Psilocybin: Is it Really a Magical Solution?

Psilocybin containing mushrooms can grow worldwide and appear to be ubiquitous across many cultures. The most common strain used is Psilocybe cubensis. These mushrooms have been used for recreational, spiritual, and religious purposes, which are evidenced by anecdotal reports and scientific studies. Since the use of psilocybin has largely been associated with the ‘hippie’ counterculture movement, there is still a lingering negative stigma surrounding psychedelics. In addition, psilocybin was classified as a Schedule I substance in the mid 20th century – effectively putting the research delving into the therapeutic potential psilocybin could bring to millions of people on hold.

Ingestion of psilocybin can cause euphoria, and visual and auditory hallucinations, more colloquially known as ‘trips’. A common misconception is that psilocybin has psychotomimetic effects – this is not the case. First, psilocybin must be metabolised to psilocin, the active compound responsible for its effects. Psilocin can be found 20 – 40 minutes after taking psilocybin. Psilocybin is quickly converted to its metabolite in the stomach or via first pass metabolism, has a bioavailability of around 50%, and a half life of 2.5 hours.

Psilocin acts as an agonist at the serotonin type 2A (5 HT2A) receptors, leading to hallucinogenic effects which downstream mediates an antidepressant and anti anxiety effect (Figure 1). Psilocybin and psilocin do not interact with the dopamine D2 receptors. While the exact mechanisms of psilocin’s actions are not fully understood, it is thought that psilocin could reduce the hyperactivation of the medial prefrontal cortex. Psilocin could mediate its antidepressant effects via the prefrontal and limbic brain regions, including the amygdala. Unlike mescaline and lysergic acid diethylamide (LSD), there is no evidence to suggest that psilocybin alters circulating oxytocin. Psilocin may exert analgesic effects by interacting with nociceptive and antinociceptive pathways.

Psilocin influences the brain’s dynamics and functional connectivity, particularly between the cortex and thalamus. It is thought to affect associative networks and sensory function networks by acting on the serotonergic system. Preliminary data suggest these changes in brain activity and the beneficial effects of psilocybin assisted psychotherapy in reducing symptoms of major depressive disorder (MDD) can last for up to 12 months. Similarly, in patients with life-threatening cancer (N=56), preliminary data showed that improvements in anxiety may be long-term as 80% of patients with life-threatening cancer had sustained decreases in both depressed mood and anxiety at 6 months after psilocybin consumption. Further research is required to understand the duration of these neurological changes after psilocybin consumption, which will impact dosing frequency.

 Over 1 billion people worldwide have been diagnosed with psychiatric conditions. Psychiatric conditions are the leading cause of disability worldwide and increase the risk of mortality. In the United States (US), psychiatric illnesses cost the economy $1.6 trillion in 2019. It is well documented that quality of life (QoL) is lower in patients with a psychiatric condition than the general population. QoL decreases with increased symptom severity. Psychiatric conditions greatly impact all aspects of life and without adequate treatment can impair QoL. For example, patients with a diagnosis of MDD and generalised anxiety disorder (GAD) report lower QoL than those with a single diagnosis, suggesting the impact on QoL is accumulative. About 40% and 75% of individuals with a diagnosed anxiety disorder or MDD, respectively, experience sleep disturbances which subsequently impacts their QOL. Moreover in a study evaluating the effect of post traumatic stress disorder (PTSD) in 524 war veterans, 50% of male war veterans reported that their work was impacted by their diagnosis compared to just 16% of male war veterans without a diagnosis of PTSD. Additionally,17% of male war veterans diagnosed with PTSD reported that their ability to function as a parent was “often” or “always” impaired compared to just 4% of male war veterans without a diagnosis of PTSD.

There is preliminary evidence from clinical trials that psilocybin assisted therapy (the supervised administration of psilocybin) for treating depression and anxiety disorders, alongside early data to support its efficacy in reducing harmful drinking in patients with alcohol use disorders. Psilocybin could also alleviate pain, demonstrating analgesic effects for cluster (‘suicide’) headaches, chronic pain, and intractable phantom limb pain. In fact, Australia has approved psilocybin assisted psychotherapy and methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in a clinical setting for PTSD and TRD.

At the time of writing, there have been 140 clinical trials researching how psilocybin works and whether it has therapeutic potential in disease (Figure 2a). The US is leading the way in clinical research regarding psilocybin. Of these clinical trials, 53% are active with just over half of the active clinical trials being Phase 2 studies (Figure 2b). Most ongoing clinical trials focus on mental illnesses, particularly MDD and SUD (Figure 2c). However, psilocybin is also being investigated as a potential treatment for indications outside of psychiatric conditions including chronic pain, functional neurological disorder, and migraines.

To truly understand whether psilocybin is a magical solution, large-scale head to head clinical trials against standard of care treatments are needed. Completed clinical trials of this nature for psilocybin are scarce as most clinical trials have/are comparing psilocybin to placebo. One of the few clinical trials compared psilocybin to escitalopram in MDD. Dr Robin Carhart-Harris, the leading investigator of the clinical trial, said that patients reported feeling "recalibrated, reset like they haven't for years" and "enjoying life". However, there was no notable difference in the depression score, a 16 item Quick Inventory of Depressive Symptomatology Self Report between psilocybin and escitalopram. The response rate was 70% in patients treated with psilocybin compared to 48% in the escitalopram group. Further large scale clinical trials are needed with comparisons to other common antidepressants e.g., citalopram to truly understand the therapeutic potential of psilocybin in MDD.

Psilocybin is often coined the psychedelic with the most favourable safety profile as an overdose from consumption is extremely rare, has low toxicity, and has low additictiveness. The Registry of Toxic Effects of Chemical Substances (RTECS) evaluates the lowest dose known for a substance to cause a toxic effect and based on this dose assigns a therapeutic index value. The higher the therapeutic index, the safer the substance. Interestingly, RTECS assigned psilocybin a therapeutic index of 641 whereas nicotine and aspirin have lower values of 21 and 199, respectively.

Common adverse events (AEs) are summarised in Figure 3 and are exacerbated when psilocybin is consumed in conjunction with alcohol or other substances.

.A question that currently remains unanswered is what, if any, drug to drug interactions does psilocybin have? As psilocybin modulates serotonin neurotransmission there is potential for drug interactions with antidepressants including SSRIs, serotonin and noradrenaline reuptake inhibitors, and tricyclic antidepressants. There is also an assumption that since LSD was found to interact with SSRIs, psilocybin will also interact with them. However, one clinical study where healthy participants (N=27) were titrated with escitalopram (20 mg) over 14 days and then administered psilocybin (25 mg) demonstrated that escitalopram did not interact with SSRIs. Pre treatment with escitalopram, had reduced bad hallucinations, anxiety, and adverse cardiovascular effects compared to those treated with psilocybin and placebo. Larger well-designed clinical trials are needed to confirm thee findings. This information would be invaluable as it would give a preliminary understanding of whether it may be possible to enhance the beneficial effects of psilocybin by combining it with conventional medications.

It is important to note that psilocybin is not the only psychedelic substance to show promise in treating psychiatric disorders. When you think of ketamine you most likely associate it with being an anaesthetic. However, ketamine also has dissociative effects and has shown promise as a treatment for MDD whilst LSD may be beneficial for treating the symptoms of PTSD. Therefore, it is important that future clinical trials evaluate psilocybin against ketamine, LSD, and other psychedelics. This information is imperative to better understand which psychedelics will be the most beneficial in certain patient populations.

Most clinical trials testing psilocybin’s efficacy have been small in size, <20 participants, and are open label. This is similar to the size of clinical trials for psychedelics in general. The strict legislation surrounding psychedelic use and the stigma of using psychedelics may account for the small clinical trial sizes. However, large scale studies are needed to provide the strong medical evidence required for policymakers to make favourable legislative changes and to help destigmatise the use of psychedelics. Such large scale clinical trials will also provide crucial and valuable insights into the optimum dose and setting for psilocybin administration. Additionally, artificial intelligence could be used alongside these trials to identify biomarkers that will predict a response to treatment with psilocybin.

Project Manager and Medical Writer