This review (2021) summarizes the available evidence regarding the potential of LSD, psilocybin, and ayahuasca as rapidly effective antidepressant therapies. Results are promising but still limited.
Abstract
“Major depressive disorder (MDD) is among the most prevalent mental health disorders worldwide, and it is associated with a reduced quality of life and enormous costs to health care systems. Available drug treatments show low-to-moderate response in most patients, with almost a third of patients being non-responders (treatment-resistant). Furthermore, most currently available medications need several weeks to achieve therapeutic effects, and the long-term use of these drugs is often associated with significant unwanted side effects and resultant reductions in treatment compliance. Therefore, more effective, safer, and faster-acting antidepressants with enduring effects are needed. Together with ketamine, psychedelics (or classic or serotoninergic hallucinogens) such as lysergic acid diethylamide (LSD), psilocybin, and ayahuasca are among the few compounds with recent human evidence of fast-acting antidepressant effects. Several studies in the 1950s to 1970s reported antidepressive and anxiolytic effects of these drugs, which are being confirmed by modern trials (LSD, one trial; psilocybin, five trials; ayahuasca, two trials). The effects of these drugs appear to be produced primarily by their agonism at serotonin (5-hydroxytryptamine, 5-HT) receptors, especially the 5-HT2A receptor. Considering the overall burden of MDD and the necessity of new therapeutic options, the promising (but currently limited) evidence of safety and efficacy of psychedelics has encouraged the scientific community to explore more fully their beneficial effects in MDD.“
Authors: Rafael Guimarães dos Santos, Jaime E. C. Hallak, Glen Baker & Serdar Dursun
Summary
Background
Major depressive disorder is common, causes disability worldwide, and is associated with increased suicidality and enormous costs to health care systems. The monoamine theory does not explain several aspects of the etiology of depression, and many medications based on this theory produce unwanted side effects.
Ketamine, LSD, psilocybin, and ayahuasca are drugs with fast-acting and enduring antidepressant effects. These drugs are considered a major advance in understanding the etiology and treatment of mood disorders.
Major depressive disorder is among the most prevalent mental health disorders worldwide, and currently available drug treatments show low-to-moderate response in most patients. Psychedelics have been shown to have fast-acting antidepressant effects, but more evidence is needed to confirm these effects.
Receptor-level evidence
Serotoninergic psychedelics have been reported to produce profound modifications in affect, perceptions, and cognition. The 5-HT2A receptor seems to be the main receptor activated by psychedelics, and it activates different signaling transduction pathways from those activated by 5-HT1A/2C receptors. Activation of the 5-HT2A receptor by LSD and DMT increases dendritic arbor complexity, promotes dendritic spine growth, and stimulates synapse formation.
Evidence from animal models
Preclinical evidence shows that 5-HT2A receptor agonists have antidepressant effects. However, a rodent study with psilocybin and psilocin showed no antidepressant effects, and ayahuasca induced fast and prolonged antidepressant effects in a juvenile primate model of depression.
Evidence from human studies
Until the late 1960s/early 1970s, psychedelics were investigated in humans for the possible treatment of mood, anxiety, and substance use disorders. However, previous studies often had methodological shortcomings and used heterogeneous experimental paradigms.
Controlled trials using LSD or psilocybin reported fast and enduring improvements of depression and anxiety symptoms in patients with life-threatening diseases/cancer. Ayahuasca was well tolerated and produced fast and enduring reductions in anxiety and depressive symptoms in patients with treatment-resistant depression.
Two open-label trials with 12 volunteers with TRD and 24 patients with MDD reported rapid and sustained decreases in depression and anxiety symptoms. Psilocybin was well tolerated and no serious adverse events were reported.
Preclinical studies
Preclinical studies consistently show that activation of the 5-HT2A receptor in the PFC is the main mechanism of action of psychedelics. This increased neuroplasticity is also produced by ketamine, which is currently thought to be one of the main mechanisms involved in its antidepressant effects.
Psychedelics could improve memory and learning (thus cognitive flexibility) in depression by deactivating the default mode network (DMN) and creating an opportunity to re-learn new patterns of thought. Repeated administration of psychedelics induces desensitization of 5-HT2A receptors, which can be associated with enhanced learning and reduced hippocampal 5-HT2A receptor signaling and normalization of learning in an animal model of depression. Psychedelics act as partial agonists at the 5-HT2A receptor and thus can also behave as functional antagonists at the receptor-level.
Human studies
Human studies show that 5-HT2A receptor antagonists block most of the subjective effects of psychedelics, including increases in excitatory tone, decreased functional connectivity, and reduced amygdala reactivity to threat. These effects are accompanied by disruptions of neural hierarchies and enhanced brain entropy.
Ayahuasca increases neurogenesis and BDNF levels, and a negative correlation between BDNF levels and depressive symptoms was observed. Ayahuasca’s effects on BDNF are modulated by cortisol levels and inflammatory markers, and should be further explored in healthy volunteers and patients with psychiatric disorders.
Psychotherapeutic techniques could enhance the antidepressant and anxiolytic effects of psychedelics. However, recent molecular, behavioral, and neuroimaging studies suggest that these effects also have a biological basis, and future studies should compare the effects of these drugs with and without such interventions.
Conclusions
The scientific community should reopen the doors to the possible clinical use of psychedelics to treat depression, keeping in mind that detailed records must be kept of side effects as well as beneficial effects.