commonly found in the Western Hemisphere tropics and trees in the widespread Primula genus [43,44]. All flavones are based around the same chemical backbone and are a subset of the larger class of flavonoids.

Figure 1. Molecular structures of: (a) Psilocybin; (b) LSD (lysergic acid diethylamide); (c) mescaline;
(d) 7,8-DHF (7,8-dihydroxyflavone).

Research on their neuropsychiatric effects was initiated in the second half of the last century [42,45], though works on 7,8-DHF have appeared only recently [46]. All of these compounds, except psilocybin (a prodrug to psilocin), are active drugs. Furthermore, all of them show high and robust pharmacological potency without the need for modification [42]. Since psychoplastogens work through distinct mechanisms (although ultimately converging), their mechanisms and effects have been described separately.

Serotonergic Psychedelics

Mechanism of Action

In general, serotonergic psychedelics possess a broad spectrum of receptor activity. Their effects are most commonly derived from the 5-hydroxytryptamine 2A receptor (5-HT2AR) activation [47,48]. They also jointly activate 5-HT2B and 5-HT2C receptors, while some of them express 5-HT1AR activity. Other minor effects are derived from their adrenergic, dopaminergic, and histaminergic activity [47].

5-HT2AR is a Gq/11 coupled metabotropic receptor and leads to activation of phospholipase Cβ (PLCβ), hence the rise of [Ca2+] and activation of PKC [42]. This leads to excitatory postsynaptic currents [49] and activation of mitogen-activated protein kinase (MAPK) [50].

Interestingly, 5-HT2AR forms a heterodimer with metabotropic glutamate receptor 2 (mGluR2), inhibiting the activity of each other upon activation. Binding of psychedelic agonists to 5-HT2AR leads to a particular change in conformation and to inhibition of mGluR2, while the activation of mGluR2 by glutamate leads to inhibition of 5-HT2AR activity.

This leads to inhibition of either phospholipase A2 (PLA2) or PLCβ, respectively [51]. This gives rise to “biased agonism” [52] and has been described to play a role in differential activation of down-stream pathways on 5-HT2A receptor activation [50,53]. Though possessing similar chemical structure and binding at the same binding site, there appears to be an important difference between psychedelic and non-psychedelic 5-HT2AR agonists (such as

lisuride or ergotamine). Serotonergic psychedelics also up-regulate PLA2, in addition to PLCβ, when compared to serotonin [50,53,54]. This is achieved by stabilization of receptor in different conformation, which preferentially interacts with Gi/o rather than Gq α-subunit of G protein heterocomplex. Psilocin has been found to activate PLA2 with 30-fold potency over PLCβ when compared to serotonin. However, the PLCβ activation is still physiologically relevant [54]. More recently, psychedelics activating 5-HT2A receptors have been found to activate mTOR and increase neurite length, the number of dendrite spines, and overall network complexity [8], which is the first step, suggesting a possible therapeutic use.

Animal Studies

5-HT2ARs are typically expressed at dendrites of glutamatergic neurons in PFC, with the strongest expression in layer V pyramidal neurons. Activation of these receptors leads to an increase in excitatory post-synaptic potentials (EPSPs) [49].

Simultaneously, 5-HT1AR is present at the initial segment of the same neurons and drive inhibition of local currents. Functional integration of these two receptors might work as a gain control mechanism of incoming excitatory signalization, thus modulating percepts or mental representations coming to working memory [55].

Medial prefrontal cortex (mPFC) portion of these neurons projects to the basolateral amygdala, where they exert inhibitory tone via GABA neurons and decrease the amygdala reactivity [56]. These connections are thought to form a basis for fear extinction learning [57,58].
Several studies on the effects of 5-HT2AR agonists on anxious and depression-like behavior have been performed. Their effects are summarized in Table 1.

For example, a synthetic 5-HT2AR agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) has an anxiolytic effect in the four-plate test and elevated plus maze (EPM) [59]. Effects of natural psychoplastogens psilocybin and DMT have been explored in fear extinction protocols and forced swim test (FST).

First, psilocybin has cue-potentiated fear on the first extinction trial, and DMT has shown post-acute anxiogenic effects. However, both substances have been shown to generally facilitate the extinction of fear conditioned by a cue, but not by context, which may have been mediated by its action on the amygdala [60,61]. This two-way effect is consistent with the observation that the effects of psychedelics in humans are heavily dependent on the context in which they are used. In other words, they induce emotional lability and potentiate both positive and negative emotions [62].

Both substances also decrease locomotion in EPM, suggesting that increased swimming is not due to a general increase in locomotor activity [60,61]. In addition to receptor stimulation studies, a 5-HT2AR knock-out mice have shown marked anxious and depressive-like behavior in comparison to wild-type mice [63]. However, one study found no effects of psilocybin and psilocin on anxiety and depressive-like behavior.

Authors noted that they might have used an inappropriate model—Flinders Sensitive Line, a strain developed for the screening of antidepressant drugs. They further hypothesized that low basal expression of 5-HT2AR in the frontal cortex and hippocampus in this strain was potentially responsible for negative results [64].

Remarkably, these substances produce positive effects hours to days after administration, despite the fact that they are cleared out in minutes to hours. Thus, these effects must be produced by persistent changes to brain function [60].
Positive effects might be primarily exerted in mPFC, as it is responsible for fear extinction memory and direct inhibition of the amygdala [57]. Moreover, lesion studies show that the destruction of mPFC produces a depression-like phenotype in rodents [65].

Dysfunction of this region is known to play a role in depression and is related to amygdalar hyperactivation in response to negative stimuli in humans [66–68]. Besides its inhibitory tone on the amygdala, it also works as a hub within the default mode network (DMN), which is also found to be deregulated in depression [69,70] (see the section on human studies below).

Human Studies

Psychedelics are well known to cause visual illusions, (pseudo-)hallucinations, synesthesia, changes in mood (both positive and negative), changes in body-space relations, alterations in time and space, depersonalization, derealization and ego dissolution [73]. These effects are completely blocked by pretreatment with selective 5-HT2AR antagonists (e.g., ketanserin), or atypical antipsychotics (e.g., risperidone) [74].

Several studies on therapeutic effects of psychedelics, including depression, end-of-life existential distress, substance abuse disorders, have been carried out with promising results [75–77].

The summary of key studies is provided in Table 2. Out of all-natural psychedelics, research on psilocybin has reached the most promising therapeutic potential. It is labeled as a “breakthrough therapy” for MDD by U.S. Food and Drug Administration and approved for phase 3 clinical trial by European Medicines Agency [45].

Additionally, phase 2 clinical trial on LSD for depression treatment is currently conducted by Bogwart and colleagues [78].
Psilocybin has produced a significant decrease in depression and trait anxiety measures in patients with moderate to severe treatment-resistant depression. The effects are sustained from 1 week to at least 6 months after treatment [76,79].

It is also used as a possible treatment of existential distress in patients with terminal cancer. In two studies, psilocybin has induced a marked decrease in depression and anxiety measures at day one after administration and lasted at least up to 26 weeks post-treatment. Moreover, overall well-being and life satisfaction are improved in most participants [77,80].

Comparable results are achieved with LSD [81,82]. Similar studies have been performed with ayahuasca, an Amazonian brew containing DMT and monoamine oxidase inhibitors. Early studies have reported on the positive psychological effects of ayahuasca in religious context [83,84]. Subsequent clinical studies have explored its effects on patients suffering from recurrent or treatment-resistant depression.

Ayahuasca has produced immediate, robust, and significant decrease in anxiety and depression symptoms, at least up to 3 weeks follow-up [85,86].
These positive changes might be explained by the remodeling of brain networks involved in the development of depression. It has been found out that psychedelics cause acute disruption of the default mode network (DMN) by reduction of activity of its structures and connectivity between them [48,87].

In contrast, psilocybin promotes the post-acute strengthening of DMN [88]. Functional connectivity within DMN and activity of its constituents have been independently found to be altered in patients with depression and associated with self-centered negative rumination [69,70].

Carhart-Harris et al. [88] hypothesized that disruption of DMN by psychedelics facilitates remodeling of the connections responsible for negative rumination. Co-administration with psychotherapy helps to better integrate the insights and subsequently change patients’ attitudes towards issues [89]. Moreover, psilocybin induces positive affect in healthy volunteers, which is correlated with a decrease in amygdala reactivity to neutral and negative stimuli [90]. It also reduces the connectivity of the amygdala in emotional face discrimination [91].

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Technical University of Denmark

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