Depressive disorders include conditions such as major depressive disorder (MDD), chronic depression and treatment-resistant depression (TRD), all of which are associated with high rates of morbidity, reduced quality of life, and in severe cases, mortality (Mrazek et al., 2014, Otte et al., 2016). Epidemiological studies suggest that a substantial proportion of the population—some estimates approach half—will encounter depressive symptoms at least once in their lifetime, underscoring this disorder’s relevance (Kessler et al., 2005). Currently, patients with MDD are being treated with either pharmacological, psychotherapeutic or combined interventions, most typically selective serotonin (5-HT) reuptake inhibitors (SSRIs) and cognitive behavioural therapy. However, approximately one-third of patients with MDD fail to achieve remission after the initial course of treatment, ultimately culminating in TRD (Al-Harbi, 2012, Rush et al., 2006). According to the Diagnostic and Statistical Manual of Mental Disorders (DSM) 5, patients with an ongoing major depressive episode that fail to achieve clinically meaningful improvement (a ≥50 % reduction in depressive symptoms as measured by standardized rating scales) after adequate dose and duration (typically 4–6 weeks) of two or more different antidepressants in the same depressive episode are diagnosed with TRD (Lam, Wan, Cohen, & Kennedy, 2002). Due to limited treatment options, the TRD population presents a formidable challenge in clinical practice, reflecting the limitations of existing paradigms and underscoring the urgent need for novel and effective treatments.

Serotonergic psychedelics are an emerging class of compounds showing therapeutic promise for the treatment of depression. Like SSRIs, serotonergic psychedelics primarily act through modulation of the serotonergic system, but they also induce transient altered states of consciousness commonly referred to as “trips” (Reiff et al., 2020). These compounds all have partially overlapping pharmacological profiles, as they all act as agonists at the 5-HT type A (5-HT2A) receptor but differ in the specificity and duration of their subjective effects and the additional receptors they target (Ley et al., 2023). The serotonergic psychedelics (sometimes called “classic psychedelics”) are often contrasted with atypical (or non-classic) psychedelics such as ketamine (Mion & Villevieille, 2013), ibogaine (Glick & Maisonneuve, 1998) and 3,4-methylenedioxymethamphetamine (MDMA) (de la Torre et al., 2004), which do not exert their primary mechanism of action via 5-HT2A receptor binding. This category of psychedelics includes lysergic acid diethylamide (LSD), psilocybin, mescaline, N,N-Dimethyltryptamine (DMT), and ayahuasca (traditional DMT formulation combined with monoamine oxidase inhibitors) (Nichols & Barker, 2016). While 5‐methoxy‐N,N‐dimethyltryptamine (5-MeO-DMT) is not typically defined as a classic psychedelic (Reckweg et al., 2022), it exerts its action primarily by the serotonin (5-HT) system and meets the criteria of serotonergic psychedelics. On the other hand, MDMA exerts its effects primarily by reversing the function of monoamine transporters (especially serotonin transporter- SERT), causing increases in extracellular serotonin, dopamine, and norepinephrine, with a much weaker partial agonism at 5-HT receptors (Rudnick & Wall, 1992). Due to different pharmacological properties as well as it’s unique subjective effects profile, MDMA is excluded from this category.

Preliminary findings suggest that serotonergic psychedelics are safe and produce significant and long-lasting antidepressant effects, demonstrating efficacy also in cases of TRD (McIntyre et al., 2023). However, research on their broader clinical applications remains in the early stages and further investigation is needed to establish their large-scale efficacy and tolerability. This chapter will explore the potential of serotonergic psychedelics including psilocybin, LSD, DMT, ayahuasca and 5-MeO DMT, as a safe, effective, and scalable treatment for clinical depression. Additionally, their possible neurobiological mechanisms of action will be reviewed and discussed. We focus on evidence coming from modern era1 clinical trials assessing the efficacy of serotonergic psychedelics (5HT2A agonists) as antidepressants for MDD, TRD, and bipolar depression (BD). Results from studies using atypical psychedelic-like compounds will not be reviewed here.