How serotonin-based psychedelics may affect the brain to help depression

Major depressive disorder (MDD) is a chronic and debilitating mood disorder impacting the lives of approximately 300 million people worldwide (1). First-line pharmacotherapy options include selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) (2). Other antidepressants, adjunctive pharmacotherapies, psychotherapies, and brain stimulation can be used in patients who do not respond to first- or second-line treatment (2). However, 30–50% of patients do not respond to available treatments (3). Moreover, several weeks are required to determine the efficacy of pharmacotherapies and they are associated with adverse effects (e.g., weight gain, sexual dysfunction) (4, 5). Given the high prevalence of MDD, novel treatments with rapid onset are needed.

Serotonergic (“classic”) psychedelics are a broad category of drugs that includes psilocybin, dimethyltryptamine (DMT, the psychoactive ingredient of ayahuasca), and lysergic acid diethylamide (LSD). These psychedelics have been used as therapeutic agents for thousands of years in various cultures (6). Clinical research into psychedelic treatments began in the 1950s; about 40,000 individuals had been studied by the late 1960s when concerns about their safety and their recreational use led to their classification as Schedule 1 narcotics in the US (7). This precluded human studies until the late 1990s when a “second wave” of modern clinical trials restarted investigating the efficacy and safety of classic psychedelics for major depressive disorder (MDD) and other mental disorders.

Emerging evidence suggests serotonergic psychedelics have antidepressant effects (8–12). Most studies have been conducted using psilocybin for MDD, treatment-resistant depression (TRD), or end-of-life distress (11–15). Psilocybin is primarily administered in conjunction with a form of non-directive and supportive psychotherapy (11–13). Adverse effects are transient and mild, including nausea, anxiety, and minor blood pressure elevations generally resolving within the 8-h dosing session (11–13).

Despite preliminary evidence suggesting serotonergic psychedelics have rapid antidepressant effects, their mechanism of action is not well-understood. This narrative review provides an overview of their putative antidepressant mechanisms of action.

Table 1 presents a summary of the reviewed neuroimaging findings. Most studies of psychedelics have used functional magnetic resonance imaging (fMRI) with network connections assessed using functional connectivity (FC). FC measures correlations between Blood-Oxygen-Level-Dependent (BOLD) signal fluctuations (55) as a proxy for brain activity (56). Research has focused on the default mode network (DMN), encompassing the medial prefrontal cortex (mPFC), posterior cingulate cortex (PCC), precuneus, and angular gyrus. The DMN is implicated in self-referential thinking, memory, and rumination. Alterations in DMN connectivity may underlie the excessive internal focus and rumination of depression. DMN hyper-connectivity has been reported in MDD patients and correlates positively with rumination (57). Imaging data indicates that psychedelics generally reduces within-network DMN FC. This is evidenced by studies in healthy volunteers showing reductions of within-DMN FC during the acute psychedelic experience or post-treatment with psilocybin, ayahuasca, or LSD (55, 56, 58–65). Positron emission tomography (PET) scans show psilocybin increases in glucose metabolism in the PFC, anterior cingulate, and temporomedial cortex (66). In depressed patients, reductions in within-DMN FC has been observed after treatment with psilocybin (67–69), specifically between the vmPFC and right angular gyrus (69), and between the parahippocampus (PH) and PFC (67). Reduced PH-PFC FC has been associated with improvements in depression scores post-treatment (67), supporting the hypothesis that hyper-connectivity of the DMN underpins depressive symptoms. Thus, administration of a psychedelic could alleviate symptoms by reducing FC in the DMN. Indeed, increased glucose metabolism in the DMN area is positively associated with changes to perception and ego dissolution (66). Also, psychedelic-induced reduction in DMN FC has been correlated with positive changes in psychosocial functioning, attitudes and mood, 4 months post-administration (55) and with decreased mental reflection on one’s past (59).

However, increases in FC have been observed post-psilocybin in depressed patients between the vmPFC and the bilateral inferior lateral parietal cortex (iIPC) (67) and between the ACC and PCC (67, 70). Increased vmPFC-iIPC FC (but not increased ACC-PCC FC) was associated with treatment response at 5-weeks (67). It has been theorized that these discrepancies may result from differences in neural effects immediately following the acute psilocybin experience vs. those that occur later. Like electroconvulsive therapy (ECT), psychedelics may cause acute decreases in network integrity followed by a period of re-integration and subsequent improvements in mood and functioning (67). This interpretation is speculative and more research is needed to elucidate how altered connectivity patterns mediate antidepressant activity of psychedelics.

Emotional processing is also altered by psychedelics through changes in amygdala responsiveness and FC changes between the DMN, amygdala, and visual cortices. Single photon emission tomography (SPECT) in depressed patients administered ayahuasca showed increased blood perfusion in the left nucleus accumbens, right insula, and left subgenual area (9). These areas play a major role in emotional regulation and are less active in depressed patients (9). The amygdala is also hypersensitive to negative stimuli in depressed patient (71, 72) resulting in negative cognitive bias (73) and deficits in emotional regulation (74). SSRIs reduce amygdala responsiveness (75, 76) and a similar mechanism has been proposed for the antidepressant effect of psychedelics. In healthy volunteers, LSD reduce reactivity of the left amygdala to fearful faces (77) and psilocybin reduces response of the right amygdala to negative and neutral stimuli, with these reductions correlating with increases in positive affect (78). In depressed patients, opposite results have been reported: psilocybin induced increased right amygdala BOLD response to emotional faces (with a larger increase with fearful than with happy faces) 1 day post-treatment; larger responses to fearful faces correlated with higher improvements in depressive symptoms (79). This suggests psychedelics may actually restore emotional responsiveness in depressed individuals, in contrast to the emotional blunting associated with SSRIs (79). In patients with TRD, 1 day post-psilocybin, fMRI scans taken while viewing fearful faces also revealed reductions in connectivity between the vmPFC and right amygdala; it was associated with less rumination 1 week later, suggesting that disinhibition of the right amygdala by the vmPFC mediates psilocybin-induced increases in amygdala responsiveness in these depressed individuals (69). Under the same conditions, higher connectivity was also observed between the vmPFC and the right lateral occipital cortex, occipital pole, and fusiform gyrus; it was associated with improvements in depressive symptoms (69). Similar hyper-connectivity between the DMN and the occipital cortex has been reported in healthy volunteers after administration of LSD (64) or psilocybin (65), and between the amygdala and occipital cortex after administration of psilocybin (80). Deficits in down-regulation of the visual cortex in response to negative emotional stimuli has been demonstrated in MDD (81). Thus, psychedelics may help to normalize emotional processing in depressed patients by increasing vmPFC-mediated inhibition of the occipital cortex in response to negative stimuli, thereby reducing negative attentional bias. Taken together, these findings suggest a complex interplay among signals from the DMN, amygdala, and visual cortex may be involved in regulation of emotional response induced by psychedelics in MDD.

Finally, psychedelics increase connectivity between the intrinsic functional networks, i.e., spatially distinct brain regions that are functionally related (82). Brain-wide network disconnectivity is associated with depressive symptoms (83). Thus some antidepressant effects of psychedelics may also result from their ability to increase between-network FC. These increases have been observed in healthy volunteers after administration of psilocybin (56, 61, 84) or LSD (60, 62), particularly in areas rich in 5-HT2AR (60). In depression, psilocybin has been shown to increase global FC (68, 70). In one open-label trial, increase in global FC 1 day after psilocybin dosing was associated with improvement in depressive symptoms 6 months later (68). Specific increases were observed between the DMN and Executive Network (EN), Salience Network (SN). A randomized controlled trial comparing two doses of psilocybin vs. 6 weeks of daily escitalopram for depression saw increased EN dynamic flexibility with psilocybin only–reflecting an increase in the frequency of connectivity changes seen the during fMRI scan. This correlated with symptom improvement 6 weeks post-dose (68). Psilocybin has also been shown to alter connectivity patterns between the task positive network (TPN) (85), which is involved with external or other-processing (82), and the claustrum, or the DMN. Theoretically, the claustrum, known to be volumetrically reduced in depression, may mediate psychedelic-induced network disruptions due to its widespread connectivity (85).

Most psychedelic studies discussed in this section suffer from limitations, in particular difficulties in blinding and small sample sizes. Still, fMRI studies in depression have produced relatively consistent findings and their designs have been rigorous. As summarized in Table 1, of the six fMRI depression studies reviewed, five were preregistered (68–70, 79), all used validated depression scales (67–70, 79) and one was double-blinded and placebo-controlled (68).

As summarized in Table 2, neurophysiology studies provide further support for DMN-related alterations. Electroencephalogram (EEG) recordings in healthy volunteers given LSD or ayahuasca show reductions in broadband oscillatory power and cortical synchrony particularly within areas of the DMN (86–88). Similarly, magnetoencephalography (MEG) shows broadband desynchronization of cortical oscillatory rhythms and decreases in network integrity after ingestion of psilocybin (89), supporting that psychedelics can disorganize spontaneous brain activity (58, 89). In participants who ingested LSD, EEG, and MEG studies have also showed a relationship between decreased alpha power and the hallucinatory experience and subjective reports of ego dissolution (87, 90).

High frequency gamma waves appear when individuals are performing cognitively challenging tasks requiring focus (66). The limited current literature reports increases in gamma power in individuals administered psilocybin. This supports the theory that the DMN is affected by psychedelics as the PFC and hippocampus are activated during tasks requiring concentration in which gamma waves are present (66). However, given the sparsity of relevant human data, this theory remains speculative. Evidence suggests that changes from delta to gamma waves are consistent across different psychedelics (91). Additionally, LSD, ayahuasca, and psilocybin induce alpha power reductions within the occipital and parietal cortices, which are important structures for the interpretation of visual stimuli (88). It is believed this reduction explains subjective reports of visual hallucinations as alpha oscillations have been found to play a role in cortical processing of sensory information (92). Finally, under the influence of ayahuasca and LSD, psychedelic effects such as ego dissolution and spiritual feelings have been reported during moments of global decreases in alpha waves (92). Alpha oscillations are correlated with functions in which the DMN plays a major role such as self-reflection; as discussed above, fMRI studies support this association (93). Psychedelic-induced ego dissolution in patients with MDD is correlated with improvement in depressive symptoms, supporting the theory that ego dissolution is associated with decreased connectivity within the DMN and further establishing a possible link between alpha oscillations and the DMN (92, 93).

Many depressed individuals experience ruminations, with intense self-focus and narrowed thinking. Enhanced neural and cognitive flexibility associated with psychedelics may enhance psychological flexibility, affording them access to a broader frame of mind (68). Thus, it has been hypothesized that psychedelics facilitate transitions away from maladaptive thought patterns, which can be amplified during the “integration” component of psychedelic-assisted psychotherapy (PAP) post-treatment (70). The antidepressant effect of psychedelics has also been postulated to result from their ability to restore emotional responsiveness (86), allowing people to fully experience and accept their emotions (76, 86). This emotional release is thought to be facilitated by disruption of connectivity in regions with high density of 5-HT2ARs (75). Ego dissolution, characterized by a blurring of the distinction between self and other (68) is commonly experienced with psychedelics (63, 67, 68). It has been speculated it allows for an enhanced sense of connection with others and lessen feelings of loneliness. Finally, “mystical experiences” may also play some role in relieving depressive symptoms but this has not yet been evaluated (74). In summary, psychedelics may facilitate some degree of psychological transformation, possibly allowing patients to move beyond their depression.

Overall, available evidence suggests serotonergic psychedelics impact depression, in part through serotonin receptor agonism, neurogenesis, immunomodulation, widespread changes in connectivity within the brain, and psychological effects. To date, neuroimaging studies provide the most robust investigation into the mechanisms of action of psychedelics, but their results remain limited. More studies with larger and more diverse samples are needed to replicate and extend current findings. Future studies should also account for symptom severity and comorbidities while assessing whether and how PAP and social supports contribute to the therapeutic action of psychedelics. Neural correlates of the antidepressant effects of psychedelics and other pharmacotherapies should be compared directly to quantify differences between mechanisms of action.

Understanding the role of the psychedelic experience and its relationship with antidepressant effect should also be a focus of future research. As it stands, alterations in perception induced by psychedelics are a major barrier to their clinical adoption because they require intensive psychological support. As stated above, it is possible that psilocybin’s antidepressant effect is mediated through rapid activation of 5-HT receptors other than those involved in the psychedelic experience. This raises the possibility of blocking the psychedelic experience by co-administering 5-HT2A antagonists, like ketanserin or risperidone, without impeding the antidepressant therapeutic effect. More research is needed to explore this possibility and better understand the relationship among serotonin receptors, psychedelic effect, and antidepressant effect.

As use of, and research on, psychedelics expand, understanding their mechanism of action through molecular science, neuroimaging, and neurophysiology is critical. With several relevant competing theories, well-designed studies need to determine which mechanisms are central to their therapeutic action and which ones are epiphenomenal.

MIH and DC conceived and designed the manuscript. MIH drafted and critically reviewed the manuscript. NL conducted the literature search, reviewed available data, and contributed to the writing, editing, and preparation of the manuscript. EF and JB contributed to the literature search, data review, and writing of the manuscript. JR, DB, BM, and DC drafted the manuscript. All authors approved the manuscript.

MIH received research support from the Brain and Behavior Research Foundation, Canadian Institutes of Health Research (CIHR), CAMH Foundation, Grand Challenges Canada, the PSI Foundation, and the University of Toronto and provided consultancy to Mindset Pharma, PsychEd Therapeutics, and Wake Network. JR received research grant support from the Canadian Institute of Health Research (CIHR), Physician Services Inc (PSI) Foundation, Labatt Brain Health Network, Brain and Cognition Discovery Foundation (BCDF), Canadian Cancer Society, Canadian Psychiatric Association, Academic Scholars Award, American Psychiatric Association, American Society of Psychopharmacology, University of Toronto, University Health Network Centre for Mental Health, Joseph M. West Family Memorial Fund and Timeposters Fellowship and industry funding for speaker/consultation/research fees from iGan, Boehringer Ingelheim, Janssen, Allergan, Lundbeck, Sunovion, and COMPASS. He is the Chief Medical and Scientific Officer of Braxia Scientific and the medical director of the Canadian Rapid Treatment Centre of Excellence (Braxia Health). BM hold and received support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto and currently receives or has received with the past 5 years research support from Brain Canada, the Canadian Institutes of Health Research, the CAMH Foundation, the Patient-Centered Outcomes Research Institute (PCORI), the US National Institute of Health (NIH), Capital Solution Design LLC (software used in a study founded by CAMH Foundation), and HAPPYneuron (software used in a study founded by Brain Canada); has also been an unpaid consultant to Myriad Neuroscience. DC (past 36 months: September 2022) received grant monies for research from Servier, Boehringer Ingelheim; Travel Support and Honoraria for Talks and Consultancy from Servier, Seqirus, and Lundbeck. He is a founder of the Optimal Health Program (OHP), and holds 50% of the IP for OHP; and is part owner (5%) of Clarity Healthcare. He is an Advisory Board Chair of an Australian not-for-profit institute specializing in psychedelic medicines research. He does not knowingly have stocks or shares in any pharmaceutical company. DB received research support from the Canadian Institutes of Health Research (CIHR), National Institutes of Health—US (NIH), Brain Canada Foundation and the Temerty Family through the CAMH Foundation, and the Campbell Family Research Institute. He received research support and in-kind equipment support for an investigator-initiated study from Brainsway Ltd. and he was the site principal investigator for three sponsor-initiated studies for Brainsway Ltd. He received in-kind equipment support from Magventure for investigator-initiated studies. He received medication supplies for an investigator-initiated trial from Indivior. He participated in an advisory board for Janssen. He participated in an advisory board for Welcony Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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