Psychedelics for depression is a thing now, but how can a compound repair the psychological results of a fragmented world?
Dr Richard Wise | Clinical Psychologist | Melbourne, Australia
People have been getting happily wrecked for millennia. Although the modern, Western world got hip to psychedelics largely after Albert Hoffman synthesised accidentally ingested LSD in 1943 (several years after he had initially isolated the compound from ergot), they’d been around for centuries prior, and had been crucial to the rituals and spiritual exercises of many cultures, often facilitating the religious or mystical experience central to these rites (Nichols, 2004). One radical theorist has even suggested they may have contributed to increasing the pace of humanity’s evolutionary development (see Terrence McKenna’s speculative but enjoyable Food of the Gods for this interesting thesis).
But it was only in relatively recent decades that tripping was written off as a moral failure by the state, thanks to the development of rather puritanical laws and the protracted scare campaigns to back them up (Davenport-Hines, 2001). In empirical fact, psychedelic substances are far safer than drugs such as alcohol or cocaine, which is something you can read a bit about here.
Popular and political opinion, however, diverges from science, and psychedelics are commonly considered relatively dangerous, often backed purely by shrill anecdotal evidence that, if it occurred at all, represents the exception.
In the 1960s and 70s, psychology began to examine psychedelic substances as potentially useful for the alleviation of psychological distress. The findings were good. But then the studies got wrapped up and shut down for a variety of complex politico-legal reasons (Davenport-Hines, 2001).
But over the past 10 or 15 years, a resurgence of similar hypotheses has been taking place, alongside a proliferation of research into the utility of psychedelic compounds such as psilocybin (the primary psychoactive component of magic mushrooms) and LSD for treating mental health problems, with a particular focus on depression. There’s also rather advanced work looking at the dissociative anaesthetic ketamine, with clinical trials currently happening in my current home city, Melbourne.
Studies so far, in summary, have demonstrated that these compounds can have quite a marked anti-depressive effect, especially in severe and treatment-resistant depression. Psychologically, we know they contribute to a deep sense of subjective inter-connectedness with nature and others, alongside a long-term shift in openness to experience and perspective.
How would something like this happen? The answer, at least according to psychiatric psychopharmacology, appears to ultimately be a neurotransmitter called glutamate, which is what’s known as an excitatory neurotransmitter. Sit back for a second while things get pharmacological — explanations of the mode of actions of drugs depend, naturally, on the scientific method, which usually reduces our understanding of things to small component parts and their interactions, an epistemic position called reductionism. The small parts, when it comes to pharmacology, are often neurotransmitters, which are, in a nutshell, the tiny compounds our brain’s nerves use to communicate with each other electro-chemically. If this next summary is a bit much, skip down a couple of paragraphs for the rub.
Evidence suggests that classical hallucinogens (such as LSD or psilocybin) produce a large component of their direct effects via action at Serotonin (otherwise known as 5-hydroxytryptamine) 2A (5-HT2A) receptors (Hasler, 2004; Nichols, 2004; Julien, 2008; Vollenweider & Kometer, 2010). Administration of 5-HT2A receptor antagonist ketanserin almost entirely stops psilocybin producing its behavioural effects in rats (Wing, Tapson & Geyer, 1990), and restoration of 5-HT2A receptors in cortical pyramidal neurons restores hallucinogen-induced head-shaking in mice (Gonzalez-Maeso et al., 2007). Descending neural circuits implicated in perception and emotion projecting from various pre-frontal pyramidal neurons to ventral tegmental area and dorsal raphe nucleus express 5-HT2A receptors (Vazquez-Borsetti, Cortes & Artigas, 2009), and are thought to modulate 5-HTs acute psychedelic effects (Vollenweider, & Kometer). Although pharmacological differences exist between LSD and psilocybin, psychedelically they function via similar mechanisms, and hold experiential similarity also (Sessa, 2005). Ketamine, however, diverges from the classical hallucinogens in that it functions chiefly as an N-methyl-D-aspartate (NMDA) glutamate antagonist (Julien, 2008), providing little activity at 5-HTergic neurons.
Despite these differing profiles, there is evidence that both classical hallucinogens and ketamine ultimately enhance glutamate release in the pre-frontal cortex, including key emotional processing centres - the anterior cingulate, medial prefrontal cortex and insula (Maeng & Zarate, 2007). Studies have demonstrated that stimulation of post-synaptic 5-HT2A receptors can lead to increases in spontaneous glutamatergic expression within cortical layer V pyramidal neurons, which can be abolished by 5-HT2A antagonists, indicating the capacity of 5-HT 2A receptors to enhance glutamate transmission with this cortical network (Beique, Imad, Mladenovic, Gingrich & Andrade, 2007). NMDA antagonism, on the other hand, can also increase glutamate activation in the cortex, likely due to pharmacological blockade of NMDA receptors on GABA neurons within cortical and/or subcortical neural areas, leading to a reduction of inhibitory control over prefrontal glutamate release (Vollenweider & Kometer, 2010).
The observation that glutamate is a key neurotransmitter involved in both depression and neuroplasticity also raises possibilities around its utility in the treatment of mood disorders, which have demonstrated abnormal neuroplastic functioning within the neural areas that psychedelics promote glutamate release (Brunon, Lopes & Fregni, 2008).
It may thus be that the shared ability of a variety of psychedelics to increase or alter the expression of neural glutamate within cognitive-emotional systems may provide one explanation for their therapeutic effect (Krishnan & Nestler, 2008; Vollenweider & Kometer, 2010). This could occur via several mechanisms. An animal study observed that reductions in depressive behaviours following ketamine administration were associated with increased expression of brain-derived neurotrophic factor (Garcia et al., 2008), which could counter the decreased BDNF expression observed in depression (Krishnan & Nestler, 2008) and foster renewed neuroplasticity and neural growth (Brunoni, Lopes & Fregni, 2008). Others have speculated that more acute decreases in depressive symptoms may be facilitated by increased AMPA-NMDA receptor stimulation (Maeng & Zarate, 2008). Over time, it may be that the likely facility of psychedelics to enhance neuroplasticity may function to a) more easily shift what were previously rigid cognitive or emotional processes central to common psychopathologies, and b) enhance the psychotherapeutic process, allowing necessary changes within cognitive and emotional cortico-limbic neural pathways (Vollenweider & Kometer, 2010, or see this 2020 article).
So, here the modern world stands, once again ready to appropriate another previously mystical act into the medical model of psychological suffering, similarly to how we did with meditation in recent years.
The irony here is in the action of psychedelics to promote a sense of inter-connectedness between, well, everything, because the reductionistic tenets of the scientific and medical models run precisely counter to this. A large proportion of this essay so far has been about minute methods of action, and has largely ignored the much broader, but perhaps much more important context to our psychological suffering — our global, mutual disconnection from nature, disconnection from community, disconnection from purpose — all on a backdrop of meaningless consumer capitalism, structural racism, structural sexism, and economic systems that stimulate drastic inequality and interpersonal separation. I’ve written about this in more detail here.
Both anecdotally and empirically, psychedelic experiences have awakened people to the synthetic nature of their disconnection from the natural world, and it has been in the profound awe of the recognition of their connection to all other things, across time and space, that the psychological suffering endemic to gross disconnection has often abated somewhat. Now, psychedelics are being adopted by a model that reduces experience to molecules, finally sanctioned by a deeply ill society that itself has been profoundly dissected into solitary component parts, and appears to be becoming more so. Beyond provoking mass revolt against this unwell status quo, how can it really help beyond suspending a delusion?
I’m becoming readily more unsure about the trend towards medical appropriation of mystical practices to subjectively paper over problems that arise from the psycho-sociological and developmental consequences of what the medical model ultimately reflects — the problematic separation of component parts of a systemic whole. A related irony is that the medical world also disavows systemic and social explanations of mental ill-health by favouring biologically deterministic and reductionistic explanatory models for psychiatric issues. It’s no surprise, then, that psychiatry, having by lost its way many decades ago, yet having somehow retained its status with funding bodies, has by all empirical accounts profoundly failed to solve the problem of mental ill-health. There is no reason to believe that this shift towards psychedelics will be its redemption.
We will see what transpires. I anticipate something akin to the boom of meditation as it subsequently gave way, once again, to the realities of our current world, its resultant psychologies, and the deeper problems it barely touched upon, as much hope was maintained for it at its zenith within the mental health treatment world. Without a genuine and persistent attempt to both recognise and solve the profuse systemic problems that underly the development and maintenance of psychological pain, what more can it really do? A subjective sense of inter-connectedness is hollow in the absence of the real thing.
Our collective mental health is impacted by the problems that psychedelics help identify — our fundamental, deep, and apparently irresolvable disconnectedness from nature and other people. These compounds are now being appropriated by a model that emblemises the problem, and at best may function to awaken multitudes to this issues. What happens next, if it’s not broad societal change, may be all the more disappointing for this awakening.