Similar investigations have been conducted with ayahuasca, a brew containing DMT from the Psychotria viridis plant and monoamine oxidase inhibitors from the Banisteriopsis caapi vine. These findings have been further supported by randomised trials, which found psilocybin-assisted psychotherapy to produce significant reductions in depression symptomology in individuals with major depressive disorder (MD D ) and those experiencing distress associated with life-threatening cancer. Symptom reductions remained significant 6 months following treatment. An open-label feasibility study reported significant symptom reductions in participants with treatment-resistant depression (TRD defined as experiencing no improvements in depression symptoms despite two courses of antidepressant treatment) 1 week post-treatment. These trials have mostly studied psychedelic-assisted psychotherapy, whereby a psychedelic is administered in conjunction with psychological support or therapy. Recent clinical trials have reported promising results on the clinical benefits of classic psychedelics across a range of psychiatric disorders, including depression. This paved the way for further human trials to be conducted. It was not until the 1990s that ethics approval was granted for several healthy participant studies that utilised psychedelics with less notoriety than LSD, including DMT, psilocybin and mescaline. However, increasing restrictions to the access of psychedelics in the late 1960s, and the subsequent criminalisation of psychedelics in 1970, led to a significant decrease in human psychedelic research in the following 20 years. The synthesis and ingestion of LSD in 1942 sparked Western scientific interest into psychedelics and led to numerous studies investigating the efficacy of LSD and psilocybin as a treatment for psychiatric disorders. Similarly, psilocybin-containing mushrooms may have been used in Mesoamerican ceremonies for at least 3500 years. The sacramental consumption of mescaline, via ingestion of the Peyote cactus ( Lophophora williamsii), occurred in Native American ceremonies as far back as 5 millennia, and there is evidence to suggest that DMT-containing plants have been ingested by some in South America since 2130 BC. The use of classic psychedelics by non-Western cultures can be traced back thousands of years. It is through this receptor agonism that classic psychedelics primarily exert their psychoactive effects. Despite having distinct characteristics, the classic psychedelic compounds are often grouped together as they all act as agonists of serotonin 5-hydroxytryptamine (5-HT) 2A receptors. When ingested or administered, these compounds can elicit altered states of perception, cognition and emotion. Systematic reviewĬlassic psychedelics are a group of psychoactive drugs that includes lysergic acid diethylamide (LSD), psilocybin, N,N-dimethyltryptamine (DMT) and mescaline. We intend for this review to present the current state of the literature, identify gaps and generate candidate variables that warrant further investigation. The preliminary nature of this research field is expected to result in the review having several limitations, namely heterogeneity between studies and the inclusion of limited empirical research. This systematic review will be the first to collate available evidence on the psychological processes associated with psychedelic therapy for depression. A narrative synthesis approach will be used to report psychological processes identified in the literature. Empirical and non-empirical research will be extracted and synthesised separately. Two authors will independently screen articles, complete quality assessment tools and conduct data extraction. Studies will be included if they discuss the use of a classic psychedelic to treat depression symptomology in an adult population and report or propose psychological processes responsible for depression symptom change. Scopus, PsycINFO, PubMed and Web of Science databases will be searched using relevant terms. The proposed systematic review will aim to identify, evaluate and summarise the psychological processes of change underlying psychedelic therapy for depression in the current literature and consider the implications these processes may have on the psychotherapy component of treatment. There is currently renewed interest in the use of psychedelic therapy in the treatment of psychiatric disorders, including depression.
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