Classic psychedelics are a group of psychoactive drugs that includes lysergic acid diethylamide (LSD), psilocybin, N,N-dimethyltryptamine (DMT) and mescaline (1). When ingested, these compounds can elicit altered states of perception, cognition and emotion (2). Despite having distinct characteristics, the classic psychedelic compounds are often grouped together as they all act as agonists for serotonin 5-hydroxytryptamine (5-HT) 2A receptors (3). It is through this receptor agonism that classic psychedelics primarily exert their psychoactive effects (1).
The use of the classic psychedelics by non-Western cultures can be traced back thousands of years. The sacramental consumption of mescaline, via ingestion of the Peyote cactus (Lophophora williamsii), has occurred in Native American ceremonies for at least 5 millennia (4), and there is evidence to suggest that DMT-containing plants have been ingested by some in South America since 2130 BC (5). Similarly, psilocybin-containing mushrooms may have been used in Mesoamerican ceremonies for 3500 years (6).
The clinical use of psychedelics first sparked interest in modern Western medicine in the 1940s (2), when LSD was first synthesised and ingested (7). This discovery sparked numerous studies into the use of the classic psychedelics (namely LSD and psilocybin) in the treatment of psychiatric disorders. However, political motivations in the beginning of the 1970s caused an abrupt end to this era, when known psychedelics were prohibited under the Controlled Substances Act (8). A 20 year research hiatus followed (9), until several studies in healthy participants gained ethics approval (10-13) through utilising psychedelics with less notoriety than LSD. This paved the way for research to slowly recommence.
Classic Psychedelics and Depression
Since research has resumed, promising results have been reported on the clinical benefits of classic psychedelics across a range of psychiatric disorders, including depression (14). Several trials have reported psilocybin to produce significant and long-lasting improvements for those with treatment resistant depression (15, 16) and depression associated with life threatening cancer (17, 18). Similar reductions in depression symptoms have been described with ayahuasca, a brew containing DMT from the Psychotria viridis plant and monoamine oxidase inhibitors from the Banisteriopsis caapi vine (19-21). In fact, recent systematic reviews have reported significant, rapid and sustained reductions in depressive symptoms in all modern trials which utilise either psilocybin or ayahuasca (22, 23). Psychedelic therapy offers several advantages over conventional anti-depressant treatment. Most notably, psychedelic therapy appears to produce greater reductions in depression symptoms when compared to typical pharmacological and psychological treatments (24). These symptom changes typically result from a short treatment program and usually occur immediately following treatment, unlike the weeks or months typically seen in current treatments (25). Reductions in depression symptomology appear to be well sustained post-treatment (15), yet additional longitudinal outcomes are needed to corroborate this.
Exactly how classic psychedelics work to reduce depression symptoms is still largely unknown, although several potential mechanisms have been proposed. Increased functional connectivity within the default mode network (DMN), a group of brain regions which show increased activity during rest and decreased activity during cognitively demanding tasksas well as decreased functional connectivity between executive networks and the DMN, has been associated with the pathophysiology of major depressive disorder (26, 27). A number of studies have now shown that classic psychedelics reduce activity and internal functional connectivity within the DMN, potentially reducing abstracted (perceptually-decoupled) and self-referential rumination, a hallmark of depressotypic thinking (22, 28). Moreover, there is now evidence to suggest that the psychedelic state produces co-activation between the DMN and task positive networks (a network of brain regions which activate during attention demanding tasks), two networks which are usually anti-correlated (29). It is possible that this co-activation may be contributing to the novel experiences and outcomes which occur during psychedelic therapy (29). Several other neurological mechanisms of action have been proposed. Alterations in amygdala reactivity to emotional stimuli (30-32), increased concentrations of glutamate and brain-derived neurotrophic factor (33, 34) and reductions in inflammatory agents (35) have been suggested to contribute to the antidepressant effects of psychedelics, with varying degrees of evidence. However, more research is required to comprehensively understand how psychedelics may be acting on the brain to alleviate depressive symptoms.
Set and Setting: Psychological Processes in Psychedelic Treatment
It is important to note that the context in which classic psychedelics are used requires significantly greater consideration than traditional depression pharmacotherapies. This is due to both the positive therapeutic effects of the interpersonal context in which consumption takes place (36), as well as a number of risks associated with psychedelic consumption. These risks include transient anxiety, panic and, very rarely, prolonged psychosis (37). It has long been recognised that both set (the mindset of the participant, including their expectations, assumptions and intentions for the psychedelic experience, as well as stable variables such as personality and the presence of psychopathology) and setting (the physical, social and cultural environment in which the experience occurs) have the potential to greatly impact the outcomes of the psychedelic experience (38, 39). Psychedelic-assisted psychotherapy aims to account for this by conducting psychotherapy with participants (usually in addition to the psychedelic consumption) in order to ensure participants approach psychedelic therapy with a suitable set. Participants take part in several sessions of psychotherapy before their psychedelic session, which act to set constructive expectations and intentions for the experience (37). Additional sessions are provided following the psychedelic session, to assist in integrating their psychedelic experience once it is complete (40). Contemporary clinical trials have also addressed setting, by providing a comfortable and aesthetic environment, in addition to music and eye masks, for the psychedelic session to take place (37). During these dosing sessions, a non-directive therapeutic style is adopted, with therapists instructing participants to ‘focus inward’ (41). They may also provide support or encouragement for participants to engage with any challenging thoughts or memories that emerge (41).
As indicated by the above procedures, the psychological and social context in which psychedelic-assisted psychotherapy occurs is of particular importance. This raises questions regarding the potential psychological process which may be contributing to changes in depression symptoms. A focal point of this research area to date has been investigating mystical-type experiences, which includes the occurrence of “profound unity with all that exists, a felt sense of sacredness [and] a sense of the experience of truth and reality at a fundamental level” (13). This experience is often operationalised into four factors; mysticism (a sense of unity, sacredness and noetic quality), positive mood, transcendence of time and space, and ineffability (difficulty in describing the experience; 41). Undergoing a mystical experience has been associated with positive wellbeing in healthy volunteers (43, 44), and reductions in depression symptoms in participants with life-threatening cancer (18, 45). Others have reported significant increases in the personality traits openness and extraversion, along with decreases in neuroticism, following therapy (46, 47). Additional psychological variables which have been suggested to be involved include increased emotional connectedness and acceptance (48), greater psychological flexibility (49) and experiencing an emotional breakthrough during dosing (50).
However, little is currently known about the importance of these, and other potential psychological mechanisms involved in psychedelic-assisted psychotherapy for depression. Given the importance of the psychological and social context in the delivery of this treatment, knowledge advancement in this area has the potential to strengthen treatment outcomes and minimise associated risks. A greater understanding of the underlying psychological processes may allow for treatment protocols to be refined, ensuring the most effective and safe treatment is delivered. One method of advancing our understanding is to conduct a thorough systematic review of the current literature, to collate evidence, uncover gaps in the literature, and facilitate future research. Therefore, the overarching aim of this systematic review will be to identify how classic psychedelics may operate at the psychological level to improve depression symptoms. The review will address two main questions: (i) what psychological processes of psychedelic therapy for depression symptoms can be discerned in existing literature, and (ii) what implications do proposed psychological processes have for the psychotherapy component of psychedelic-assisted psychotherapy?