Exploring the Therapeutic Potentials of Psilocybin in Mental Health Treatment

Psilocybin

In 1956, psychiatrist Humphry Osmond, who was studying lysergic acid diethylamide (LSD), first coined the term 'psychedelic,' derived from the Greek words 'psyche' (mind or soul) and 'delos' (to display). Psychedelics, also known as hallucinogens, are substances that induce altered states of consciousness and reality when consumed. These altered states often lead to hallucinations, delusions, emotional fluctuations, alienation, and derealisation. 

Generally speaking, hallucinogens fall into two main categories: dissociative drugs (example, ketamine, dextromethorphan (DXM), phencyclidine (PCP), and Salvia divinorum) and traditional serotonergic and dopaminergic hallucinogens, which operate on serotonin and dopamine receptors, respectively.

Among the traditional classes of serotonergic and dopaminergic hallucinogens are (1) ergotamine, lysergamides (amides of lysergic acid)—LSD/LAD, (2) Phenethylamines like MDMA (ecstasy), MDMA-like drugs like p-methoxy methamphetamine (PMMA), mescaline and compounds derived from mescaline like TMA, DOM, DOET, DOI (2,5 dimethoxy-4-iodoamphetamine), and DOC (2,5-dimethoxy-4-chloroamphetamine), and (3) Tryptamines like N, N-dimethyltryptamine (DMT) and its derivatives alpha-methyltryptamine (AMT), 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT), 5-methoxy-N, N-diisopropyltryptamine (5-MeO-DIPT), psilocin (4-hydroxy-N, N-dimethyltryptamine, also known as 4-OH-DMT), and psilocybin ([3-(2-Dimethylaminoethyl-4-yl] dihydrogen phosphate).

Other metabolites of psilocybin, in addition to psilocin, include 4-hydroxyindole-3-yl-acetaldehyde (4-H1A), 4-hydroxyindole-3-yl-acetic acid (4-H1AA), and 4-hydroxytryptophan (4-HIT). Psilocybin, lysergic acid diethylamide, and lysergic acid amide are all categorised as indoleamine hallucinogens, respectively.

The serotonin receptors (5-HT/5-hydroxytryptamine receptors) and their subtypes, which are widely distributed throughout the brain, are impacted by traditional psychedelic (serotonergic) substances. In addition to other biological, neurological, and neuropsychiatric processes, these receptors govern emotions and moods, including anxiety, aggression, cognition, sex, learning, memory, and hunger.

Both the central and peripheral nerve systems include these 5-HT receptors. Many pharmacological and recreational medications, including hallucinogens, empathogens, antipsychotics, antidepressants, antiemetics, antimigraine agents, and anorectics, target serotonin receptors.

Among psychedelic substances, psilocybin is reputed to have the best safety record. The large body of evidence supporting psilocybin alone indicates that it may be the most effective psychedelic drug for treating mood and anxiety disorders, even though there aren't many studies comparing the effectiveness of psilocybin and psychedelic drugs for treating these conditions.

 According to a 2017 Global Drug Survey, 20.6% of persons who took drugs of any kind globally are thought to have taken magic mushrooms on occasion over the previous year. This blog will concentrate on psilocybin, the primary hallucinogenic ingredient in magic mushrooms (also known as psilocybin-producing mushrooms), which has been used in ancient societies' mushroom worship rituals for thousands of years.

Magic mushrooms have a substantial medical utility in addition to their well-known recreational, spiritual, and religious applications, as supported by anecdotal evidence and scientific research. The burden of mental health and substance-use disorders, including bipolar disorder, autism, schizophrenia, depression, anxiety-related disorders, and substance-dependence disorders, is substantial worldwide. One billion individuals are predicted to be impacted by a mental health or drug abuse disease by 2020.

An estimated 284 million individuals worldwide suffered from anxiety-related illnesses in 2018, making them the most prevalent mental health condition. Depression, on the other hand, was thought to have impacted 264 million people worldwide in the same year.

Furthermore, an estimated 107 million individuals worldwide suffered from alcohol use problems in 2018, whereas 71 million people worldwide suffered from drug use disorders (apart from alcohol). Another worldwide cost is suicidality, which is closely correlated with mental health.

According to statistics, an estimated 800,000 individuals kill themselves every year. Given the findings of elevated rates of anxiety, sadness, and distress, it is anticipated that the COVID-19 pandemic may worsen risk factors for mental health and substance use problems. Psychedelic-assisted psychotherapies, especially psilocybin-assisted psychotherapies, may help relieve some of the issues facing traditional psychiatric care in light of the rising prevalence of mental illnesses worldwide, which is now being made worse by COVID-19.

Numerous clinical trials on the treatment of cluster ("suicide") headaches, intractable phantom limb pain (PLP), and chronic pain have suggested that psilocybin has analgesic benefits in addition to its ability to treat mood and anxiety problems. Using the nociceptive and antinociceptive pathways in conjunction is one potential method by which this analgesic characteristic works. Psilocybin was effective in some situations, perhaps even more so than more conventional drugs like opioid analgesics.

Traditionally, the pharmaceutical sector, in reflection of public knowledge and governmental acceptability, resisted psychedelic research for a long time. Research on psychedelics has just lately begun to reappear in the mainstream of contemporary science, and several clinical investigations support the idea that psilocybin-assisted therapy might be a valuable addition to psychotherapy. LSD-25 has been used to treat the characteristic uncontrollable conduct associated with early infantile autism and childhood schizophrenia, according to early clinical investigations with hallucinogens. Despite less stringent clinical criteria, more than 40,000 people participated in psychedelic research trials by the 1960s.

Researchers at the University of California, Los Angeles (UCLA) started psilocybin clinical studies in 2004 to treat patients with advanced-stage cancer for pain, anxiety, and depression. One may refer to this as the "third psychedelic renaissance." Interest in psychedelic research was rekindled globally in 2006 after a Johns Hopkins University article signalled the beginning of a new era. As a result, the psychedelic research unit was established, and in 2006, Johns Hopkins University's Centre for Psychedelic and Conscious Research was established. Since then, the centre has produced more than 80 peer-reviewed publications on psychedelic research.

The first of its kind, the Centre for Psychedelic and Consciousness Research was established at Johns University in September 2020. More than 27,000 psychedelic drug-related scholarly publications have been published so far, with more than 1000 of them focusing specifically on psilocybin. The most researched psychedelic at the moment is psilocybin. Pharmaceutical interest has also grown in tandem with this resurgence of interest in psychedelic research. For a psilocybin treatment they created for treatment-resistant depression, Compass Pathways Ltd. (London, UK) was granted the "breakthrough therapy" classification by the U.S. Food and Drug Administration (USFDA) in 2018. The bulk of current research on traditional psychedelic neurotherapeutics focuses on psilocybin's potential for treating mood and anxiety problems, including the psychological discomfort associated with cancer.

Examples of Mushrooms That Produce Psilocybin

 Numerous mushroom species worldwide generate psilocybin. These nations include the United States, Southeast Asia, Europe, Mexico, and Central America. The most common species in the genus Psilocybe is the fungus Psilocybe cubensis.

Example of magic mushrooms (psilocybin-producing mushrooms).

Figure 1

Figure 2

The list of mushroom species can be formatted as:

 a. Psilocybe cubensis (Earle) Singer a.k.a is.

b. Psilocybe caerulescens Murrill (a.k.a. Landslide Mushrooms, Derrumbes).

c. Psilocybe m (a.k.a. Teonanacatl, Pajaritos).

d. Psilocybe caerulipes (Peck) Sacc. (a.k.a Blue Foot Mushroom).

e. tzii Guzmán and J. Ott (a.k.a. Blue Ringer Mushroom, Stuntz's Blue Legs).

f. Psilocybe cyanescens Wavy Caps).

g. Psilocybe azurescens Stamets and Gartz (a.k.a Flying Saucer Mushrooms).

h. OSA (A.H. Sm.) Singer and A.H. Sm.

i. Psilocybe tampanensis Guzmán and Pollock (a.k.a Magic Trufr’s Stone.

j. Psilocybe baeocystis Singer and A.H. Sm.

k. Psilocybe Hoogshagenii R. Heim nom. inval. (a.k.a. Little Birds of the Woods).

Synthesis of Psilocybins

 In humans, nonspecific esterase in the intestinal mucosa and alkaline phosphatase in the liver rapidly dephosphorylate psilocybin to psilocin (4-hydroxy-N, N-dimethyltryptamine). Before psilocybin reaches the systemic circulation of rats, it undergoes a complete conversion to psilocin. Despite the widespread belief that psilocybin is responsible for the psychotomimetic effects, psilocin, not psilocybin, is the primary pharmacologically active ingredient in magic mushrooms. It is believed that psilocybin is a prodrug of psilocin.

Psilocin's mode of action. 5-HT2A has a strong affinity for psilocybin. 5-HT serotonin receptors are widely distributed in the prefrontal cortex and other parts of the brain that mediate mood and anxiety disorders. The molecular mechanisms of action are yet unknown.

Synthetic Psilocybin Production

 Synthetic psilocybin must be produced to meet market demand, driven by the growing interest in psilocybin research over recent years. Although there is interest in psilocybin extraction from grown or naturally occurring mushrooms, the yield of psilocybin (0.1–0.2% of dry weight) is not commercially feasible for pharmacological research and development. It may only be used for recreational purposes. The reliance on psilocybin, which is derived directly from mushrooms, is complicated by the documented variations in batches of psilocybin recovered from different sources.

Nichols and Frescas (1999) outlined the complex and costly chemical synthesis used to create the majority of synthetic psilocybin. The last phase focused on the stereoselective 4-hydroxylation of the aromatic ring and the phosphorylation of psilocin to form psilocybin, even though this approach improved upon the original method discovered by Hoffman and colleagues in 1958. The yield of semi-pure psilocybin has increased to 75% using a recently patented technique by COMPASS Pathways, as opposed to 20%, as first reported by Hoffman and associates in 1959. The need for 4-hydroxyindole as the starting substrate, which might lead to high manufacturing costs, has made this approach costly despite the yield improvement.

Psilocybin bioengineering has also been investigated; it can effectively lower the cost of chemically synthesised psilocybin by producing it from less expensive starting materials, such as glucose. With yields of up to 1.16 g/l, bioengineering has enabled the production of psilocybin in the filamentous fungus Aspergillus nidulans, following the clarification of the biosynthesis mechanism for psilocybin production in P. cubensis in 2017. Since then, further techniques that rely on Escherichia coli's (E. coli) in vivo bioconversion of substrates, including 4-hydroxyindole, serine, and methionine, have been developed with an enhanced titer of 1.16 g/l. This technology is not scalable because it uses pricey initial substrates that can be produced using less costly chemical synthesis techniques.

The manufacture of psilocybin and psilocin from S. cerevisiae has greatly aided the development of less expensive psilocybin synthesis techniques. Because S. cerevisiae is widely used in industry and produces few tryptophan derivatives, using it to manufacture psilocybin can significantly increase titer uniformity and streamline downstream processing. The optimisation of psilocybin production, however, requires ongoing investigation. Considering the current surge in psilocybin research, the market can potentially reap even greater benefits from the development of improved synthesis techniques.

Psilocybin's Mode of Action

 Psilocin's antidepressant and anti-anxiety actions are mediated by its agonistic interaction with serotonin (5-hydroxytryptamine) type 2a (5-HT2A) receptors, which results in a "mystical-like" hallucinogenic experience because of induced frontal hyperfrontality. The reduction or normalisation of the medial prefrontal cortex's (mpfc) hyperactivity is one potential antidepressant mode of action of psilocybin. The MPFC is usually overactive during depression. The prefrontal and limbic brain areas, as well as the amygdala, are modulated by psilocybin to produce its antidepressant effects. In networks that process perception and emotions, the amygdala is crucial. When someone is depressed, they usually become less sensitive to emotional cues.

Magic Mushroom Effects

 The effects of magic mushrooms depend on a person's mental state, body type (especially weight and metabolism), tolerance level, and the specific mushroom species (and, ultimately, the concentration of active metabolites in a particular species). The acute psychedelic effects of psilocybin usually start to show about 30 to 60 minutes after a low to moderate (2–10 g) dosage. According to different research, 3–5 mg p.o. can have sympathomimetic effects without producing hallucinatory ones. A dosage of 8–25 mg produces hallucinogenic effects in 70–90 minutes. Equimolar concentrations of psilocybin and psilocin have been shown to have comparable psychotropic effects in people. Subjective effects might linger for three to six hours before diminishing to insignificant levels. Four types of psilocybin effects can be distinguished:

 (1) Emotional, (2) Cognitive, (3) Perceptual, and (4) Dissolution of Ego. Moreover, there are two types of psilocybin effects: physical and psychological.

In conclusion, Current problems in the traditional treatment of mental illnesses may be addressed by psychedelic-assisted therapies, which might provide fresh and essential prospects. As demonstrated by decades of numerous clinical trials and thousands of anecdotal reports, psilocybin-assisted treatment may be a practical, effective, and physiologically well-tolerated option. It may have immense potential in mental care. Some obstacles need to be addressed before it can be recognised as a component of psychiatric treatment. These limitations include the highly sensationalised history of psychedelic drugs around the world and the persistent negative stigmatisation of these drugs, especially in the United States; difficulties with federal regulations, approval and funding from the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (USFDA) for clinical psychedelic studies; the lack of standardised diagnostic and therapeutic practices for psychedelic and psilocybin, especially when it comes to inducing "mystical experiences" that are crucial to the effectiveness of psilocybin therapy; the absence of larger, more sufficient double-blinded, randomised clinical studies to evaluate safety, pharmacology, and dose-response relationships for each mood and anxiety disorder; and difficulties with intellectual property (IP) and obtaining enforceable patents, given that mushrooms grow naturally.

Reference

Lowe, H. et al. (2021) 'The therapeutic potential of psilocybin', Molecules, 26(10), p. 2948. doi:10.3390/molecules26102948.