This book chapter (2021) describes the current research on psychedelics for depression (MDD), the clinical trials as well as the neurobiological mechanisms are described. The chapter end with a description of future challenges.
The volume of research on the therapeutic use of psychedelic drugs has been increasing during the last decades. Partly because of the need of innovative treatments in psychiatry, several studies have assessed the safety and efficacy of drugs like psilocybin or ayahuasca for a wide range of mental disorders, including major depression. The first section of this chapter will offer an introduction to psychedelic research, including a brief historical overview and discussions about appropriate terminology. In the second section, the recently published clinical trials in which psychedelic drugs were administered to patients will be analysed in detail. Then, in the third section, the main neurobiological mechanisms of these drugs will be described, noting that while some of these mechanisms could be potentially associated with their therapeutic properties, they are commonly used as adjuvants in psychotherapeutic processes. The last section suggests future challenges for this groundbreaking field of research and therapy.
Psychedelic compounds — including plant preparations, fungi and synthetic molecules — produce profound alterations in consciousness and have millennia‑long ritual and medicinal uses in many indigenous cultures. The terminology and conceptual framing of these substances remain contested: early Western research distinguished psycholytic (low‑dose, therapy‑assisting) and psychedelic (high‑dose, spiritual experience) paradigms, and contemporary work generally focuses on serotonergic psychedelics (LSD, psilocybin, DMT/ayahuasca) that act largely at 5‑HT2A receptors. Renewed scientific interest since the 1990s has reflected both advances in neuropharmacology and the perceived need for novel psychiatric treatments. Bouso and colleagues set out to review recent clinical trials that have tested psychedelic medicines for anxiety and depressive disorders, to summarise proposed neurobiological mechanisms that might underlie antidepressant effects, and to outline the main challenges facing clinical development and implementation. The chapter is a narrative synthesis rather than a systematic review and aims to integrate clinical findings, neuroimaging and molecular data with practical and regulatory considerations for translating psychedelic‑assisted therapies into clinical practice.
Papers cited by this study that are also in Blossom
Akers, B. P., Ruiz, J. F., Piper, A. et al. · Economic Botany (2011)
Bonson, K. R. · Psychopharmacology (2017)
Reiche, S., Hermle, L., Gutwinski, S. et al. · Progress in Neuro-Psychopharmacology and Biological Psychiatry (2018)
Grob, C. S., Danforth, A. L., Chopra, G. S. et al. · JAMA Psychiatry (2011)
The extracted text does not present a dedicated Methods section or a formal search strategy; the paper is a narrative review summarising historical background, published clinical trials, mechanistic studies and implementation issues. Accordingly, the researchers synthesised findings from randomized controlled trials (including crossover and parallel designs), open‑label studies and preclinical work, and discussed neuroimaging, molecular and physiological evidence relevant to antidepressant mechanisms. Where clinical trials are described, the review reports key design features as stated in those trial reports (for example, sample sizes, dosing regimens and outcome scales) but does not report a prespecified inclusion/exclusion criterion for which studies were reviewed or a formal risk‑of‑bias assessment. Because the paper is a chapter-style synthesis rather than a systematic meta-analysis, no pooled statistical methods or meta‑analytic models are reported in the extracted text.
Clinical trial evidence: The chapter summarises two bodies of clinical work: trials of psychedelics for anxiety/depression in the context of life‑threatening illness, and trials in primary major depressive disorder (MDD) and treatment‑resistant depression (TRD). Since 2011, four randomized, double‑blind, placebo‑controlled, crossover trials investigated LSD (one trial) or psilocybin (three trials) in patients with cancer‑related anxiety/depression; of these, three psilocybin trials assessed depressive symptoms specifically. Sample sizes in these controlled trials ranged from 12 to 51 patients, and oral psilocybin doses were typically 14–30 mg per 70 kg. All three psilocybin trials reported significant reductions in Beck Depression Inventory (BDI) scores at 6 months; two trials that used the Hospital Anxiety and Depression Scale (HADS) also reported significant HADS reductions at 6 months. Reported adverse events were generally transient (acute anxiety/distress, sensorimotor illusions, transient psychotic‑like symptoms, headache, nausea/vomiting) with mild increases in blood pressure and heart rate; no serious safety signals were reported in those trials. For MDD and TRD outside the cancer setting, results are more heterogeneous but promising. An open‑label ayahuasca study initially treated six patients and later reported a final sample of 17 patients with MDD; a single oral dose (2.2 mL/kg; 0.8 mg/mL DMT in the pilot and a separate RCT dose of 1 mL/kg; 0.36 mg/mL DMT) was associated with significant reductions on HAM‑D, MADRS and the anxiety–depression subscale of the BPRS at 1, 7 and 21 days in the open‑label work, and in the randomized, placebo‑controlled trial (n=29) ayahuasca produced significant reductions in MADRS at 1, 2 and 7 days and in HAM‑D at 7 days. In that controlled ayahuasca trial, ayahuasca was also associated with subacute normalisation of low baseline cortisol (hypocortisolaemia) and increases in brain‑derived neurotrophic factor (BDNF); increases in BDNF were negatively correlated with antidepressant response and appeared modulated by acute cortisol increases. Adverse effects were mostly transient nausea and vomiting; no serious adverse events were reported. An open‑label psilocybin study in 12 TRD patients administered two oral doses (10 mg and 25 mg, 7 days apart) and reported significant BDI reductions at 1 week and 3 months, and improvements on QIDS and SHAPS up to 6 months in an expanded follow‑up. Neuroimaging in that study showed decreased amygdala blood flow and changes in functional connectivity (increased connectivity within elements of the default‑mode network and between ventromedial prefrontal and inferior lateral parietal regions, and decreased parahippocampal–prefrontal connectivity), which the authors related to clinical improvement; social‑cognitive gains and personality changes (reduced pessimism and neuroticism; increased extraversion and openness) were also reported. A randomized waitlist‑controlled psilocybin trial in 22 MDD patients compared immediate versus delayed dosing (two oral doses of 20 and 30 mg per 70 kg). Significant group differences on the GRID‑Hamilton Depression Rating Scale favoured the immediate group at 1 and 4 weeks. Clinically, 62% of participants in the immediate condition met response criteria and 39% met remission criteria at both 1 and 4 weeks, whereas no patients in the delayed condition achieved clinically significant response or remission in the reported timeframe. Reported adverse events across psilocybin studies included transient anxiety, confusion, nausea, headache and some autonomic or perceptual effects; serious adverse events were not reported in these small trials. The authors stress that open‑label designs and small sample sizes limit causal inference and generalisability, though several controlled trials nonetheless showed antidepressant effects. Neurobiological mechanisms: The review emphasises that psychedelics are not mechanistically uniform and classifies them broadly into serotonergic hallucinogens (indolamines such as LSD, psilocybin, DMT), dissociative anaesthetics (ketamine) and entactogens (MDMA). For serotonergic psychedelics, agonism at the 5‑HT2A receptor is held central to the characteristic subjective and neurophysiological effects; antagonism at 5‑HT2A reduces or blocks these effects in imaging and pharmacological studies. Many psychedelics have multi‑target profiles: LSD interacts with multiple serotonin subtypes and dopamine receptors and binds to trace amine‑associated receptor 1 (TAAR1); DMT is an agonist at the sigma‑1 (σ1) receptor; and the β‑carbolines in ayahuasca (harmine, tetrahydroharmine, harmaline) are reversible MAO‑A inhibitors with additional receptor interactions. Mechanistic effects that could relate to antidepressant outcomes include rapid promotion of neuroplasticity and neurogenesis. Serotonergic psychedelics appear to enhance glutamatergic tone and AMPA receptor activity following 5‑HT2A activation, increasing cortical electrical activity and information processing; DMT and LSD have been described as 'psychoplastogens' for their capacity to promote structural and functional plasticity (increased c‑fos expression, enhanced BDNF expression in prefrontal regions). Neuroimaging findings are heterogeneous: PET/SPECT studies generally report increased perfusion/metabolism in prefrontal and medial temporal regions and amygdala, whereas fMRI studies report both decreases and increases in connectivity of networks including the default‑mode network (DMN), executive control and attention networks. A convergent pattern described is increased prefrontal and limbic activity alongside decreases in key DMN hubs, which could relate to reduced rumination. Psychedelics also reduce amygdala reactivity to negative emotional stimuli and can alter emotion recognition, potentially improving social cognition. Additional lines of evidence include anti‑inflammatory and neuroprotective effects seen in preclinical models: DOI showed potent anti‑inflammatory activity (EC50 ~15 picomolar) in vitro and in systemic models; proteomic work with 5‑MeO‑DMT downregulated inflammation‑associated proteins in human cerebral organoids. DMT and β‑carbolines may exert neuroprotective effects via σ1 receptor modulation and MAO inhibition respectively. Psychedelics also produce neuroendocrine changes (oxytocin and cortisol release), with cortisol increases noted after ayahuasca that moved hypocortisolaemic patients toward normal levels for at least 48 hours.
Bouso and colleagues identify several practical and scientific challenges that must be addressed for psychedelic medicines to become established treatments. Chief among these is the small size and selective samples of published trials — the mean sample across trials described is about 26 subjects — and strict inclusion/exclusion criteria that commonly exclude people with a history of psychosis or bipolar disorder. The authors note that many trials preferentially recruit participants with prior psychedelic experience (up to 75% in two trials and 50% in two others), which may bias safety and tolerability findings; they argue for pragmatic trials that include psychedelic‑naïve participants to improve external validity. The integration of psychotherapy and drug administration poses additional challenges: psychedelic sessions are long and require trained support (reported session durations are roughly 5–6 hours for ayahuasca, 6–8 hours for psilocybin and 12–15 hours for LSD), which has implications for clinical infrastructure, workforce training and cost. The authors compare this to the esketamine model, where patients are monitored for at least 2 hours post‑dose, and suggest a supervised‑setting model is likely to be required for serotonergic psychedelics as well. Regulatory and cultural issues are also highlighted: ayahuasca already has widespread ritual and medicinal use in parts of South America and beyond, so biomedical applications may need to coexist and enter dialogue with traditional practices, and local legal frameworks (including decriminalisation movements) will influence how these treatments are delivered and governed. Despite these hurdles, the authors consider psychedelic‑assisted psychotherapy an innovative approach that combines psychotherapeutic and pharmacological mechanisms and note that several mechanistic pathways (neuroplasticity, anti‑inflammatory effects, neuroendocrine modulation) remain incompletely explored. They recommend replication of controlled findings by multiple research groups, larger pragmatic and comparative trials versus established treatments, and further mechanistic research to clarify how these drugs might exert sustained antidepressant effects.
Psychedelics are a series of compounds, active principles, plants, fungi and animal secretions that induce dramatic altered states of consciousness that have central roles in the worldviews and ontologies of many indigenous cultures around the globe. The term 'psychedelic' is derived from the Greek words ψυχή (psyche, 'soul, mind') and δηλείν (delein, 'to manifest'), hence 'mind-manifesting'. The word describes a state of consciousness in which human potentialities can be manifested. The term was coined by the English psychiatrist Humphry Osmond in 1957 as an alternative to 'hallucinogen' [from the combination of the Latin word alucinor, 'to wander in mind', with the Greek word gen, 'producing']. Although the term 'hallucinogen' is commonly used in the scientific literature, some authors consider the term pejorative because it refers to something that is pathological and that is not a main effect of these drugs (i.e. hallucinations). In that sense, the so-called psychedelic experience is 'real' and not a hallucination and indeed may have psychological benefits if it is properly conducted. However, it could be argued that the term 'psychedelic' is too related to the counterculture of the 1960s and would not be adequate to describe the ritual and religious uses of some of these compounds. Therefore, both terms have their limitations, and both are the ones currently mostly used in the scientific literature. The terminology for referring to those active principles and plants is challenging because of the unspecific nature of their effects, which are often ineffable and context-and cultural-dependent. For indigenous people, for example, which have the larger (probably millenary) historic use of psychedelic compounds and plants, the terms psychedelic and hallucinogens do not reflect the meaning that they attribute to those practices. For them, the use of psychoactive plants goes beyond the effects over the single person but are conceived as the main spiritual tool that connect the individual with the community, as well as with their environment and with the geographical and spiritual territory. In that sense, psychoactive plants for the indigenous cultures are considered sacred because they operate in their spiritual world, where all the above-mentioned connections take place. Every single culture has a specific name for their traditional plants, being psychedelic (or hallucinogen) the term used by our Western scientific culture, that does not necessarily mean the same for members of other cultures. The early Western psychedelic researcher Leo Hollister characterized the effects of psychedelics as follows: (1) a small dose produces great effects; (2) compared to other effects, the changes in thought, perception and humour predominate; (3) intellectual or memory deterioration must be minimum with high-medium dose; they can be produced with large doses; (4) sedation or stimulation should not be an integral part of the action;the side effects on the nervous system must not be incapacitating or severally disturbing;the addiction potential must be minimum. According to these categories, the prototype of psychedelic drug is lysergic acid diethylamide (LSD). Nowadays the term psychedelic is mainly used to refer to substances that act as agonists or partial agonists on cortical 5-HT 2A serotonin receptors, such as LSD, psilocybin, mescaline and dimethyltryptamine (DMT). Thus, these drugs are also known as serotonergic psychedelics or hallucinogens, and all of them fulfil Hollister's criteria. The history of use of psychedelic drugs is probably millenary. The oldest archaeological evidence corresponds to a post-Palaeolithic rock paint in Spain where supposedly Psilocybe mushrooms (containing psilocybin) are represented, indicating the first direct evidence for possible ritual use of psychedelics. Other Neolithic paintings of Psilocybe mushrooms have been found in the Sahara Desert, in South Africa and in Australia, and numerous anthropomorphic sculptures representing Psilocybe mushrooms have been found in Mexico and Guatemala. The ritual use of Psilocybe mushrooms survives in remote mountains of Mexico, as well as the use of iboga roots (Tabernanthe iboga) in tropical Africa, peyote and San Pedro cactuses (containing mescaline) in areas of Canada, the United States, Mexico, Peru, Ecuador, Bolivia, Chile and Argentina, ayahuasca (an Amazonian decoction containing DMT) along all the Amazonia and DMT-containing snuffs (yopo or epená) in Venezuela and Brazil, among others. Western culture has also a long history and tradition of psychedelic drug uses for psychospiritual and social integration purposes. The main example is the Eleusis ritual in ancient Greece, where for 2000 years a ritual using a drink with eventual LSD-like properties ('kykeon') was used with spiritual and self-transformative purposes. Philosophers like Plato, Aristotle or Seneca participated in the rituals until the temple of Eleusis was destroyed by the Christians and the rites were forbidden. But similar rituals survived in different parts of Europe over the centuries. With the advances of modern chemistry, the active principles of different psychedelic plants were isolated. The first isolated compound was mescaline in 1897 from the peyote cactus. In 1938 LSD was first synthetized by the eminent chemist Albert Hofmann. In 1955 DMT was identified in Virola peregrina, and in 1958 Albert Hofmann isolated psilocybin from Psilocybe mushrooms, publishing its synthesis process in 1969. The isolation of mescaline and the discovery of LSD and psilocybin inaugurated the modern era of psychedelic psychotherapy in the 1950s. The Sandoz pharmaceutical company marketed LSD and psilocybin for the following uses: (1) in analytical psychotherapy, to elicit repressed material and provide mental relaxation, particularly in anxiety states and obsessional neuroses, and (2) in experimental studies on the nature of psychoses. In that sense, above all Europe, psychedelics were used in psychotherapy to boost the therapeutic process, using relatively low doses, in what is known as the 'psycholytic' ('to decompose the mind') paradigm. Psychedelics were used in disorders like anxiety, depression, alcoholism, autism, schizophrenia and even in survivor syndrome in holocaust survivors. At the same time, these drugs were self-administered by psychiatrists and psychiatry students under training in order to better understand the process of psychosis in what is known as the 'psychotomimetic' paradigm. In the United States, although psychiatrists also used psychedelics under the psycholytic paradigm, Dr. Humphry Osmond, working with alcoholic patients, discovered that high doses of psychedelics could induce a spiritual experience that could lead patients to withdraw from alcohol. The paradigm of administering high doses to induce spiritual experiences was named the 'psychedelic' paradigm. This method was predominant in the United States and was used for all kinds of diseases and psychological disturbances, mainly depression, obsessive-compulsive disorders, anxiety and depression in end-of-life diseases, cancer-related pain and drug dependence, among others. Scientific research with psychedelics was interrupted for some decades because of technical and political reasons. But in the early 1990s, psychotherapeutic and neuropharmacological research with these drugs started again, in what some authors call the 'Psychedelic Renaissance'. Since then, several studies have been conducted, and the main compounds being currently investigated are LSD, psilocybin and ayahuasca/DMT for the treatment of depressive and anxiety disorders and drug dependence. The general assumption is that psychedelics enhance the psychotherapeutic process instead of having intrinsic therapeutic properties, although there are some biological mechanisms of action that can explain their therapeutic properties and in particular their antidepressant effects (see below). In that sense, the term often used to describe this intervention is 'psychedelic-assisted psychotherapy'.
In the late 1960s and early 1970s, psychedelics were investigated in the treatment of mood disordersand existential anxiety and depression associated with cancer and other life-threatening diseases. Since 2011, four randomized, double-blind, placebo-controlled, crossover trials using LSD (one trial) or psilocybin (three trials) were published investigating the effects of these drugs on anxiety and depressive symptoms in this clinical population. Regarding depressive symptoms specifically, the three trials with psilocybin, assessed these symptoms, while the LSD study only assessed anxiety symptoms. The main characteristics and results of these trials are presented in Table.1. These trials included samples of 12-51 patients and administered oral psilocybin doses of 14-30 mg/70 kg in a supportive environment. Depressive symptoms were assessed using the Beck Depression Inventory (BDI) in all three studies, and two studiesalso used the Hospital Anxiety and Depression Scale (HADS). All studies found a significant reduction in BDI scores 6 months after psilocybin administration, and the two studies that used the HADS also found significant reductions on this scale at the 6-month follow-up. Moreover, these two studies also reported significant reductions on the scores of these and other scales in the days/ weeks after drug intake (see Table.1 for details). Importantly, psilocybin was well tolerated. Adverse reactions included transitory anxiety and distress, sensorial illusions and transitory psychotic-like symptoms, headache, nausea and vomiting and mild increases in blood pressure and heart rate. Regarding mood disorders unrelated to cancer and other life-threatening diseases, since 2016, four clinical trials were published involving the administration of psychedelics in patients with depressive disorders (see Table.1 for details). These studies included one open-labeland one controlled study with ayahuasca/DMTand one open-labeland one controlled study with psilocybin. The first of these studies was published in 2015 and involved an open-label study assessing the effects of a single oral ayahuasca dose (2.2 mL/kg; 0.8 mg/mL DMT) to six patients with major depressive disorder (MDD). This study presented the preliminary results of the final study with 17 MDD patients (including the initial 6 patients), published in 2016. Ayahuasca intake was associated with significant reductions in the scores of the Hamilton Rating Scale for Depression (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS) and the Anxiety-Depression subscale of the Brief Psychiatric Rating Scale (BPRS) at 1, 7 and 21 days after its administration. Moreover, ayahuasca intake was also associated with increased blood perfusion in brain areas related to introspection and emotional processing (left nucleus accumbens, right insula and left subgenual area) 8 h after its administration. The promising results of the open-label trial were confirmed in a randomized, double-blind, parallel-arm, placebo-controlled trial involving the administration of a single oral ayahuasca dose (1 mL/kg; 0.36 mg/mL DMT) to 29 patients with treatment-resistant MDD. Compared to placebo, ayahuasca produced significant reductions in MADRS scores at 1, 2 and 7 days after its administration and significant reductions at HAM-D scores 7 days after its administration. Moreover, ayahuasca administration was also associated with subacute (48 h) normalization of low cortisol levels (hypocortisolemia) and increases in brain-derived neurotrophic factor (BDNF) in these patients. Indeed, increases in BDNF levels were negatively correlated with the antidepressive effects of ayahuasca and were modulated by acute increases in cortisol levels. In the open-label and controlled trials, ayahuasca was well tolerated. No serious adverse effects were observed, and the most common adverse effects included transient nausea and vomiting. Some months after the publication of the open-label trial with ayahuasca in 2016, an open-label trial involving the administration of 2 oral doses of psilocybin (10 mg and 25 mg, 7 days apart) to 12 volunteers with treatment-resistant MDD was published. Eight more patients were included in a 6-month follow-up. This study reported significant reductions in BDI scores 1 week and 3 month after psilocybin intake and at 1 week and 3 and 6 months in QIDS (Quick Inventory of Depressive Symptomatology) and SHAPS (Snaith-Hamilton Pleasure Scale) scores. Psilocybin administration was associated with decreased blood flow in the amygdala and increased functional connectivity within the default-mode network (DMN) and the ventromedial prefrontal cortex-bilateral inferior lateral parietal cortex and decreased functional connectivity in the parahippocampal-prefrontal cortex. These changes were related to antidepressive effects. Psilocybin administration was also associated with significant improvements in social cognition (processing of emotional faces), which was significantly correlated with a reduction in anhedonia. Psilocybin intake was also related to significant decreases in pessimism 1 week after its administration, and with significant decreases in neuroticism and increases in extraversion and openness 3 months after its administration. Psilocybin was well tolerated, with adverse effects including transient anxiety, confusion, nausea and headache. After the open-label study, the most recent psilocybin trial for depression was a randomized, waitlist, controlled trial investigating the effects of two oral psilocybin doses (20 and 30 mg/70 kg) administered in an immediate compared to a delayed condition (the time between conditions was not specified) in 22 MDD patients. Significantly higher reductions in scores of the GRID-Hamilton Depression Rating Scale were observed between immediate vs. delayed treatments at 1-and 4-week follow-ups. Furthermore, while no patients showed clinically significant response or remission in the delayed condition, in the immediate condition, 62% presented response and 39% presented remission 1 and 4 weeks after psilocybin treatment. Psilocybin was well tolerated, with no serious adverse events reported. The adverse events reported included headache, chest pressure, dizziness, visual distortion, stiffness/soreness and mild repetitive muscle motion. Although the results described above with LSD, psilocybin and ayahuasca/DMT are promising, they should be interpreted with caution. The results of the controlled trials of LSD and especially psilocybin for existential depression are the most robust evidence showing positive results of this treatment, which included administration of these drugs in a safe setting with a non-directive approach (basically the same approach used in all trials reviewed here). This treatment should be better explored by other research groups to further replication, and ayahuasca/DMT was not investigated in this clinical population, yet. The data for MDD and treatment-resistant depression is less compelling, but it is still promising. For instance, the results of the open-label trials with ayahuasca and psilocybin reporting not only symptom reduction but also neural and biological changes simply cannot be causally attributed to the effects of these drugs because of the study design. Thus, together with the small sample sizes of these trials, their results are preliminary and exploratory. However, both ayahuasca and psilocybin showed antidepressive effects in controlled trials. Indeed, the US Food and Drug Administration (FDA) granted psilocybin therapy a breakthrough therapy designation (i.e. support for clinical development of the treatment) two times in a year. In October 2018, the designation was given to the use of psilocybin in treatment-resistant MDD, and in November 2019, it was given for treating MDD. The first designation is related to the work of the for-profit organization COMPASS Pathways, investigating psilocybin as a therapy for treatment-resistant depression in a large, multicentre, phase 2 trial in several sites in the United States, United Kingdom and Europe. The second designation is related to the work of the non-profit organization Usona Institute, investigating psilocybin as a therapy for MDD in a seven-site, phase 2 trial in the United States. Thus, depending on the results of these trials, it is possible that we will see psilocybin being used for the treatment of MDD and treatment-resistant MDD in the following years.
Psychedelic drugs should not be conceived as a unitary category sharing the same mechanism of action across different substances. Indeed, they can be classified at least in three distinct groups, depending on their primary mode of action: first, serotonergic hallucinogens, which include indolamines such as the semi-synthetic lysergic acid diethylamide (LSD) and the natural compounds psilocybin (present in several mushroom species) and N,N-dimethyltryptamine (DMT; main psychedelic present in ayahuasca) and phenylethylamines such as mescaline (present naturally in some cactuses) and the synthetic 2,5-dimethoxy-4-iodoamphetamine (DOI); second, dissociative anaesthetics like ketamine or phencyclidine; and third, a group of 'entactogens' as have been named due to their emotion-enhancement effects. These compounds are less hallucinatory/psychedelic, and the most representative substance would be 3,4-methylenedioxymethamphetamine (MDMA). Other compounds like salvinorin A (present in Salvia divinorum) or tropane alkaloids present in Solanaceae plants, which have other mechanisms of action, have also psychedelic properties. The psychedelic drugs of interest in the case of the treatment of depression are serotonergic psychedelics, particularly the substances classified as indolamines, and some dissociative anaesthetics, such as ketamine. Since Chap. 17 of this book is dedicated to ketamine, we suggest readers to consult that chapter if interested in its mechanism of action. The following sections would be dedicated to describe the mechanisms of action of indolamine psychedelics, such as LSD, psilocybin and DMT. Psychedelic drugs activate different G-protein-coupled receptors (GPCRs), but the behavioural effects of most of them have been attributed to their agonistic activity on the 5-HT 2A receptor. This has been observed in neuroimaging studies, where the administration of 5-HT 2A antagonists reduced or blocked both the subjective and neurophysiological effects of serotonergic psychedelics. The 5-HT 2A receptor is widely distributed in the human brain, but pyramidal neurons and interneurons of the prefrontal cortex (PFC) have a remarkable density. Other regions with notable 5-HT 2A receptor density are the parietal, temporal and occipital cortices, the entorhinal area and the mammillary bodies of the hypothalamus, claustrum and the lateral nucleus of the amygdala. All of them are involved in several cognitive processes, emotion regulation, introspection and self-awareness, so the modulatory effects of psychedelic drugs on these regions could partially explain the induced modifications in perception, cognition or interoception, among others. Besides 5-HT 2A receptor, the multi-target profile of most of psychedelic drugs should not be overlooked when elucidating their mechanisms of action. For instance, LSD binds to other serotonin receptors ( 2C , 1A , 6 , 7 ) and dopamine (D 1 and D 2 ), adrenergic and trace amine-associated (TAAR1) receptors. Notably, TAAR1 agonists have been associated with antidepressant, antipsychotic and antiaddictive effects. In the case of ayahuasca, DMT is also an agonist of sigma-1 (σ1) receptor, which is involved in depression, drug dependence, amnesia, cancer and pain. Regarding depression, other σ1 receptor agonists have shown antidepressant effects. This effect, although not completely understood, has been attributed to the modulating effects of σ1 receptor on serotonergic and dopaminergic transmissions. The β-carbolines that ayahuasca contain (such as harmine, tetrahydroharmine and harmaline) are reversible and specific inhibitors of monoamine oxidase type A (MAO-A) and can also interact with opioid, dopamine, GABA, serotonin, glutamate, acetylcholine and imidazoline receptors. Considering the complexity of the pathophysiology of depression and the failing of the classical monoaminergic hypothesis in providing a potential neurobiological explanation for depression, we consider that hypotheses regarding the therapeutic effect of psychedelic drugs for this and other mood disorders must include their multi-target profile. We suggest that in the near future, disciplines like systems pharmacology could provide valuable contributions to the field of psychedelic medicine attending to the complex effects of these drugs and vegetal materials. A significant effect of most psychedelic drugs that could be related to their antidepressant effects is the enhancement of both neurogenesis and neural plasticity. In contrast to ketamine, which induces these effects through its antagonism on the N-methyl-D -aspartate (NMDA) glutamatergic receptor, serotonergic hallucinogens do it through their agonism on the 5-HT 2A receptor. The activation of the 5-HT 2A receptor produces an increase in the glutamatergic tone and the activation of alpha-amino-3-hydroxy-methyl-5-4-isoxazolpropionic (AMPA) receptors, which increases cortical electrical activity and information processing. Notably, certain psychedelic drugs like DMT and LSD have been termed 'psychoplastogens' due to their promotion of rapid structural and functional neural plasticity. The mechanisms underlying these effects consist in an enhanced c-fos expression in the medial prefrontal (mPFC) and anterior cingulate (ACC) cortices. The expression of brain-derived neurotrophic factor (BDNF), which is associated with both neuritogenesis and spinogenesis, is also enhanced in PFC. However, the enhancement of BDNF levels and the subsequent therapeutic effects does not necessarily inform about the pathophysiology of depression, since not all the patients show lower BDNF levels. Remarkably, this was also observed in a clinical trial in which the psychedelic drug ayahuasca was administered, where baseline BDNF levels did not predict the depressive state. But there is evidence showing that atrophy in neurons of the PFC plays a key role in mental and neurological disorders, including depression, and that this atrophy can be counteracted by compounds capable of increasing neural plasticity in the PFC. Other receptors, such as the 5-HT 1A receptor, are also involved in neuroplasticity and neurogenesis. Remarkably, when this receptor is blocked with an antagonist (pindolol), the subjective effects of DMT are enhanced, so this receptor could be also acting as a neuromodulator of DMT and other serotonergic psychedelics. The complex effects of psychedelic drugs have been studied through different neuroimaging techniques, showing acute increases and decreases in the activity of several brain regions, depending on the neuroimaging technique and protocol. Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) have provided consistent results, informing about the excitatory effects of different serotonergic psychedelics (mescaline, psilocybin and ayahuasca) in brain regions like the frontolateral/frontomedial cortex, the medial temporal lobe and the amygdala. In contrast, functional magnetic resonance imaging (fMRI) studies reported less consistent results. A study with psilocybin observed a decreased connectivity between the thalamus and ACC and posterior cingulate (PCC) cortices. A decrease in resting-state connectivity between mPFC and PCC was also observed. A posterior fMRI study with psilocybin reported increases in connectivity of different networks, including the default-mode network (DMN), executive control and dorsal attention networks. In another fMRI study using ayahuasca, a reduction of activity in key hubs of the DMN, such as mPFC and PCC, was observed. In a later study using LSD, an increase of hemodynamic activity in several brain regions was reported, mostly in those rich in 5-HT 2A receptors. The authors concluded that the overall effects of LSD were related to an increased functional connectivity between different brain regions. Finally, a recent fMRI study with LSD showed a decrease in functional connectivity in visual, sensorimotor, auditory and the DMN. It has been suggested that the inconsistencies between PET/SPECT and fMRI studies could be related with the timescales considered in different techniques. For instance, in the first case, radiotracers to measure blood perfusion or glucose metabolism have long half-lives (110 min in the case ofF-FDG or 6 h in the case of technetium-99 m). Thus, the detected effects by these techniques can actually consist in compensating or rebound effects. A recent review about neuroimaging studies using psychedelic drugs concluded that the overall effect of serotonergic psychedelics consist in the modulation of brain areas associated with different cognitive functions, such as perception, introspection and emotion processing. Generally, these drugs induce increases in the activity of prefrontal and limbic areas and decreases in key hubs of DMN. The disintegration of DMN could partially explain the therapeutic effect of serotonergic psychedelics, since an increased DMN functional connectivity has been associated with some symptoms of mood disorders, particularly rumination. The effects of these drugs on the amygdala are also relevant, since they reduce its activation to negative emotions and also reduce the recognition of these emotions, therefore improving social cognition. In depressed patients, there is an increased response of the amygdala to negative faces, which is normalized after the administration of selective serotonin reuptake inhibitors. Additionally, modifications in certain brain regions have been observed in long-term users of ayahuasca. Specifically, cortical thinning in mesotemporal and inferior frontal gyri, precuneus, superior frontal gyrus, PCC and superior occipital gyrus was associated with the regular use of ayahuasca. The cortical thickness (CT) alterations in the PCC were inversely correlated with age of onset and intensity of ayahuasca use and with the self-transcendence scale, which is related to spirituality. Remarkably, increased CT was found in the ACC, a region involved in emotional processing. Conversely, decreased CT was observed in patients with mood disorders, including depression. Inflammatory processes are closely related with depression. Patients diagnosed with major depressive disorder (MDD) show an increased expression of proinflammatory cytokines and higher levels of acute-phase reactants, chemokines and soluble adhesion molecules in both the peripheral blood and cerebrospinal fluid. Additionally, the administration of IFNα and other inflammatory cytokines to healthy individuals induces symptoms of depression. Due to the association between inflammation and depression, the anti-inflammatory effects of psychedelic drugs could be relevant not only in the case of depression but also in other psychiatric or neurodegenerative disorders in which inflammation processes are involved, such as Parkinson and Alzheimer diseases. Preclinical studies show that psychedelic drugs such as LSD and DOI induce potent anti-inflammatory effects through the activation of the 5-HT 2A receptor. DOI showed a potent antiinflammatory effect, since it has an EC 50 of 15 picomolar in preventing tumour necrosis factor alpha (TNF-α)-mediated inflammation in aortic smooth muscle cells. This effect was also found in the case of systemic TNF-α. Notably, the anti-inflammatory effects of DOI have been also observed in human cells in vitro, suggesting that these findings could translate to humans, although human studies are lacking in this area. Proteomic analyses in a human cerebral organoid administered with 5-MeO-DMT downregulated proteins associated with inflammation and degeneration. Related to the anti-inflammatory effects of psychedelic drugs, we can mention also their neuroprotective effects as potentially associated with their antidepressant action. This is especially relevant in the case of ayahuasca, where both DMT and β-carbolines induce increases in BDNF levels and neurogenesis. Activation of the σ1 receptor by DMT can modulate glutamate release and NMDA receptors and dampen the excitotoxic effects of glutamate. Additionally, σ1 receptor agonists are known to act as indirect antioxidants. Regarding β-carboline compounds, especially harmine, their MAO-inhibiting properties could be involved not only in the antidepressant effects of ayahuascabut also in their neuroprotective effects, since MAO inhibition decreases oxidative stress. Moreover, the antidepressant effects of harmine were associated with increased BDNF levels and antioxidant activities in the rat PFC and hippocampus. The neuroendocrine effects of psychedelic drugs have also been suggested as potentially implicated in their therapeutic effects. The hypothalamus has a high density of 5-HT 2A and other receptors associated with the mechanisms of action of psychedelic drugs, so their administration is associated with a release of oxytocin and other neuropeptides, an effect blocked by 5-HT 2A antagonists. While the administration of oxytocin does not seem to be associated with antidepressant effects, some single-nucleotide polymorphisms (SNPs) of the oxytocin receptor have been associated with depression, and it has been observed that its administration during the psychotherapeutic process can lead to changes in individual and dynamic factors in patients with depression. This effect can be partially attributed to improvements in social cognition. Similar findings can be observed in the case of cortisol. Deregulations of this hormone are associated with depressive symptoms, mainly consisting in lower levels of cortisol compared to healthy controls. Additionally, hypocortisolaemia has been associated with non-specific symptoms of depression, such as malaise, muscle weakness or loss of appetite. Different psychedelic drugs induce increases in cortisol. In this sense, in a placebo-controlled studyin which patients with MDD were treated with a single ayahuasca dose, lower levels of cortisol were reported in patients as compared with healthy controls. After administration of ayahuasca, cortisol increases in patients were observed, reaching similar levels to the ones registered in healthy controls. This increase was stable at least until 48 h after ayahuasca administration. Thus, the stimulation of oxytocin or cortisol by different psychedelic drugs could produce or enhance their overall antidepressant effects.
There are still so many challenges that have to be addressed in order to show that psychedelic drugs can become an available treatment for some mental disorders. First, as happens in other fields, the published clinical trials until today have been conducted with small (mean of 26 subjects) samples. Additionally, due to the intrinsic risks of psychedelic drugs in terms of exacerbating previous psychotic or bipolar disorders, patients are selected using strict inclusion/exclusion criteria. For instance, one basic strategy in order to avoid both the psychiatric side effects and the appearance of acute anxious effects (commonly known as 'bad trip') is the inclusion of people with previous experience with psychedelic drug use without having lived challenging experiences or psychiatric complications. In fact, the prevalence of patients with previous experience with psychedelic drugs included in some clinical trials is much higher than that found in general population: up to 75% of patients in two trialsand 50% of patients in two other trials. Thus, the realization of studies with subjects naïve in psychedelic use (as the clinical trials of ayahuasca for depression) and of pragmatic or real-life trials is necessary in order to better assess the efficacy and safety of this treatment in the general population. Similarly, since psychedelic therapy generally involves the combination of psychotherapy with pharmacology, comparative studies in which psychedelic psychotherapy is compared with already commercialized medicines and psychotherapy will be needed as well. Another challenge that has to be addressed is the specific healthcare structure in which psychedelic therapy will be administered. It has to be noted that these treatments require specialized practitioners, offering support to patients for hours (at least 5-6 h in the case of ayahuasca, 6-8 h in the case of psilocybin and 12-15 h in the case of LSD). The case of esketamine, recently approved by the FDA for treatment-resistant MDD, could be of interest. Patients must take esketamine under the direct supervision of a healthcare provider and must be monitored for at least 2 h post-dose to ensure the resolution of possible transient adverse effects, such as increases in blood pressure, cognitive impairment, sedation and dissociation. Thus, a similar future could be envisioned for psychedelic therapy, where patients would take these drugs under supervised conditions in safe settings. Despite all of the challenges, the current limitations of psychiatric treatments should be noted, so new strategies in mental health are urgently needed. In that sense, psychedelic psychotherapy represents an innovative approach, combining both psychotherapy and pharmacological tools. Furthermore, these tools alone have several mechanisms of action potentially associated with therapeutic outcomes, being some of them unexplored. Lastly, in the particular case of ayahuasca, we should consider its already disseminated ritual and medicinal use thorough South America mainly but also in many other parts of the world in indigenousand non-indigenouscommunities. Thus, if these promising results are replicated, maybe the traditional medicinal use of ayahuasca will exist and dialogue with a non-traditional use be regulated in a medicinal plant legislation. A similar case is the decriminalizing process of psychoactive plants that is occurring in several US cities and states and other parts of the world like the Netherlands or Spain, where private practitioners offer psychotherapeutic treatments with Psilocybe mushrooms and/or other psychoactive plants. The UN international conventions do not have scheduled plants containing psychedelic principles, so, as happens with the case of ayahuasca, it is not unlikely that biomedical approaches will coexist with cultural uses.
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