#4 - Can Psychedelics Alleviate Major Depressive Disorder?

Approximately 1 in 4 people will experience a mental health condition during their lifetime and currently, over 7 million people in England are diagnosed with major depressive disorder (MDD). Despite these numbers, there is still a stigma around mental health disorders that exist, due to a lack of education and awareness. There are many different therapies and medications available to treat certain mental health conditions, however, these are over-prescribed and as a result, are losing their effectiveness.

So what makes an MDD individual suffer on a biochemical level? Hormonal imbalances are the main reason and the most important hormone that controls one’s mood is serotonin. 

Serotonin is a neurotransmitter that has a plethora of effects on various systems within the body. A lack of production can lead to several types of depression, hence why most medications aim to prevent reuptake of serotonin back into the nerve terminals from which they were released. The most common of these are selective serotonin reuptake inhibitors (SSRIs) – doing exactly what the name indicates; preventing serotonin reuptake, so more is available in the synaptic cleft to bind to post-synaptic receptors, thus inducing its effects. These are the most widely used medications for individuals suffering from MDD and are proven as fairly effective.

One such SSRI is called escitalopram, which is the gold-standard when treating MDD patients. The efficacy and tolerability of escitalopram was investigated by Jiang et al., 2016, where a dose of 10-20mg / day was found to be effective for long-term treatment of major depressive disorder. It was shown that 55% of patients achieved remission after 24 weeks of escitalopram treatment at 10mg / day and there was a 98% patient compliance. There were very few severe treatment-induced adverse events (4 serious out of 200). Even though this study was a single-arm, open-label design (questioning the reliability of results), many researchers have proven effectiveness and safety of escitalopram for treating MDD and other forms of depression. However, there are some patients for whom this treatment is no longer effective, so alternatives need to be found.

This is where psychedelic therapy comes in. Psychedelics are hallucinogenic drugs that cause an out-of-body experience, or what are referred to as ‘trips.’ Previously, they were used for spiritual and religious ceremonies, but due to their abusive potential, they are illegal and are currently classed under the Novel Psychoactive Substances Act (2016). Some psychedelics you may be familiar with include LSD and ‘magic mushrooms’ – the active ingredient of psilocybin being converted in the body to psilocin, which is responsible for the ‘trip’ effect. The key receptor that mediates all these effects is the serotonin 5-HT2a receptor, which is found in high concentrations within various brain regions. Psychedelics cause extremely high levels of both dopamine and serotonin to be released, leading to an increased state of excitability and hallucinations.

So why hasn’t psilocybin been used for treatment if it could potentially increase serotonin levels? It’s extremely controlled and is illegal for use, but recent research has been granted access to ‘microdosing,’ which aims to improve an individual’s state of mind and depressive symptoms by using small doses of the drug. Since 2017, there has been a rise of psychedelic use for therapy in patients with depression and anorexia, with 2020 seeing the highest surge of trials. The legalities surrounding these substances make them difficult to acquire licenses for patient treatment, however, microdosing studies aim to circumvent these limitations.

You may have heard of the recent documentary entitled ‘The Psychedelic Drug Trial.’ In 2021, the researchers Dr. David Nutt, Dr. Rosalind Watts and Dr. Robin Carhart-Harris conducted a study in a group of 59 patients, who were all diagnosed with moderate-to-severe depression. The participants were split into two groups; the first group (psilocybin) received two 25mg doses of psilocybin which were 3 weeks apart, followed by placebos for the following 6 weeks. The second group (escitalopram) received two low doses of 1mg psilocybin 3 weeks apart, followed by a 6-week course of escitalopram.

Let’s take a look at their results.

One measure of treatment effectiveness between group, was an assessment of the suicidality rates. The escitalopram group increased slightly in suicidality rates from 168 to 173, however the psilocybin group had a decrease from 157 to 96. Multiple secondary outcomes were also improved in the psilocybin group compared to the escitalopram group.

However, despite the face-value biological significance of psilocybin, there was no indicated statistical significance between the two groups. This may have been attributed to the low sample size and short-term duration of the study. The researchers also stated that results were not corrected for multiple comparisons, which may have resulted in type 1 errors (false positives – obtaining statistically significant results when this may not be the case). To potentially avoid this, Bonferroni corrections could be carried out to take into account the multiple comparisons between groups.

An additional factor of variability may have been introduced by the assessment of patient symptoms through the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR). There are practical issues with questionnaires, despite their usefulness in reporting patient mood and feelings.  Patients may not be fully willing to share how they may be feeling or they may have forgotten what happened during the study. The subjective nature of this data collection method is why such variability between groups may be taking place.

These factors above prove to be extremely challenging in the licensing of psychedelic therapy, as gold-standards such as escitalopram exist and have been widely shown to have effectiveness, especially for long-term MDD treatment.

However, it cannot be ignored that psilocybin treatment had extremely positive and beneficial effects on individuals within the study. The documentary highlighted personal stories of patients and several patients reported that the therapy was life-changing and even though they were not completely MDD-free, a clear increase in quality of life was evident. From this above evidence, it is clear that longer trials with higher patient numbers are needed in order to approve controlled psychedelic therapy for patients with MDD.

 

 

References:

Carhart-Harris R, Giribaldi B, Watts R, Baker-Jones M, Murphy-Beiner A, Murphy R et al. Trial of Psilocybin versus Escitalopram for Depression. New England Journal of Medicine. 2021;384(15):1402-1411.

Documentary Link: The Psychedelic Drug Trial https://www.bbc.co.uk/iplayer/episode/m000w7bq/the-psychedelic-drug-trial

Jiang K, Li L, Xueyi W, Fang M, Shi J, Cao Q et al. Efficacy and tolerability of escitalopram in treatment of major depressive disorder with anxiety symptoms: a 24-week, open-label, prospective study in Chinese population. Neuropsychiatric Disease and Treatment. 2017; Volume 13:515-526. 

Tullis P. How ecstasy and psilocybin are shaking up psychiatry [Internet]. Nature.com. 2021. Available from: https://www.nature.com/articles/d41586-021-00187-9