Psychedelic Medicines for Mood Disorders. Current Evidence and Clinical Considerations, Jerome Sarris et al., 2022

Psychedelic Medicines for Mood Disorders

Current Evidence and Clinical Considerations

Jerome Sarris; Diego Pinzon Rubiano; Kimberley Day; Nicole L. Galvão-Coelho; Daniel Perkins

Current Opinion in Psychiatry, 2022, 35, (1), 22-29.
doi : 10.1097/YCO.0000000000000759


Abstract and Introduction


Purpose of Review: Despite advances in treatment modalities for mood disorders over recent decades, further therapeutic options are still required. Increased research is occurring, with the pursuit of psychedelic-based pharmacotherapies for a range of mood disorders and other conditions.

Recent Findings: Serotonergic psychedelics have been found to modulate brain networks underlying various psychiatric disorders, as well promoting neurogenesis and neuroplasticity. Randomized placebo-controlled trials have found psilocybin with psychological support effective at treating depression, including treatment-resistant depression; with emergent research also signalling N,N-dimethyltryptamine/ayahuasca also as a potential option for the treatment of depression. Lysergic acid diethylamide has been found to have anxiolytic effects, whereas 3,4-methylenedioxymethamphetamine (MDMA) has been used effectively to treat post-traumatic stress disorder (PTSD), with Phase III clinical trial evidence. Microdosing of psychedelics is a growing phenomenon that has shown benefits in some preclinical data; however, a recent self-directed controlled trial reported no evidence of improved mood.

Summary: Current research with medicinal psychedelics, usually as an adjunct to psychotherapy, has shown encouraging results in treating mood disorders. However, there are challenges regarding blinding and sample sizes remain small, and there have been no definitive Phase III studies (aside from MDMA for PTSD). Further work exploring novel formulations, interface with pharmacogenomics and the microbiome, and inflammatory pathways can be advised.


Ancient preindustrial cultures have used psychoactive plants to facilitate a process akin to psychotherapeutic healing, with archaeological evidence suggesting use of psychoactive plants by humans for milenia.[1] In Western culture, from the early 1950s to the mid-late 1960s psychedelic substances were used in psychiatry, with encouraging signs of therapeutic potential.[2] However, the prohibition of these substances from the 1960s halted scientific research in the areas of medical and life sciences.[3] One of the consequences of this ban was the lack of innovation with new medicines in this area. Nevertheless, the past decade has seen a rebirth of research with psychedelic substances.[4]

There are currently over 70 clinical trials being conducted across the world using psychedelic-based pharmacotherapies for mood disorders.[5] One of the main areas of research has been the use of ‘classical’ psychedelics, which modulate the serotonergic pathway. These include compounds such as psilocybin, N,N-dimethyltryptamine (DMT; usually in the form of the South American plant-based preparation ‘ayahuasca’) and lysergic acid diethylamide (LSD), which have their primary pathway of action via the 5-HT2A receptors. The compound 3,4-methylenedioxymethamphetamine (MDMA), while not a classical psychedelic, has also been increasingly studied for use as a psychoactive agent within the field. Classical psychedelics have a lower harm profile than many drugs both legal and illegal, and are considered not to create physical dependence, abuse, or withdrawal.[6] However, they are contraindicated for people diagnosed or at risk of psychotic disorders.[7] MDMA is rarely addictive, has a low potential for abuse, and no known neurotoxic effects at doses used clinically.[8] The recent Australian Drug Harms Ranking Study, identified psilocybin and MDMA as among the five least harmful drugs out of 22 investigated, scoring 5 and 7, respectively. Alcohol was ranked as the most harmful, scored at 71, fentanyl 51, prescription opioids 30, and cannabis 17.[9]

Our present aim is to summarize current research within the evolving field of medicinal psychedelics for use in mood disorders. We provide a concise review of the key mechanistic and clinical data for all major classical psychedelics (psilocybin, LSD, and DMT/ayahuasca), and MDMA. A review of the English language literature was conducted from inception up to September 2021, with clinical data being located and synthesized on major depressive disorder, post-traumatic stress disorder (PTSD), and social anxiety. No clinical trial data were found for other affective disorders in which these were the primary outcome measure (e.g., generalised anxiety disorder, panic disorder, dysthymia). Further, we provide a ‘clinician friendly’ table summarizing the data and suggested applications, in addition to a clinical considerations section.

Mechanisms of Action

Due to mood disorders having overlapping aetiologies and comorbidity, treatments that take a transdiagnostic approach, while addressing underlying neurochemical/circuitry dysfunction, may be of greater therapeutic benefit.[10] Psychedelics may help with neurocircuitry rewiring while also modulating an array of relevant neurochemical pathways. This can also assist with addressing negative emotional processing and negativity bias, which can lead to more rumination, which is a common symptom of major depressive disorder (MDD).[11]

Serotonergic psychedelics such as psilocybin and DMT have been shown to alter mood and perception through affecting the serotonergic, dopaminergic, and glutamatergic systems.[12] Effects on serotonin 5-HT2A receptors, which are found in frontal and paralimbic brain areas, are involved in emotional processing and regulation, introspection, and interoception. The activation of these pathways has been linked to a modulation of amygdala and default mode network (DMN) activity, as well as an increased synthesis of brain-derived neurotrophic factor (BDNF).[13,14] The consequence of these effects is the disruption of dysfunctional neural networks that are thought to be at the root of many psychiatric diseases.[15,16]

In patients with depression who took part in psilocybin studies, alterations in resting state functional connectivity (RSFC) in the DMN were observed, and these changes were predictive of treatment response.[17] This could be interpreted as a therapeutic ‘reset’ process. Such effects are also important in mood disorders, where aberrant RSFC patterns in the DMN have been associated to decreased self-awareness, unpleasant feelings, and rumination.[18]

Ayahuasca has been classified as a ‘multitarget’ medication due to the discovery of several additional mechanisms of action. The activation of both sigma-1 and trace amine-associated receptors by DMT is thought to play a role in depression, anxiety, and fear extinction.[19] Preclinical studies of harmine, another component of ayahuasca for example, have shown antidepressant-like effects (equivalent to fluoxetine in one study), which are posited to come about via astrocyte-mediated restoration of BDNF protein levels and hippocampal neurogenesis, as well as antiaddictive effects, possibly via the glutamate transporter 1 subtype.[20]

Unlike serotonergic psychedelics, MDMA’s principal mode of action is as an indirect serotonin agonist, increasing monoamines (dopamine, serotonin, norepinephrine) release.[21] Furthermore, it has been shown to increase connectivity between amygdala and the hippocampus, elevates oxytocin levels, increases release of monoamines, reduces amygdala and right insular activity in response to negative emotional stimuli, and increases superior frontal cortex activity.[21–25] Despite the fact that neuropharmacological interactions have received a lot of attention, the effects of psychedelics are perhaps best explained in terms of their psychological action.

Psychological Mechanisms

Psychedelics likely work by disrupting activity in networks that encode habits of thoughts and behaviour,[26] which relate to the common characteristics of internalizing disorders: depression, addictions, obsessive compulsive disorder, and anorexia.[27] The particular commonality of these disorders is that they are ego syntonic. Features of these disorders like rumination and rigid behaviour are concordant with needs of the ego or self-image. For instance, the depressed person ruminates in negative thinking which fulfils the need of their personal narrative. Neuroimaging studies have shown that serotonergic psychedelics disrupt the DMN, which is also associated with rumination.[17,28,29] These functional characteristics of psychedelics may be responsible for their therapeutic benefit for these conditions. In the case of MDMA, the compound has been reported to increase self-reported feelings of closeness to others and euphoria, empathy, decrease in anxiety and fear responses, prosocial mood states, while blunting responses to social rejection and facilitating fear extinction learning.[30–34] These effects can foster a strong therapeutic alliance and enable the patient to work with traumatic memories.

Current Evidence


Our team conducted the first systematic and meta-analytic review evaluating double-blind placebo-controlled clinical trials involving classic serotonergic psychedelics on both negative mood state and symptoms of depression outcomes.[35] From our search criteria 12 studies were eligible (n = 257), with data from randomized controlled trials (RCTs) of psilocybin (n = 8), LSD (n = 3), and ayahuasca (n = 1). In comparison with placebo, meta-analyses of acute (3 h to 1 day after treatments) and long-term (16–60 days after treatments) mood outcomes demonstrated moderate effect sizes (acute: standardized mean difference [SMD] −0.690, P < 0.001; long-term: SMD −0.495, P = 0.004) favouring psychedelics in reducing negative mood states. The largest clinical response was identified for medium-term effects (2–7 days after treatment) in those with depression (measured on depression rating scales), with a large effect size (SMD = −0.841, P = 0.001) in favour of psychedelics in symptom reduction. In this cohort, moderate impact sizes were found in both acute (SMD −0.720, P = 0.003) and long-term outcomes (SMD −0.792, P < 0.001). Concerns over adequate blinding and small sample sizes is a noted weakness of many studies ().