This review summarises preclinical and clinical evidence that ketamine, psilocybin, LSD and MDMA have therapeutic potential for psychiatric disorders — with robust support for ketamine in depression, emerging evidence for psilocybin and LSD in treating depression and modulating functional brain connectivity, and MDMA showing efficacy in PTSD. It also delineates the pharmacology and behavioural effects of psychedelic versus non‑psychedelic hallucinogens and entactogens.
A revamped interest in the study of hallucinogens has recently emerged, especially with regard to their potential application in the treatment of psychiatric disorders. In the last decade, a plethora of preclinical and clinical studies have confirmed the efficacy of ketamine in the treatment of depression. More recently, emerging evidence has pointed out the potential therapeutic properties of psilocybin and LSD, as well as their ability to modulate functional brain connectivity. Moreover, MDMA, a compound belonging to the family of entactogens, has been demonstrated to be useful to treat post-traumatic stress disorders. In this review, the pharmacology of hallucinogenic compounds is summarized by underscoring the differences between psychedelic and nonpsychedelic hallucinogens as well as entactogens, and their behavioral effects in both animals and humans are described. Together, these data substantiate the potentials of these compounds in treating mental diseases.
Psychiatric disorders impose a heavy global burden, and progress in new therapeutic approaches has been slowed by regulatory restrictions that curtailed research on hallucinogens for decades. Since the 2000s there has been a renewed research interest, with two broad pharmacological groupings commonly distinguished: classic serotonergic hallucinogens (psychedelics), which primarily act at 5-HT2A receptors, and dissociative anesthetics such as ketamine, which act principally on glutamatergic systems. Compounds that produce prosocial or entactogenic effects, most notably MDMA, are typically classed separately because their mechanisms and behavioural profiles differ from classic psychedelics. This review by Hibicke and colleagues sets out to summarise preclinical and clinical evidence for LSD, psilocybin, MDMA and ketamine, emphasising pharmacology, behavioural effects in animals and humans, and neuroimaging findings. The authors focus particularly on three domains: (1) effects of psychedelics in rodents and their impact on human brain functional connectivity; (2) preclinical and clinical data on ketamine's antidepressant effects; and (3) the prosocial actions of MDMA and its therapeutic applications, notably in PTSD.
Papers cited by this study that are also in Blossom
Abdallah, C. G., Averill, L. A., Gueorguieva, R. et al. · Neuropsychopharmacology (2020)
Ionescu, D. F., Vande Voort, J. L., Niciu, M. J. et al. · Journal of Psychiatric Research (2014)
Barrett, F. S., Doss, M. K., Sepeda, N. D. et al. · Scientific Reports (2020)
Belouin, S. J., Henningfield, J. E. · Neuropharmacology (2018)
Psychedelics and receptor pharmacology: Hibicke and colleagues describe classic serotonergic psychedelics (LSD, psilocin/psilocybin, DMT) as primarily 5-HT2A receptor agonists, while underscoring that their pharmacology is broader. These compounds also interact with 5-HT1A, 5-HT2B, 5-HT2C, 5-HT6 and 5-HT7 subtypes and can trigger intracellular signalling cascades (for example, involving β-arrestin and early growth response proteins EGR1/EGR2) in cortical pyramidal neurons. LSD shows dose-dependent effects on serotonergic and dopaminergic neuronal firing in animal work and binds to dopamine receptors (D1, D2, D4) in vitro; possible interactions with TAAR1 are noted but require further study. The overall message is that psychedelic pharmacology is pleiotropic and extends beyond simple 5-HT2A agonism. Preclinical behavioural evidence for psychedelics: Rodent studies indicate that LSD, psilocin/psilocybin and DMT can produce long-term behavioural changes relevant to antidepressant effects, coping strategies and cognitive functions, and can enhance associative learning. However, the literature is heterogeneous: outcomes depend strongly on model choice, dosing regimen and timing. Examples reported include chronic low-dose LSD (0.13 mg/kg/day) and intermittent dosing regimens such as 1 mg/kg DMT every third day; conversely, intermittent LSD (0.16 mg/kg every other day) increased aggression and reduced sociability in one study. Single doses (psilocybin 1 mg/kg, LSD 0.15 mg/kg) produced long-term, time- and context-dependent behavioural changes in Wistar-Kyoto rats. The authors emphasise the influence of ‘‘set and setting’’ even in rodents, illustrating that prior testing experience and timing of behavioural assays (for example, forced swim tests at different intervals after dosing) altered outcomes, consistent with a window of increased behavioural plasticity after psychedelic administration. Human neuroimaging and network effects: Functional neuroimaging studies in healthy volunteers show that LSD and psilocybin alter large-scale brain connectivity rather than uniformly increasing or decreasing it. LSD increased thalamic connectivity with sensory-somatomotor cortical regions and posterior cingulate cortex while decreasing thalamic connectivity to temporal cortex. Data-driven voxelwise analyses reveal increased interactions among sensory and somatomotor networks and reduced communication within associative networks, including the Default Mode Network (DMN). These changes are hypothesised to heighten sensory processing (possibly via reduced thalamic gating) while diminishing integrative associative function, which could underlie altered self-experience and reduced rigid or ruminative thinking. Psychedelic-induced visual alterations associate with reductions in posterior alpha oscillations, indicating increased visual pathway excitability. Seed-based studies linked subjective psilocybin effects to changes in claustrum low-frequency BOLD fluctuations and to altered amygdala–frontal connectivity that correlated with positive mood. Neuroimaging in clinical populations remains limited: in one MDD cohort, decreased PFC–parahippocampus connectivity and increased PFC–inferior parietal connectivity one day after psilocybin predicted treatment response at five weeks, and decreased amygdala cerebral blood flow correlated with symptom reduction, although amygdala reactivity showed complex temporal dynamics that may relate to emotional processing prior to integration therapy. Ketamine: mechanisms and clinical effects: Ketamine is framed as a rapid-acting antidepressant that acts as a noncompetitive NMDAR antagonist and engages the mTORC1 pathway. Preclinical data implicate both NMDAR-dependent and NMDAR-independent mechanisms: metabolism to hydroxynorketamine (HNK) enantiomers, especially (2R,6R)-HNK, appears necessary for some antidepressant-like effects in rodents and produces antidepressant actions with reduced NMDAR-associated side effects. In rodents, ketamine and HNK transiently increase phosphorylated mTOR and downstream targets (p70S6K, 4E-BP1) in prefrontal cortex and hippocampus; intracerebroventricular rapamycin blocks ketamine-induced synaptic and behavioural changes in animals, supporting a role for mTORC1 in mediating synaptic plasticity. Clinically, subanesthetic ketamine (commonly 0.5 mg/kg infused over 40 minutes) produces rapid antidepressant onset measurable at about 4 hours and a therapeutic response rate of 50%-70% at 1 day after a single infusion. Repeated treatments can prolong benefit, although overall response rates may be similar to single-dose regimens. Open-label data report a 69% decrease in suicidal ideation with repeated injections. Safety concerns include abuse liability and bladder/neurologic toxicity. Translational complexity is highlighted by a clinical study where peripheral rapamycin coadministration enhanced rather than blocked ketamine's antidepressant effect, indicating species differences or more complex pharmacodynamics in humans; other receptor systems such as opioid receptors may also contribute. The role of the subjective dissociative experience in ketamine's antidepressant action remains debated, with some studies linking dissociation to efficacy and others finding it neither necessary nor sufficient. MDMA: preclinical and clinical evidence for prosocial and therapeutic effects: MDMA is characterised as an entactogen that induces large releases of serotonin, dopamine and norepinephrine via transporters (SERT, DAT, NET) and increases hormones such as oxytocin. In animal models, MDMA enhances affiliative and prosocial behaviours, can increase sensitivity to social reward via nucleus accumbens 5-HT mechanisms, and facilitates fear-extinction processes via basolateral amygdala 5-HT release. Rodent studies suggest that SERT-mediated 5-HT release is necessary and perhaps sufficient for key therapeutic-like effects; oxytocin signalling may not be required for acute prosocial effects but could contribute to longer-term processes. Early clinical work in the 1970s and later Phase 1 studies (doses roughly 0.25–1.0 mg/kg p.o. in experienced subjects) established tolerability; common acute side effects include jaw clenching, headache, nausea and fatigue, usually mild-to-moderate and transient. A series of approximately a dozen Phase 2 trials in treatment-resistant PTSD have reported encouraging and durable reductions in symptoms, with pooled analyses contributing to FDA Breakthrough Therapy designation and enabling a Phase 3 programme. Preliminary open-label lead-in data from the Phase 3 trials show robust attenuation of core PTSD symptoms. MDMA-assisted psychotherapy is thus presented as a promising adjunctive approach for PTSD, with ongoing trials in alcohol use disorder and autism spectrum disorder. Barriers to broad adoption include abuse potential and interactions with SSRIs, and the authors stress the need to define optimal therapeutic frameworks (set and setting) and specific psychotherapeutic approaches.
Hibicke and colleagues conclude that hallucinogenic compounds differ in mechanism and behavioural outcomes but share the capacity to produce profound subjective and neural changes that can be harnessed therapeutically. They emphasise that the mechanisms are more complex than was traditionally assumed: psychedelics involve multiple 5-HT receptor subtypes and intracellular signalling pathways, ketamine engages both NMDAR-related and NMDAR-independent mechanisms (including active metabolites and mTORC1-dependent synaptic plasticity), and MDMA exerts prosocial effects primarily via transporter-mediated 5-HT release with downstream neural-circuit consequences. The authors position ketamine as an established rapid antidepressant with clear clinical data in treatment-resistant MDD, and present MDMA-assisted psychotherapy as having strong Phase 2 evidence in PTSD with Phase 3 trials underway. Evidence for psilocybin and LSD in depression and anxiety is promising but still limited; the authors note a recent meta-analysis suggesting more trials are required to confirm efficacy, and ongoing clinical trials for alcohol use disorder and obsessive–compulsive disorder are highlighted. Limitations and uncertainties are acknowledged throughout: preclinical literature is heterogeneous with respect to dosing, models and timing, clinical neuroimaging in patient populations is sparse, and translational gaps remain (for example, differences between rodent and human pharmacology and the surprising clinical rapamycin result for ketamine). Safety concerns (abuse liability, organ toxicity) and drug–drug interactions (notably with SSRIs in MDMA trials) are cited as practical barriers to widespread clinical implementation. The authors call for further mechanistic work and controlled clinical trials to clarify therapeutic mechanisms, optimise dosing and psychotherapeutic context, and better define safety and durability of benefits. They also highlight the value of these compounds for probing neural circuits relevant to psychiatric disorders as well as for developing novel interventions.
Psychiatric disorders are a major public health concern affecting ;350 million people and imposing social and economic burdens worldwide. Despite tremendous efforts to uncover pathophysiological determinants, our understanding of psychiatric diseases and their treatment remains limited. After a long hiatus stemming from regulations that placed psychedelics in a restrictive regulated drug schedule, investigation of these compounds is experiencing a renaissance in the research and clinical communities, especially with regard to their therapeutic application in mental disorders. Generally speaking, since the 1960s, hallucinogenic drugs have been classified into two groups: the "serotonergic classic hallucinogens" or "psychedelics," and the "dissociative anesthetics." Classic hallucinogens exert their pharmacological effects primarily through the 5-HT system, acting as agonists of the 5-HT 2A receptor. In contrast, "dissociative anesthetics," including ketamine, are considered to act on the glutamatergic system and not on the 5-HT system, and they do not produce the same so-called "trip" as psychedelics, but are still considered hallucinogens. In the last decade, numerous studies in laboratory animals and humans have confirmed the usefulness of ketamine for the treatment of resistant depression. Research has also suggested potential antidepressant and mood-modulating properties of psilocybin and LSD, respectively, as well as the ability of these compounds to modulate functional brain connectivity. Other compounds, including 3,4-methylenedioxymethamphetamine (MDMA), are called entactogens. They produce psychotropic effects, but they do not share the same mechanism of action as hallucinogens. MDMA has been demonstrated to increase sociability in animalsand humansand to be useful in treating post-traumatic stress disorder (PTSD). This review summarizes the pharmacological mechanism of psychedelics, nonpsychedelic hallucinogens, and entactogens as well as their impact on psychiatric research. In particular, we overview: (1) data on the effects of psychedelics in rodents and on brain functional connectivity in humans; (2) preclinical and clinical data on the antidepressant effects of ketamine; and (3) data on the prosocial effects of MDMA and its therapeutic applications in both animals and humans. Psychedelics: the 5HT 2A receptor Psychedelics, also defined as "classic serotonergic hallucinogens" because they interact with the 5-HT system, are strongly involved in the treatment of psychiatric disorders, including depression, anxiety, and cognitive deficits. Psychedelics primarily act as 5-HT 2A receptor agonists, but their mechanism of action is more complex than originally thought. Indeed, psychedelics, including LSD, psilocin, psilocybin (a prodrug of psilocin), and N,N-dimethyltryptamine (DMT), have been demonstrated to also interact with 5HT 1A , 5HT 2B , 5HT 2C , 5HT6, and 5HT7 receptors. Furthermore, a growing body of evidence demonstrates that both nonhallucinogenic (e.g., lisuride) and hallucinogenic 5-HT 2A agonists can activate intracellular signaling cascades in cortical pyramidal neurons, thus modulating downstream signaling proteins, including b -arrestin, early growth response protein 1 (EGR1), and EGR2. Moreover, the activation of 5HT 2A and 5HT 1A receptors by LSD in the mPFC activates both the serotonergic and dopaminergic activity in the dorsal raphe nucleus and VTA, respectively. In particular, low doses of LSD (up to 30 mg/kg) decrease the firing of 5-HT neurons without affecting the dopaminergic firing rate of VTA neurons, whereas higher doses (40-60 mg/kg) decrease the firing of dopaminergic VTA neurons. While the 5-HT system is implicated in mood and anxiety regulation, the dopaminergic system plays an important role in the mechanism of action of psychedelics. Drug discrimination tasks in rodents revealed that the behavioral effects of LSD involve 5-HT 2A receptors in an initial phase, followed by a second phase that requires the dopamine D 2 receptor. Furthermore, in vitro studies showed that LSD binds to the recombinant human D 2 receptor in HEK 293 cells. A similar experimental approach demonstrated that LSD also shows affinity for dopamine D 1and D 4receptors. Finally, in vivo and in vitro evidence indicates a potential interaction of psychedelics, particularly LSD, with the trace amino associate receptor 1 (TAAR1), although more research is needed to understand the role of TAAR1 in the mechanism of action of psychedelics. A schematic representation of LSD, psilocybin, and DMT mechanism of action is shown in Figure. Overall, psychedelic compounds display a pharmacological activity that goes beyond their action as 5HT 2A agonist, and further investigations are needed to better elucidate their pleiotropic mechanisms of action (for a detailed discussion of the mechanism of action of psychedelics, see.
There is evidence from studies in rodents that classic psychedelics, LSD, psilocin, psilocybin, and DMT, create long-term behavioral outcomes comparable to those of traditional antidepressant treatment in measures of coping strategy and cognitive function. Additionally, animal studies pointed out that psychedelics can enhance associative learning, a cognitive function commonly impaired by neuropsychiatric disorders, particularly major depressive disorder (MDD). However, a gold-standard protocol for assessing the behavioral effects of psychedelics has yet to be established, and a number of factors may confound the results, including which animal model and behavioral measures are used, as well as the kind of psychedelic drug tested. The literature addressing the effects of psychedelics on rodent behaviors relevant to psychiatric and cognitive function is sparse, and results of different studies may appear to align or to conflict with each other without being truly comparable. Dosing strategies must be taken into account. Whereas some studies have reported cognitive and/ or behavioral enhancements using chronic (0.13 mg/kg/day LSD to male Wistar rats)or intermittent dosing (1 mg/kg DMT every third day to mixed sex Sprague Dawley rats), intermittent dosing (0.16 mg/kg LSD every other day) has been shown to dramatically decrease sociability and increase aggression in male SD rats. Further investigation found that a single dose of psilocybin (1 mg/kg) or LSD (0.15 mg/kg) profoundly affected longterm behavioral measures of male Wistar-Kyoto rats in a timeand context-dependent way. Time intervals between dosing and behavioral testing is another factor influencing the results of studies with psychedelics. While there is some evidence that acute DMT increases active coping strategies in the forced swim test, psychedelics are not reliably rapid antidepressants, and antidepressant-like behavioral changes may not be measurable until 4 or more weeks after the psychedelic experience. As in humans, "set and setting" seems to play a role in the long-term behavioral outcome of rodents given psychedelics. Wistar-Kyoto rats given a single dose of psilocybin (1 mg/kg) then tested in the forced swim test at various time points between 1 and 5 weeks after administration, and in the elevated plus maze 6 weeks after administration, develop distinct behavioral responses depending on when they first encounter the forced swim test. Rats tested only once in the forced swim test (one swim, 5 weeks after psilocybin) were significantly and profoundly more likely to use active coping strategies (swimming/climbing) than a passive coping strategy (immobility) in that assay, but were not different from control rats in their elevated plus maze behavior a week later. However, rats tested in the forced swim test weekly for 5 weeks (five total swims), or 1 and 5 weeks (two swims) were only slightly (but significantly) more active in the forced swim test than control animals, and displayed significantly less anxiety-like behavior in the elevated plus maze 6 weeks after psilocybin. One explanation for these differences is that psychedelic administration produces a period of behavioral flexibility in which new coping strategies can be learned. These animal studies suggest that psychedelic-assisted therapy may become a powerful tool for treating psychiatric and cognitive disorders, as the timing and the environmental context of administration are relevant for psychedelic therapeutics.
The development of functional neuroimaging techniques has allowed researchers to better understand the impact of psychedelic drugs on brain connectivity patterns and on the activity of specific brain regions in humans. Alteration of information processing within cortico-striato-thalamo-cortical feedback loops is one mechanism suggested to underlie the psychedelic state. In healthy human participants, two neuroimaging studies confirmed that LSD induces increases in functional connectivity between the thalamus and sensory-somatomotor cortical regions. Additionally, LSD increased connectivity from the thalamus to the posterior cingulate cortex and concurrently decreased connectivity to the temporal cortex. These empirical results are in line with the cortico-striato-thalamo-cortical model; however, they do not support the hypothesis that LSD generates an undifferentiated increase in thalamocortical connectivity and information flow, but rather suggest a strengthening of specific connections between the thalamus and specific cortical areas. Data-driven approaches investigating the connectivity between each voxel of the brain have furthermore revealed that LSD and psilocybin increase interaction between sensory and somatomotor brain networks, and decrease communication among associative bran regions, including large scale brain-network, such as the Default Mode Network. Together, these results suggest that increased processing of sensory information, potentially as a result of decreased thalamic gating, and concurrently reduced integration capacity because of diminished associative network integrity may underlie psychedelic experiences. It is possible that the altered integration of sensory perceptions facilitates a novel experience of the self and its environment and may help to reduce rigid or ruminative thinking patterns as observed in psychiatric disorders. However, this hypothesis still needs to be tested in clinical populations. Additional studies investigating a priori hypotheses using seedbased imaging approaches have shown that subjective effects induced by psilocybin are associated with changes in the amplitude of low-frequency fluctuations and the variance of BOLD signal in the claustrum. Furthermore, this study showed that psilocybin decreased connectivity between the right claustrum and the auditory network and the Default Mode Network and concurrently increased connectivity with the frontoparietal control network. Additionally, changes in positive mood after a low dose of LSD were associated with increases in amygdala, frontal cortex connectivity. Various other studies showed decreased connectivity between structures of the Default Mode Network after the administration of LSD, DMT, and psilocybin. Finally, a prominent feature of psychedelics is alterations in visual perception. Those have repeatedly been associated with decreases in a oscillations, in particular over posterior parieto-occipital brain areas, suggesting that psychedelics increase the excitability of the visual pathway. Neuroimaging studies investigating the effects of psychedelics in clinical populations with mental health conditions are still scarce. So far, it has been shown that treatment response measured 5 weeks after psilocybin treatment in patients with MDD was predicted by decreased connectivity between the PFC and the parahippocampus increased connectivity between the PFC and the inferior parietal cortex, 1 d after psilocybin administration. Furthermore, decreased amygdala cerebral blood flow correlated with reduced symptoms in the same study. The same patients showed increased amygdala reactivity the morning after psilocybin and a reduction in amygdala, PFC connectivity in response to fearful faces. These results are surprising given that decreased amygdala reactivity and increased amygdala-PFC connectivity under the acute influence of psychedelics have been shown to correlate with positive mood in healthy participants. Furthermore, reduced amygdala reactivity in response to emotional stimuli was still present in healthy people 1 week after psilocybin administration, and this reduction has been hypothesized to be an important therapeutic mechanism because it may indicate that psychedelics normalize the negative cognitive bias observed in patients suffering from depression. It has to be noted, however, that increased amygdala reactivity in depressed patients was measured before any psychological or psychotherapeutic interventions aiming at integrating the psychedelic experience. It is therefore conceivable that psilocybin facilitated the processing of negative life events, leading to markedly increased emotional processing and amygdala reactivity the morning after the session. Additional studies in clinical populations assessing long-term changes in brain activity and connectivity are necessary to clarify the mechanisms underlying the therapeutic effects of psychedelics. Ketamine, a fast-acting antidepressant acting through NMDA and mammalian target of rapamycin complex 1 (mTORC1) Ketamine is a dissociative anesthetic that marked a new era for the treatment of resistant MDD patients. Ketamine indeed produces fast antidepressant effects in both animal and humans at subanesthetic doses. Although ketamine does not appear to primarily target the serotonergic system, it is nonetheless capable of inducing psychedelic states. The antidepressant mechanism of action of ketamine remains the subject of intensive research. Ketamine is both a noncompetitive NMDAR, a glutamate receptor subtype broadly expressed in the CNSantagonist, and an activator of the mTORC1 pathway. Early studies in mice indicated that the NMDAR blocker, MK-801, and the competitive NMDAR inhibitor AP-7 decreased immobility time in the forced swim test, prompting the idea that NMDAR antagonism had antidepressant potential. Despite the initial evidence in mice, NMDAR antagonism appears nonessential for ketamine's antidepressant action. For example, other noncompetitive NMDAR antagonists, including memantine and MK-801, either lack antidepressant effects (e.g., memantine) or only have short-lasting effects, which are often inconsistent between studies (e.g., MK-801). This suggests that additional, non-NMDAR-mediated effects of ketamine mediate its striking antidepressant action, although the role of subtype specific binding to NMDRs of the different antagonists cannot be ruled out. Consistent with this notion, chemical alteration of ketamine (via deuteration at the C6 position), which does not change its binding affinity for the NMDAR, but dramatically decreases its metabolism to a major metabolite (2S,6S;2R,6R)-hydroxynorketamine (HNK) in vivo, nullifies ketamine's antidepressant actions in mice. Furthermore, both HNK enantiomers [(2S,6S)-and (2R,6R)-HNK] exerted dose-dependent antidepressant actions in several rodent tests. Interestingly, (2R,6R)-HNK, the enantiomer with the stronger antidepressant-like effects, is a less potent antagonist of NMDAR than ketamine itself. Because of its reduced effects at the NMDAR, (2R,6R)-HNK did not induce NMDAR inhibition-mediated side effects, such as sensorimotor dissociation. However, (2R,6R)-HNK does not appear to be as potent as ketamine in relieving the behavioral changes induced by chronic social defeat in mice, suggesting the involvement of both NMDAR-dependent and -independent pathways. Ketamine induces both synaptic and structural plasticity in the hippocampus, mPFC, and lateral habenula, involving signaling pathways that control protein synthesis, such as the mTORC1 pathway. Indeed, increasing evidence suggests that activation of mTORC1 is a critical mechanism underlying the antidepressant action of ketamine and its metabolite (2R,6R)-HNK. Numerous studies demonstrated that a single dose of ketamine and HNK induce a transient increase in phospho-mTOR and its targets, phospho-p70S6 kinase and phospho-4E-BP1, in the PFC and hippocampus of mice and rats. More importantly, intracerebroventricular pretreatment with the allosteric mTORC1 inhibitor, rapamycin, blocked ketamine-induced synaptic molecular and behavioral effects relevant for antidepressant actions, including increased synaptic densities in the PFC, and decreased immobility in the forced swim test and latency to feed in the novelty suppressed feeding test. mTORC1 controls numerous neuronal functions, including nucleotide and lipid synthesis, glucose metabolism, autophagy, lysosome biogenesis, proteasome assembly, and 59 cap-dependent mRNA translation (also known as protein synthesis). Local dendritic translation of mRNA into protein is essential both for the homeostasis of synaptic function and for synaptic plasticity, which is thought to allow the brain to store information and display adaptive responses to subsequent related stimuli. Key targets of the local activation of mRNA translation by ketamine are the AMPAR subunits, GluA1 and GluA2. AMPARs mediate ketamine-induced synaptic facilitation in the mPFC and hippocampusfor review, see also.
Ketamine's antidepressant properties have now been appreciated for almost two decades. Several placebo-controlled clinical trials have demonstrated the effectiveness of subanesthetic doses of ketamine (0.5 mg/kg, infused over 40 min) for depression and suicidal ideation in MDD patients resistant to selective serotonin reuptake inhibitors. In depressed patients, ketamine's defining features are its rapid therapeutic onset, measurable at 4 h, and its week-plus-long efficacy after a single infusion. Single infusions of ketamine are associated with a therapeutic response rate of 50%-70% at 1 d after treatment. Repeated treatments have the potential to sustain an antidepressant effect, although the overall response rate appears comparable to single-dose infusions, confirmed by recent results. In an open-label study, repeated injection of ketamine showed a decrease of 69% in suicidal ideation. However, ketamine has significant abuse liability, and its long-term use is associated with notable bladder and neurologic toxicity. The physiological mechanisms for inducing and maintaining ketamine's lasting effects in humans are not yet understood well enough to design similar therapeutics with improved durability and safety. As previously explained, ketamine's antidepressant mechanism has long been attributed to antagonism of the NMDAR and to the activation of mTORC1. However, other NMDAR antagonists have failed to show clinical efficacy comparable to ketamine for MDD, suggesting that the mechanism of action of ketamine as an antidepressant is more complex than its action on NMDARs. More recently, clinical trials testing some of the predictions derived from NMDAR-based models have yielded unexpected results. Concerning the mTORC1 pathway, for example, a recent clinical study demonstrated that peripheral coadministration of rapamycin to treatment-resistant MDD patients enhanced, rather than blocked, the antidepressant effect of ketamine, suggesting a more complex interaction between these drugs in humans. Nevertheless, the mTORC1 signaling pathway is downregulated in the hippocampus and PFC of MDD in postmortem tissue, consistent with this signaling pathway being relevant for the treatment of MDD. Other signaling systems, for example, opioid receptors, may also play a role, which is perhaps unsurprising in light of the diversity of ketamine's pharmacological targets. Shifting our perspective from receptor-based mechanisms to a neural-systems level analysis may provide new directions for optimizing ketamine therapy and developing novel treatments based on ketamine's mechanism. Clinical studies are just beginning to map the similarities between ketamine and other psychedelic-assisted therapies. There is still significant debate regarding the role of the conscious subjective experience (typically described as "dissociation") that patients report during the subanesthetic ketamine infusion regimen. Some studies have linked ketamine's antidepressant potency to its dissociative effectand suggest that conscious awareness and sensory processing are crucial for ketamine's antidepressant effect. On the other hand, some clinical data suggest that dissociation is neither necessarynor sufficientto account for ketamine's efficacy. It is entirely possible that ketamine antidepressant therapy in a medicalized setting is functionally and mechanistically distinct from the emerging practice of ketamine-assisted psychotherapy. MDMA, a psychotropic drug with unique prosocial effects MDMA has emerged as a powerful adjunct to psychotherapy, with growing evidence for efficacy in the treatment of PTSD. This prototypical entactogen is an amphetamine derivative, which primarily releases supraphysiological levels of serotonin, dopamine, and norepinephrine via their respective reuptake transporters (SERT, DAT, and NET). MDMA also stimulates the release of hormones, including oxytocin, vasopressin, and cortisol. A schematic representation of the mechanism of MDMA is shown in Figure. For many years, animal studies of MDMA focused on MDMA-associated neurotoxicity, hyperthermia, psychostimulant effects, and abuse potential, none of which are obviously related to its therapeutic mechanism. While MDMA's therapeutic mechanism is not fully understood, clinical experience indicates that long-lasting benefits are more likely to occur when it is used as an adjunct to psychotherapy rather than as a stand-alone therapy. Widespread adoption of MDMA-assisted psychotherapy may be limited by MDMA's potential for abuse and an incompatibility with selective serotonin reuptake inhibitors. Improving on MDMA as a psychotherapeutic adjunct requires a deeper understanding of the pharmacology and neural dynamics underlying MDMA's therapeutic effect in humans. Toward this end, recent work in rodents has modeled distinct behavioral processes hypothesized to play a role in MDMAassisted psychotherapy. MDMA's hallmark effect is an acutely enhanced feeling of openness, trust, and social connection, all of which may serve to enhance the therapeutic alliance. Similarly, in several species, MDMA can produce an array of affiliative and prosocial behaviors. MDMA may also modify the sensitivity to social reward in mice, an effect lasting weeks after a single dose, reminiscent of the "integration therapy" process after an MDMA experience, wherein a patient is encouraged to consider how emotional shifts in the aftermath of their MDMA session may be integrated into daily life. Finally, MDMA disrupts fear memories in a widely used model for PTSD, wherein a conditioned fear memory is extinguished by re-cueing the memory in a safe context. Investigators consistently find that SERT-mediated 5-HT release is necessary, and potentially sufficient, to account for the putative therapeutic mechanisms of MDMA. Notably, these models' differences could inform human mechanistic trials. Fear extinction does not involve any particular social context, and mouse data suggest that 5-HT release in basolateral amygdala fully accounts for MDMA's effect on fear memory. In contrast, social behavioral models find that 5-HT release in the nucleus accumbens explains MDMA's effects. Various 5-HT receptor subtypes appear necessary, although it is unclear whether any one subtype's activity can reproduce MDMA's prosocial effects. Finally, although MDMA and oxytocin actions overlap, available data in rodentsand humanssuggest that oxytocin receptor signaling is not required for MDMA's acute prosocial effects, but may be involved in longerterm processes initiated by MDMA effects. These studies make clear predictions that it can be tested in clinical experiments, the results of which will both refine our understanding of how clinical MDMA therapy works and improve the accuracy of preclinical models.
MDMA was first administered clinically in the 1970s, at which time there was speculation that the drug acted to "fortify the therapeutic alliance by inviting self-disclosure and enhancing trust". A series of small, uncontrolled studies followed, which together suggested that MDMA was an effective adjunct to psychotherapy, especially in those suffering from anxiety. Research was halted when MDMA was placed on the DEA Schedule 1 list in 1985, and scientific assessment of the compound's therapeutic efficacy did not resume until the mid-1990s. A Phase 1 dose-finding and safety study in MDMA-experienced subjects was conducted shortly thereafterand suggested that a range of doses (0.25-1.0 mg/kg, p.o.) could safely be administered with minimal side effects. More recent data have shown that MDMA commonly induces side effects that include teeth grinding, jaw clenching, headache, lack of appetite, fatigue, dizziness, and nausea but that these are most often mild to moderate and resolve without assistance and shortly after treatment. Additional Phase 1 data are currently being collected (Psychological Effects of Methylenedioxymethamphetamine (MDMA) When Administered to Healthy Volunteers, 2020). While there had been previous concern over the potentially toxic effects of MDMA, the paper reporting widespread dopaminergic and serotonergic neurotoxicity in nonhuman primates turned out to be deeply flawed and was eventually retracted. Early human data indicate that MDMA could be particularly useful in assisting emotional processing and, therefore, recovery in people suffering from PTSD. The first randomized and controlled pilot study found that either two or three administrations of MDMA enabled a significant and long-lasting reduction in PTSD symptoms. Perhaps most intriguing, not only were the effects of MDMA on PTSD symptomology robust, but they also appeared to be extremely durable, lasting for at least 1 year after treatment. Approximately one dozen Phase 2 studies have now been conducted using MDMA in populations with severe, treatment-resistant PTSD, and the results have been consistently encouraging. Pooled analysis from six of these Phase 2 clinical trialsenabled the FDA to grant Breakthrough Therapy status for MDMA treatment of PTSD and has facilitated the initiation of a Phase 3 clinical trial (Multidisciplinary Association for Psychedelic Studies, 2018). A randomized, double-blind, placebo-controlled, Phase 3 study of MDMA-assisted psychotherapy for the treatment of severe PTSD is currently in progress (Multi-Site Phase 3 Study of MDMA-Assisted Psychotherapy for PTSD, 2020). The open-label lead-in data from this Phase 3 trial have shown that MDMA significantly and robustly attenuates several of the prototypical symptoms of PTSD (J. Mitchell, unpublished data). While we must still await final analyses and publication of Phase 3 data, the early trial data suggest that MDMA, in conjunction with psychotherapy, may be a fruitful therapeutic for several complex treatment populations, which lends further credence to the theory that psychedelic medicines could prove to be rapid, long-lasting, novel therapeutics for mental health disorders. Recent data suggest that MDMA may also be efficacious in other clinical populations, including people with autism spectrum disorderand with alcohol use disorder. With respect to alcohol use disorder, safety and tolerability data from a pilot population have already been published, and a Phase 2 clinical trial designed to evaluate changes in alcohol use disorder is currently underway. Although therapeutic facilitation has been shown to clearly influence treatment outcome, more research must still be conducted to determine which therapeutic interaction works best for different clinical populations. Furthermore, although context is known to be an important variable in the therapeutic impact of psychedelics, little work has been conducted to date to unravel the complicated interaction between set and setting and MDMA treatment outcome. In conclusion, in this review, we offered an overview of how different hallucinogens may produce distinct behavioral outcomes with different molecular and neuronal mechanisms of action. All these psychoactive drugs can cause subjective changes in perception, thought, emotion, and consciousness, although with a different mechanism. From preclinical studies, it is clear that the mechanism of hallucinogens is more complex than thought before since their effects on the 5-HT and glutamatergic system as well as their capacity to modulate transcriptional mechanisms seem to emerge very clearly (for review, see. Importantly, clinical studies have demonstrated the effects of ketamine in treatment-resistant MDD. Moreover, a double-blind, placebo-controlled clinical trial has shown the use of MDMA associated to psychotherapy in PTSD. In addition, open-label studies and double-blind studies have demonstrated the effects of psylocibin in depression and anxiety, even if a recent meta-analysis suggests that more studies are needed to demonstrate its efficacy. Intriguingly, the potential use of psilocybin in alcohol use disorder and obsessive-compulsive disorder seems also promising, and several clinical trials are ongoing (Clinical and Mechanistic Effects of Psilocybin in Alcohol Addicted Patients, 2020; Efficacy of Psilocybin in OCD: a Double-Blind, Placebo-Controlled Study, 2020). Finally, LSD showed promising results in patients with depression and anxiety, and clinical trials are ongoing for MDD (for review, see. Along with the potential use of hallucinogenic compounds in the clinic, it is undeniable that they also represent an important tool to better understand the neuronal circuitries, brain connectivity, pharmacological targets, and signaling cascades behind the pathology of mental disorders.
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