The potential medicinal use of psilocybin in the treatment of major depressive disorder

By Morgan Phelps

This review article will aim to focus on the potential for the medicinal and therapeutic use of psilocybin to treat major depressive disorder (MDD). The ‘feel good hormone’ serotonin (5-HT) is a neurotransmitter and is believed to play a large role in MDD (Berger et al, 2018). On a basic level, it is considered that low levels of serotonin is partially responsible for depressive symptoms and so patients will typically be treated with selective serotonin reuptake inhibitor (SSRI) antidepressants; this aims to increase the levels of serotonin in synaptic clefts (by stopping reuptake) to boost its ‘feel good’ effects (Ruhé et al., 2007).

The recreational use of psychedelics such as psilocybin mushrooms have been recorded throughout history for their spiritual and euphoric effects (Guzman, 2008). The use of psychedelics to treat mental health disorders, such as MDD, has been a contentious area of research, namely due to the stigma that arose in the 1960s surrounding the use of psychedelics (Carhart-Harris et al, 2018) . In 2006, however, a National Institute of Drug Abuse-funded study showed that two months after taking psilocybin, 79% of patients reported increased life satisfaction and whilst 36% experienced a sense of dysphoria during the session, this did not continue to have an effect on the subject’s sense of well-being (Griffiths et al, 2006).

In addition, the traditional use of SSRIs to treat MDD have possible side effects of weight loss/gain, sexual dysfunction and nausea; this is likely because serotonin also plays a major role in the gastrointestinal tract, and although less understood it too plays a role in sexual behaviour (Wang et al, 2018). These side effects of the use of SSRIs could perhaps be negated by the use of a drug like psilocybin, as this is more specific and has greater affinity to specific 5-HT receptors (Passie et al., 2002) and so may only alter mood behaviour rather than appetite and sexual behaviour. It is also worth noting that whilst the effects of SSRIs can take up to six weeks to take effect, psilocybin takes as little as two hours (Passie et al, 2002).

Psilocybin (4-phosphorylase-N,N-dimethyltryptamine) is a psychoactive alkaloid found in many species of mushroom, colloquially known as magic mushrooms (Passie et al., 2002). Psilocybin is also a tryptamine compound, meaning it is a monoamine compound, containing an indole ring and is structurally similar to the amino acid tryptophan; it is similar to the neurotransmitter serotonin in that the indole ring is connected to an ethyl-amine substituent (Azmitia, 2010). Psilocybin itself is considered a prodrug, as evidence suggests it is completely converted to its psychoactive form, psilocin, prior to entering systemic circulation (Eindvindvik, 1989).  Psilocybin’s likeness to serotonin (being a serotonergic psychedelic) is what makes it a valuable drug to study. The monoamine, serotonin (5-HT), is a neurotransmitter that has a plethora of biological functions ranging from mood regulation and memory to cognition and learning (Young, 2007). Likely due to serotonin’s vast repertoire of functions, there are seven serotonin receptor subtypes with different functions; the receptor subtypes: 5-HT1a, 5-HT1d, 5-HT2a and 5-HT2c are the subtypes largely studied in relation to psilocybin’s medicinal use due to its affinity for them (Passie et al., 2002). Agonists of 5-HT receptors can exhibit both inhibitory (5-HT1) and excitatory (5-HT2) responses. It is thought to have its largest influence of the 5-HT2a receptor however, acting as an agonist with a Ki of 6nM (Tyls et al., 2014).

It has been recorded that patients with MDD and suicidal thoughts have more 5-HT2a receptors than normal, leading to a belief that post-synaptic 5-HT2 over-density is partially responsible for the onset of depression (Eison, 1996). In agreement with this, Van Oekelen (2003) argues that the down-regulation of 5-HT2a receptors is what mediates the effects of antidepressants. Thus greater expression of the HTR2A gene (codes for the 5-HT2a receptor) through the absence of down-regulation would result in a higher concentration of receptors and this may be a factor in depressive disorders. 

Moreover, 5-HT2a receptors are often concentrated in the frontal cortex – this is the region of the brain responsible for personality expression and social behaviour (Hensler, 2012) – and notably, through functional magnetic resonance imaging, Carhart-Harris et al. (2012) showed that psilocybin consistently deactivated the medial prefrontal cortex; which has been shown to be hyperactive in depressed patients. This reinforces the theory that over-density of the 5-HT2a receptor can play a role in depression. 

In Carhart-Harris’ (2012) study, patients were given a 10mg oral dose of psilocybin  followed by a 25mg dose a week later. All 12 patients showed significantly decreased depressive symptoms (measured by the Quick Inventory of Depressive symptoms and the BDI) at both 1 week and 3 months post-treatment.  However, Carhart-Harris’ methodology can be considered somewhat tenuous as placebo effects were not considered and 5 out of 12 patients had previously used psilocybin and so were predisposed to its mood-lifting results. Nonetheless, it helps show the potential of the medicinal and therapeutic use of psilocybin to combat depression.

Johnson and Griffiths (2008) also explain how paramount place and setting is when looking at psilocybin’s therapeutic effects. Whilst it is known that psilocybin is an agonist of the 5-HT2a receptor, the complex nature of brain networking and the somewhat persistent nature of its effects have led to belief that classic psychedelics, like psilocybin, create a plastic state in regard to brain activity and the nature of the session is what helps mould enduring, long-term changes to brain network activity. If a hypothesis such as this holds true, it adds a new dimension to the safety and administration of a drug like psilocybin in the treatment of MDD. 

Griffiths et al. (2016) also agree with the potential of psilocybin’s therapeutic effect. Although their study focused on cancer-related psychiatric distress, their results were promising and showed that after a 6 month follow-up, psilocybin gave enduring antidepressant effects.Finally, in terms of its viability with respect to production, genetically engineered E.coli have been shown to produce large amounts of psilocybin (Megha, 2019) as well as yeast having the ability to produce it de novo. (Technical University of Denmark, 2020).

Despite its apparent advantageous uses, there are potential detriments too. There is a link between increased 5-HT2 receptor stimulation and schizophrenia-like symptoms, with treatment here being 5-HT2 antagonists (Vollenweider, 1998). Psilocybin is an agonist of the 5-HT2a receptor and so works in contradiction to antagonists of this receptor. This perhaps poses a gap in research of the treatment of depression using psilocybin. A more sound understanding of the pharmacokinetics and mechanism of action of psilocybin, as well as a more solid understanding of roles and functions of 5-HT receptors would therefore be needed before a drug was issued. 

Furthermore, patients with existing health conditions, such as high blood pressure, are advised not to take psilocybin due to its additional effect of increased blood pressure (Johnson and Griffiths, 2017). Also, although studies have been conducted to show psilocybin has no measurable effect on electrolyte or blood sugar levels or liver toxicity tests (Passie et al., 2002), more research would have to be conducted to examine other potential deleterious side effects.

In addition, a John Hopkins 2016 study showed 7.6% sought help for enduring psychological symptoms after a year of talking psilocybin (Carbonaro et al., 2016). There is also the fear of psychedelics causing hallucination persisting perception disorder (HPPD). Yet whilst there is correlation to psilocybin drug use, it is widely thought this is only correlation and not causation, instead that it is poly drug use and other variables which result in HPPD (Amsterdam et al. 2011). 

Lastly, psilocybin has a ‘very low’ dependency potential, scores very highly in safety (calculated by looking at active and lethal dosage), and when compared to 19 other recreational drugs it was seen as the ‘lowest harm’ (Amsterdam et al., 2010). It additionally has no direct effect on dopamine receptors, unlike LSD, and only affects noradrenergic system at very high dosages (Passie et al., 2002), making it a suitable candidate for medicinal/therapeutic use.

As discussed above, it is clear that psilocybin can have an impact on the treatment of MDD. It’s structural similarity to M-HT and its affinity to act as an agonist for 5-HT2a receptors, therefore causing down-regulation of gene expression and thus a decrease in activity of the medial prefrontal cortex, demonstrates this. Also, despite our understanding of brain network activity and the indirect effects of psilocybin not being fully known, the studies mentioned above all point to it having a significant and long-lasting improvement in well-being – when taken under the correct circumstances.The future of psilocybin research is clear, however. Although historically research on this subject has been tenuous from lack of funding (due to social stigma surrounding psychedelics) and outdated safety standards (Passie et al., 2002), a recent revival of interest in this area means advancement in our understanding is likely forthcoming. Openings of centres such as the Imperial College London Centre for Psychedelic Research (2019), are examples of this and hold profound capacity for scientific advancement in this field.

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