Written by Tiago Vasconcelos
Psychiatric disorders can be considered to disturb the brain’s equilibria, emerging when different factors converge to push the brain towards inefficient states. Depression and anxiety are two of the most pervasive mental health conditions, and are challenging to treat; an estimated 30% of depression sufferers prove resistant to first-line treatment (Al-Harbi, 2012), with this figure rising to 40% for anxiety disorders (Bystritsky, 2006).
Depression is the largest burden of illness in the west. Globally, more than 100 million people are affected by treatment-resistant depression and as many as 30% of these may attempt suicide at least once in their lifetime. Up to 15% of people with major depression will commit suicide.
Mental health has reached crisis levels during the COVID-19 pandemic. 21% of adults experienced depression from January 27th to March 7th 2021; an increase of 11% from pre-COVID levels (Office of National Statistics, 2021).
When it comes to medication, the same first-line treatment is used for both depression and anxiety. These are a class of drugs called selective serotonin-reuptake inhibitors (SSRIs). For example citalopram (trade name Cipramil) and sertraline (trade name Lustral), SSRIs work by inhibiting the reuptake (back into the neurone) of serotonin in the brain, thereby increasing serotonin signalling in numerous brain regions. However, despite their moderate success in treating the symptoms of mild to moderate depression and anxiety, many people do not respond, they have a large side effect burden and many people stay on them for years.
Only 36.8% of patients experience remission despite being prescribed SSRIs. Jakosbsen and colleagues conducted a systematic review of the evidence for SSRIs versus placebo, including 131 trials and 27,422 participants, and reported that although the short-term effects (3-month) of SSRIs were better than placebo, this effect was still below the threshold of clinical significance. The benefits of SSRIs were even lower in the longer term. They were also accompanied by a substantial side effect burden, including: sexual dysfunction, insomnia, dizziness, headache, nausea & vomiting.
For decades, the hegemonic stance framed both depression and anxiety as the result of ‘deficits in serotonin signalling’. But it seems that reductively focusing on monoamine neurotransmitters misses the mark when it comes to mental health and new drug discovery focuses on drugs with mixed mechanisms of action. For example, the rapid acting antidepressant effects of ketamine are likely to be multimodal (Strasburger et al. 2017). Advances in neuroscience now consider the brain more holistically, considering not just certain neurotransmitters, but also the configuration of entire brain networks and their intricate dynamics. We can see that chronic depression and anxiety correlate with abnormally rigid brain activity; patients’ brains become locked into patterns of activity. And, in consonance, it seems that all effective depression and anxiety interventions primarily work by enhancing neuroplasticity (Liu, 2017).
Neuroplasticity refers to the brain’s ability to form and reorganise synaptic connections. Synapses are the points of connection between neurons, permitting communication that allows the consolidation of memories, recall old information and learn new skills. Virtually all psychiatric disorders involve a loss of synaptic flexibility; this is particularly notable in the hippocampus, a sea-horse-shaped region nestled deep in the medial temporal lobe. Being responsible for essential memory- and emotion-related processes, the hippocampus is hit particularly hard during mental turmoil. Chronic states of depression and anxiety can even lead to atrophy, or death, of the neurons it comprises (Sheline, 2011).
Another brain region known to be affected by depression and anxiety is the amygdala, a nearby hub implicated in fear and the processing of emotions. Critically, both of these subcortical areas are modulated by the cortex, the part of the brain involved in higher-level rationality, decision-making and emotional regulation.
In depression, neurons in the cortex become less willing to form new, helpful connections. When SSRIs offer relief, it is mainly through their ability to restore cortical plasticity over a period of weeks, leading to new cortical connections and improved regulation of the more primitive emotional regions (Pittenger & Duman, 2008). Importantly, stressing the importance of neuroplasticity in mental health does not negate serotonin’s role in mood regulation. When the brain’s plasticity is reinstated following mental illness, the activity of neurotransmitters like serotonin and dopamine gets regulated as a natural side effect.
Given the influence that neuroplasticity has on mental health, it is unsurprising that psychedelics have returned to the forefront of psychiatric research. One or two high doses can catalyse profound psychological change, particularly when preceded and followed by psychotherapy. Psilocybin and lysergic acid diethylamide (LSD) are the most popular, both inducing an altered state of consciousness and emotional effects primarily through their initial interaction with the serotonin 5HT2A receptor. A protein found throughout the brain but concentrated in the cortex, this receptor is believed to rapidly induce a period of enhanced neuroplasticity when it receives adequate stimulation, due to a cascade of events including the release of glutamate. It thus seems highly likely that psychedelics produce their therapeutic effects via this activation of this receptor, catalysing an array of effects that allow a patient to lose their negative thought processes and emerge renewed (Calder & Hasler, 2022).
Psychedelics have a ‘profound’ effect, yet they are not actively reinforcing; while many people enjoy their experiences under the influence, psychedelic use is not associated with physiological or psychological dependence. Critically, this also separates them from addictive drugs that transiently numb the symptoms of mental illness like alcohol, benzodiazepines and barbiturates. However, despite proponents claiming their innocuousness, psychedelics present their own hazards. Their link to psychosis is contentious, but established; individuals prone to schizophrenia and/or psychotic states can see a worsening of symptoms following hallucinogenic experiences, or find them triggered for the first time (Paparelli, 2011).
However, the current scientific consensus is that low-medium doses of psilocybin and LSD are safe for the vast majority of individuals. Erring on the side of caution does not seem to constrain their therapeutic potential. Deep emotional shifts can be catalysed by light psychedelic experiences, with early-stage research reporting OCD patients find relief from their intrusive symptoms after just one low-dose psilocybin trip. Moreno et al. specifically tested the tolerability of psilocybin as an OCD treatment, finding a moderate dose to elicit no adverse effects in any participants. One individual’s blood pressure increased transiently, but this response was not associated with increased anxiety (Moreno, 2006).
The Drug Science team have investigated known risks, using currently available data from clinical trials, and in retreat settings. Overall, we found low levels of adverse events, particularly of serious risks (Schlag et al. 2022). Blood pressure and heart rate were elevated in many of the studies we examined but this tended to be transient and did not require medical attention. This is in direct contrast with perceived risks, leading to the undeserved stigmatisation of psychedelics. Furthermore, a recent trial in eighty-nine healthy participants showed that a single dose of 10 mg or 25 mg of psilocybin produced no serious adverse events (Rucker et al. 2022). There are however clear gaps in knowledge that should be addressed prior to the wider clinical application including an understanding of drug-drug interactions, and analysis of human receptor pharmacology of the various psychedelics (Neill et al. 2022)
Moreover, it seems we’re getting closer to elucidating how psychedelics promote brain plasticity in helpful ways. Researchers at Imperial College London found two moderate doses of psilocybin to markedly enhance the flexibility of higher-order functional brain networks, all of which express 5HT2A receptors throughout. The fMRI results showed that they became more interconnected and flexible, granting them tighter control of subcortical regions like the amygdala. Psilocybin also decreased connectivity between brain areas that are typically closely interconnected in the depressed brain, including the default mode, salience, and executive networks. Most importantly, these effects correlated with a significant amelioration of depressive symptoms; the first-line SSRI escitalopram produced a less robust antidepressant response than the psilocybin and elicited no observable changes in brain organisation. Primary outcome measures like depression scores and quality of life and wellbeing showed no difference, however secondary measures had better outcomes for psilocybin (Daws et al., 2022).
Psilocybin and LSD both enhance dendritic growth in cortical neurons; dendrites are the parts of neurons that receive signals, and form an integral part of the synapse. Rodent models demonstrate that all classical psychedelics upregulate genes involved in plasticity in the frontal lobe, translating to the growth of synapses and dendritic spines. Interestingly, pigs exposed to a hallucinogenic dose of psilocybin similarly exhibit increased presynaptic density in the prefrontal cortex (Raval, 2021). The mechanisms at play are believed to be very similar in humans, with PET imaging revealing upregulations in glutamate signalling in the prefrontal cortex. Glutamate is a neurotransmitter theorised to be key in psychedelic-enhanced plasticity in humans (Mason et al., 2020).
Evidently, the molecular actions of psychedelics render them well-poised to augment cortical plasticity, potentially the most crucial brain process required for emotional change. Psilocybin is paving the way, proving effective at tolerable doses in the treatment of anxiety, depression and OCD. This is promising, given that the excessive neuroplasticity induced by powerful hallucinogen trips can, it seems, be too much of a good thing. Patients plagued with mental health symptoms may be willing to get experimental, but there is no evidence to suggest that a particularly strong trip is required for transformative results. Time will tell if psychedelics truly are a panacea for mental health, but evidence yielded from their careful implementation so far seems both robust and auspicious.