This (2021) review presents the neurobiological therapeutic mechanisms by which psychedelics work, with a focus on outcomes on 1) neuroplasticity, 2) immune system, and 3) effects on neurotransmitter (-modulator) systems.

Abstract

“Mounting evidence suggests safety and efficacy of psychedelic compounds as potential novel therapeutics in psychiatry. Ketamine has been approved by the Food and Drug Administration in a new class of antidepressants, and 3,4-methylenedioxymethamphetamine (MDMA) is undergoing phase III clinical trials for post-traumatic stress disorder. Psilocybin and lysergic acid diethylamide (LSD) are being investigated in several phase II and phase I clinical trials. Hence, the concept of psychedelics as therapeutics may be incorporated into modern society. Here, we discuss the main known neurobiological therapeutic mechanisms of psychedelics, which are thought to be mediated by the effects of these compounds on the serotonergic (via 5-HT_2A and 5-HT_1A receptors) and glutamatergic [via N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors] systems. We focus on 1) neuroplasticity mediated by the modulation of mammalian target of rapamycin-, brain-derived neurotrophic factor-, and early growth response-related pathways; 2) immunomodulation via effects on the hypothalamic-pituitary-adrenal axis, nuclear factor ĸB, and cytokines such as tumour necrosis factor-α and interleukin 1, 6, and 10 production and release; and 3) modulation of serotonergic, dopaminergic, glutamatergic, GABAergic, and norepinephrinergic receptors, transporters, and turnover systems. We discuss arising concerns and ways to assess potential neurobiological changes, dependence, and immunosuppression. Although larger cohorts are required to corroborate preliminary findings, the results obtained so far are promising and represent a critical opportunity for improvement of pharmacotherapies in psychiatry, an area that has seen limited therapeutic advancement in the last 20 years. Studies are underway that are trying to decouple the psychedelic effects from the therapeutic effects of these compounds.“

Authors: Antonio Inserra, Danilo De Gregorio & Gabriella Gobbi

Summary

Psychedelic Compounds as Novel Therapeutics in Psychiatry: Overview and Comparison with Current Available Treatments, Neuroplasticity Impairments in Psychiatric Disorders, Effects of Psychedelic Compounds on Neuronal and Synaptic Plasticity, Immunomodulatory and Anti-Inflammatory Pathways Activated by Psychedelics, and Ongoing Clinical Trials.

Psychedelic compounds modulate neurotransmitter systems, including serotonin, dopamine, glutamate, GABA, and norepinephrine. These compounds include ketamine, Lysergic Acid Diethylamide, 3,4-Methylenedioxymethamphetamine, and Ayahuasca.

A. Review Outline

In the last 30 years, psychedelic compounds have been used in psychiatry for treatment-resistant disorders such as PTSD and MDD. Recently, ketamine was approved by the FDA as a first in a new class of antidepressants.

Psychedelics are a new class of therapeutic tools that can improve psychiatric symptoms but can also elicit profound changes in consciousness and perception. Specialized therapist training may be needed should this type of treatment become more widely used.

To elicit significant improvements in psychiatric symptoms, patients need to undergo a psychological journey therapy, which involves administration of a compound once or twice over a few weeks, preceded and followed by preparation and integration sessions with a trained therapist. Ideally, further psychotherapeutic integration sessions should be available to process issues that might arise and provide guidance on how to cultivate lifestyle and cognitive adjustments. This is especially relevant given that antidepressant responses are enhanced by an enriched environment but can be counteracted by a stressful one. Here, we discuss the neurobiology of psychedelic compounds, focusing on compounds that have been, or could soon be, classified as novel psychiatric medications. We will draw parallels between psychedelic compounds and current psychiatric pharmacotherapies.

B. Psychiatric Disorders and the Need for Novel Pharmacotherapies

Individuals diagnosed with a psychiatric disorder have increased odds to develop comorbid systemic illnesses, and epigenetic modifications may play a role in the current psychiatric epidemics. Therefore, the development of novel therapeutic strategies is of paramount importance to the current public health system.

C. Psychedelic Compounds as Novel Therapeutics in Psychiatry: Overview and Comparison with Current Available Treatments

Psychedelic compounds may hold potential as therapeutics for psychiatric disorders, including depression, anxiety, pain, and distress associated with a life-threatening illness. Preliminary evidence suggests that ketamine, psilocybin, and ayahuasca may be effective for these disorders.

First-line treatments for unipolar depression, anxiety, PTSD, and OCD include selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). Second-line treatments include second-generation (atypical) antipsychotics acting on 5-HT2A, 5-HT1A, and D2 receptors.

Second-generation (or atypical) antipsychotics are used for the long-term treatment of psychoses, including schizophrenia. They have a mixed DA/5-HT2A/1A receptor pharmacological profile, including antagonist action at the level of 5-HT2A receptors or partial agonism at the level of D2 receptor.

Psychedelic compounds and routinely prescribed psychiatric drugs interact with one or more 5-HT receptors or with the 5-HT transporter (SERT), and both increase 5-HT synaptic availability and inhibit dorsal raphe nucleus (5-HT) cell firing.

Ayahuasca users have decreased 5-HT2A receptor expression, suggesting that ayahuasca may affect the homeostasis of the 5-HT system via downregulating 5-HT2A receptor expression. Atypical antipsychotics are potent 5-HT2A/2C receptor antagonists, while most psychedelics are 5-HT2A receptor agonists.

Although the mechanism of action of SSRIs and psychedelics appears somewhat similar, the timing of therapeutic improvement elicited by psychedelics and routinely approved antidepressants is different. This difference may be explained by the shorter delay required by psychedelics to induce therapeutic improvements.

Studies on psychedelic compounds have yielded encouraging results, suggesting that these compounds could have a place in the treatment of several psychiatric disorders. However, their classification as schedule 1 substances in the United States hinders their potential application in psychiatry and medicine.

Steps that might reconcile the duality between the risks and benefits of using these compounds in psychiatry include increased preclinical and phase I to III clinical trials, an evidence-based approach by legislators and funding bodies, and priority funding dedicated to answering such questions through evidence-based scientific investigations.

D. Classical or Serotonergic Psychedelics versus Nonclassical Psychedelics: Definition

The definition of psychedelics is still based on a classification from the 1960s, and many compounds are still being studied. Serotonergic psychedelics include the semisynthetic ergoline LSD, plant-derived tryptamines, and phenethylamine-based synthetic designer drugs.

Serotonergic psychedelics are mostly found in nature, but can also be created in a laboratory by modifying natural psychedelics. Their pharmacology involves several receptor families, homo- and heteroreceptor complexes, and biased intracellular cascades.

LSD, psilocybin, and ayahuasca are semisynthetic ergosterols derived from naturally occurring ergot alkaloids. These alkaloids are tricyclic indole alkaloids that resemble tryptamines and are used as monoamine oxidase inhibitors to render DMT orally active.

E. Dissociative Anesthetics

Dissociative anesthetics are compounds that trigger psychedelic-like effects and a dissociative-like state, which partly resembles the anesthetic state. Esketamine is one of the most known dissociative anesthetics.

Ketamine is a phenylcyclohexylamine derivative that has been approved by the FDA for treatment-resistant MDD. It also possesses analgesic activity and may interact with the serotonergic, opioidergic, and endocannabinoid systems.

F. Empathogens-Entactogens

A third class of compounds structurally related to psychedelic phenylethylamines has been termed empathogen-entactogens. These compounds have been broadly examined in psychotherapy augmentation in the context of PTSD, and potential effects on fear extinction and memory reconsolidation have been suggested.

G. Full Dosing versus Microdosing

Most human studies so far have used “full psychedelic doses,” which elicit profoundly altered states of consciousness. Microdosing, which elicits minimal or no psychoactive effects, has emerged as an alternative therapeutic approach, but the lack of supporting clinical research has prompted some researchers to demystify these beliefs.

LSD and psilocybin are the most used substances for microdosing among the general population, and preliminary evidence suggests that this approach might be more easily managed by naive patients compared with full doses and better received by psychiatrists who have no experience in dealing with psychedelic effects.

Psychedelic 5-HT2A receptor agonists have been shown to have powerful anti-inflammatory effects in both in vivo and in vitro paradigms, and preliminary findings suggest that microdoses of these compounds may be useful for the treatment of comorbid depression and PTSD.

Preclinical findings support the notion that microdosing might have anxiogenic and neurotic effects, induce confusion, and hinder synaptic plasticity, which are undesirable effects in psychiatry.

Preliminary data suggests that 1 in 5 patients experience physical discomfort and 1 in 10 experience anxiety when microdosing serotonergic psychedelics. The repeated stimulation of cardiac 5-HT2B receptor might increase the likelihood of developing cardiovascular disease.

Although promising results have been obtained so far, there is not enough available evidence to support the use of microdosing for therapeutic purposes. Further larger RCTs are needed to determine the safety, efficacy, and tolerability of this type of treatment.

H. Historical Studies

Between the 1950s and 1970s, hundreds of human studies involving tens of thousands of people were performed with psychedelic compounds. These studies focused on psychotherapy augmentation, schizophrenia research, trauma retrieval, social impairments, alcoholism, neurosis, cognitive enhancement, and nonbinary sexuality.

I. Ongoing Clinical Trials

Psychedelics may improve mood disorders, suicidality, and emotional distress, and may also produce positive personality changes, brain activity changes, and long-term neuromorphologic changes.

Esketamine has been approved by the FDA as a medication for treatment-resistant depression, and there are currently 260 clinical trials investigating the effects of ketamine on several disease states, including suicidality, treatment-resistant MDD, bipolar disorder, ASD, borderline personality disorder, cluster headaches, epilepsy, asthma, renal colic, and opioid, alcohol, cocaine, marijuana, and cigarette use.

MDMA induces a relaxed euphoric state, feelings of emotional openness, enhanced empathy, and disinhibition, which can be used as an augmenting agent in psychotherapy for PTSD survivors and for the treatment of ASD and alcohol abuse disorder.

Psilocybin has shown promising results in studies of treatment-resistant depression, tobacco addiction, OCD, anxiety and distress associated with a life-threatening illness, and chronic cluster headache, migraine headache, and post-traumatic headache.

LSD has been investigated in RCTs for its anxiolytic properties, and it seems to help patients with a potentially life-threatening illness elaborate and accept the emotions connected to their potentially terminal illness.

Ayahuasca and DMT have been shown to rapidly relieve depression symptoms in treatment-refractory depression in controlled clinical settings, and 5-MeO-DMT may be beneficial for drug and alcohol addiction.

A. Neuroplasticity Impairments in Psychiatric Disorders

Neuroplasticity is the ability of the nervous system to respond to internal and external stimuli via a remodulation of its physical structure and functional connections. Dysregulation of neuroplasticity can lead to detrimental adaptive changes and the development of psychiatric disorders.

Psychiatric disorders share neuroplasticity impairments, such as the reduction in hippocampal and cortical volumes, and the progressive prefrontal atrophy observed in patients with PTSD who had worsening symptoms. However, condition-specific symptoms are associated with discrete neuromorphologic changes.

Neurogenesis is an essential step to achieve antidepressant outcomes in animal models and humans, and its blockade leads to the development of depressive-like behavior. Psychedelic compounds may be useful in treating neurodegenerative disorders and elderly populations with neurodegenerative disorders.

BDNF is a prototypical neurotrophin in the brain that interfaces stress susceptibility, psychiatric disorders, and antidepressant response. BDNF levels are decreased across psychiatric disorders and correlate with suicidal behavior, and pharmacological antidepressant therapies, sleep, and physical exercise increase BDNF levels. Preclinical models indicate that individual susceptibility to PTSD might be caused by sustained transcriptional downregulation of BDNF, which is mediated by epigenetic processes such as DNA methylation and histone acetylation.

BDNF enhances AMPA receptor delivery to the synapse, which might be involved in the psychedelic-induced, BDNF-mediated enhancement of neural plasticity elicited by psychedelic compounds. This effect could be exploited to achieve desirable outcomes in the treatment of psychiatric disorders.

Psychedelics increase neuronal and synaptic plasticity through mammalian target of rapamycin (mTOR) and BDNF-NTRK2 signaling, and may be involved in the psychiatric improvements observed in clinical trials.

Ketamine induces rapid, robust, and sustained antidepressant effects at least partially via activating mTOR, a key intracellular signaling pathway altered in MDD and other psychiatric disorders, such as ASD and SCZ. This may well translate to network plasticity.

Ketamine interacts with S1R and S2R, key signal transducers of neuroplastic and neurotrophic pathways, and may be involved in the antidepressant effects elicited by ketamine. Ketamine might alter the AMPA/NMDA receptor density ratio to enhance synaptogenesis via upregulating mTOR/BDNF signaling.

Neuroplastic effects have been observed in response to ayahuasca, 5-MeO-DMT, and other nonpsychedelic S1R agonists. These effects might mediate therapeutic improvements in response to psychedelics.

Ayahuasca alkaloids modulate S1Rs, which might represent a synergistic mechanism to 5-HT2A receptor modulation by psychedelics, and induce adaptive neuroplasticity. The b-carbolines harmol, harmine, harmaline, and tetrahydroharmine also induce differentiation, proliferation, and migration of neural precursors.

LSD increases BDNF levels in healthy volunteers, upregulates CCAAT/enhancer-binding protein-b in the prefrontal cortex, and increases cFOS, Egr-1, and Egr-2 in murine primary neuronal cultures. This action of LSD on S1R might be involved in the clinical improvements of drug-induced cognitive impairments.

LSD, DOI and S1R form heterodimers with D2 receptors, and this interaction may boost neurogenesis. The EGR family of transcription factors is involved in synaptic plasticity, neurogenesis, and the pathologic processes underlying psychiatric symptoms.

Psilocybin increases the expression of several genes in the prefrontal cortex and hippocampus, including CEBPB, c-Fos, dual specificity protein phosphatase 1, transcription factor jun-b, NF-kappa-b inhibitor-a (Ikba), nuclear receptor subfamily 4 group A member 1, and postsynaptic density protein 95.

The debate on the neurotoxicity of MDMA creates a long-standing divide. However, human studies indicate damaging effects on SERT homeostasis in heavy MDMA users, and sparing use of relatively low doses employed in MDMA-augmented psychotherapy elicits notable improvements in treatment-refractory PTSD symptoms.

Several metabolites from MDMA metabolism seem to be responsible for the neurotoxic effects of MDMA, given that direct intracerebroventricular administration of MDMA does not elicit neurotoxicity.

If further studies determine that MDMA administration in humans at clinically relevant doses induces neurotoxic effects, strategies could be implemented to protect against these effects.

A. Inflammation

Inflammation is a strong but short-lived cascade of events that are mobilized in response to stressful stimuli. It can cause collateral damage if the process is too violent or if it does not reach resolution within a reasonable spatiotemporal frame.

B. Inflammation-Induced Psychiatric Symptoms

Increased proinflammatory signaling in the brain results in the development of depressive-like symptoms, and dysregulated reactivity of immune cells accompanied by increased levels of central proinflammatory mediators such as IL1b, IL6, TNF-a, C-reactive protein, and the translocator protein (TSPO) correlate with symptom severity.

Patients with MDD and PTSD present a systemic low-grade chronic inflammatory state driven by a shift of immune responses toward T-helper (Th) 1 and decreased T-regulatory cell activity. Psychedelics may be able to shift this balance in favor of an enhancement of Th2 responses, which may help ameliorate psychiatric symptoms.

Inflammatory treatments are being tested as adjunctive therapies in psychiatry, with mixed results. Minocycline, a second-generation, semisynthetic tetracycline with anti-inflammatory properties, seems to be a promising adjunctive in patients with MDD, SCZ, and BD and dysregulated inflammation, potentially via its acute effects on inflammatory mediators and long-term effects over gut microbiome composition.

D. Immunomodulatory and Anti-Inflammatory Pathways Activated by Psychedelics

Psychedelic compounds activate immunomodulatory and anti-inflammatory programs mediated at least partially by 5-HT2A receptor agonism. These effects are likely involved in the anxiolytic and antidepressant effects elicited by psychedelics, and they suggest that psychedelics might be useful in “inflammaging” (conditions caused or exacerbated by age-induced chronic inflammation).

N,N-Dimethyltryptamine, 5-Methoxy-N,N-dimethyltryptamine, and Ayahuasca have been shown to have strong anti-inflammatory effects, which may be similar to the anti-inflammatory effects of some SSRIs, SNRIs, and tricyclic antidepressants, and the antidepressant outcome of some anti-inflammatory therapies.

Psychedelics may be used to treat systemic inflammatory response syndrome, a condition in which the immune system is shifted toward proinflammatory responses. This may be achieved by decreasing proinflammatory cytokines in microglial cells.

A study investigating proteomics changes in brain organoids in response to 5-MeO-DMT reported that NF-B and nuclear factor of activated T cells were down-regulated via toll-like signaling and Gq-coupled receptors, and that cortisol release was modulated, which is quite remarkable given the well characterized dysregulation in psychiatric disorders.

Psilocybin was shown to increase the levels of stress hormones such as ACTH and cortisol, but not anxiety, leading the authors to speculate that this was likely due to a transient activation of the HPA axis.

Lysergic Acid Diethylamide (LSD) is an entheogen that possesses anti-inflammatory activity in vitro and increases circulating cortisol, cortisone, corticosterone, prolactin, oxytocin, and epinephrine in humans. However, there are no reports on potential long-term immunomodulatory outcomes of LSD.

DOI is a 5-HT2A/2C receptor agonist that is powerfully anti-inflammatory and can be elicited with very low doses. It decreases TNF-a, IL1b and IL6, intracellular adhesion molecule-1, vascular cell adhesion molecule-1, monocyte chemoattractant protein 1 (MCP1), and fractalkine. A recent study suggests that DOI may be useful for the treatment of systemic inflammatory conditions, such as high-fat diet-induced cardiovascular dysfunction.

MDMA influences both the innate and adaptive arms of the immune system, and increases cortisol and prolactin levels, as well as inflammatory mediators, while decreasing CD4+ helper T cells and increasing natural killer cells, potentially as a result of increased HPA axis activation.

PTSD is characterized by an inflammatory state, a shift of cytokine production from Th2 to Th1, and chronic lymphocyte activation. MDMA might decrease the immune reactivity and therefore the damaging potential of immune cells in patients with PTSD.

Ketamine upregulates IL1b, IL6, and TNF-a, and decreases TNF-a chronically. This may be why ketamine is effective in treating psychiatric symptoms, and also why ketamine might activate necroptotic pathways that mediate fear extinction and memory reconsolidation.

Psychedelics may be involved in the antidepressant and anxiolytic effects observed in psychiatric populations via pushing the system toward a homeostatic state and ameliorating psychiatric symptoms.

E. s1 Receptor

Most compounds discussed here interact with the 5-HT system, but also with the S1R, a still-mysterious receptor whose origin remains puzzling. This suggests that the action of these compounds at S1R might be more relevant than previously thought. The S1R receptor is highly expressed in limbic areas of the human brain and in several central and peripheral immunocompetent cells, and ibogaine is the only psychedelic to have its highest affinity at this receptor. Recently, evidence of endogenously produced DMT was found in the human brain.

S1R is a protein that can be membrane-bound at the cell membrane, bound to the mitochondria-associated endoplasmic reticulum membrane, or bound to chromatin remodeling complexes at the nuclear envelope. Its activation elicits antiamnesic effects in animal models and enhances synaptic stability and plasticity in vitro.

S1R dysregulation is implicated in neurodegenerative, psychiatric, and systemic illnesses, and S1R modulation elicits prohomeostatic, neuroprotective, and immunomodulatory outcomes, suggesting that therapeutic S1R stimulation could hold promise in the treatment of these disorders.

A. Neurotransmitter Dysfunctions in Psychiatric Disorders

Psychedelic compounds have profound modulatory outcomes on serotonergic, norepinephrinergic, dopaminergic, glutamatergic, and GABAergic systems, which are of great relevance to psychiatry.

B. Serotonin

Serotonin modulates an ample spectrum of physiological and pathological behaviors, and a chronic 5-HT depletion state is a common feature of psychiatric disorders. Compounds that increase synaptic 5-HT availability have represented the core of psychiatric pharmacotherapy so far.

Lysergic Acid Diethylamide (LSD) is a 5-HT2A and 5-HT1A receptor partial agonist, and it increases firing and burst activity in the DRN via a mechanism mediated by 5-HT1A, D2, and TAAR receptors, resembling classic antidepressants. LSD is an agonist at the 5-HT2B receptor and a partial agonist at the 5-HT2C receptor. It also acts at the 5-HT1B, 5-HT1D, 5-HT1E, 5-HT6, and 5-HT7 receptors.

Although in vitro studies have reported no interaction with SERT, in vivo investigations have reported decreased LSD effects in Sert null mice, and long-term psychedelic users have increased SERT binding. The 5-HT2A-mGluR2 complex is necessary for fear extinction, and for social feedback processing.

MDMA is metabolized by several pathways into 14 metabolites, including MDA, 3,4-dihydroxymethamphetamine, N-methyl-a-methyldopamine, and 6-HO-MDMA. These metabolites all interact with the 5-HT system, making it difficult to separate the effects of one from the other.

MDMA is a 5-HT2A receptor agonist that causes an increase in extracellular 5-HT in the mPFC, striatum, NAc, and hippocampus. Repeated MDMA administration decreases 5-HT concentration in the striatum. MDMA is a weak 5-HT1A receptor agonist that causes a postsynaptic upregulation of this receptor in the cortex and hypothalamus. This upregulation is disrupted by the administration of a 5-HT reuptake inhibitor, suggesting an inhibitory effect of MDMA on SERT. MDMA use is associated with decreased SERT density, but abstinence time and SERT density correlate positively, suggesting that these alterations are reversible to extents to be determined.

The modulation of SERT by MDMA has implications in psychiatry, as SERT abundance has a dramatic impact on synaptic 5-HT and behavior. Therefore, MDMA-induced SERT modulation could be exploited therapeutically, for example, in the treatment of ASD.

MDMA has an inhibitory effect on the production of 5-HT via decreasing tryptophan hydroxylase activity, and also exerts an inhibitory effect on monoamine oxidase A and monoamine oxidase B. Repeated MDMA administration causes long-lasting depletion of cortical, hippocampal, and striatal 5-HT.

DMT, a psychedelic tryptamine, stimulates 5-HT release and inhibits its reuptake via interacting with SERT, the vesicular monoamine transporter 2, and the 5-HT1A,5-HT1D,5-HT1E, 5-HT2B,5-HT5A, 5-HT6, and 5-HT7 receptors. It also inhibits 5-HT firing in the DRN.

The tricyclic indole alkaloids harmol, harmine, harmaline, and tetrahydroharmine are obtained from B. caapi (ayahuasca) and function as MAOIs to block the metabolism of DMT, rendering it orally active. They might be involved in the fast-onset antidepressant effects of ayahuasca in treatment-resistant MDD.

Preclinical studies suggest that DMT and ayahuasca modulate neurotransmitter release in the hippocampus and amygdala, and that ayahuasca decreases neurotransmitter turnover in the hippocampus and amygdala. These findings are relevant to psychiatry.

DMT is a selective SERT releaser, whereas 5-MeO-DMT inhibits synaptosomal 5-HT reuptake. SERT polymorphisms could be investigated as predictors of positive/negative outcomes and experience intensity given that low- and high-expressing SERT genotypes have different psychopharmacological profiles.

Ketamine enhances the release of 5-HT in the DRN and mPFC, activating the 5-HT/PFC system through an AMPA receptor – independent mechanism. Its antidepressant effects are elicited via a 5-HT – dependent mechanism. Ketamine’s antidepressant effects are thought to be mediated by 5-HT1B and 5-HT2C receptor activation, as well as by increased 5-HT and NE efflux to the mPFC, which excites DRN neurons both directly and indirectly, via DRN efferents.

Psilocybin decreases DRN/5-HT firing, and serotonergic and dopaminergic activity are mutually regulated. Psilocybin binds to human serotonin receptors 5-HT1A,5-HT2A,and5-HT2B, and enhances DA neurotransmission via 5-HT.

Psilocybin modulates mood states and emotional face recognition by 5-HT2A receptors, and decreases 5-HT reuptake by inhibiting SERT. It also interacts with 5-HT1A, 5-HT1D, 5-HT1E, 5-HT2B, 5-HT2C, 5-HT5,5-HT6, and 5-HT7 receptors, although it is not known whether these interactions produce a clinically relevant effect.

C. Dopamine

Although psychedelics are mainly associated with their action over the serotonergic system, there are important interactions (direct and/or indirect) with the dopaminergic system that might mediate at least some of the therapeutic (and also the side effects) of psychedelic compounds.

Ketamine is thought to restore DA activity and synaptic plasticity, at least partially, via D1 activation in the NAc, and this might relate to its therapeutic effects in patients with treatment-resistant depression. Ketamine increases dopamine release in the mPFC and enhances striatal dopamine release, and attenuates ketamine-induced dopamine release in the mPFC and striatum. It also restores the stress-induced dopaminergic dysfunction in the VTA.

LSD is a DA D1 D2 D4 receptor agonist and modulates DA neurotransmission in a biphasic, dose-dependent fashion via a multireceptorial mechanism involving D2, 5-HT1A, and TAAR1 receptors.

MDMA stimulates dopaminergic neurotransmission by reversing the direction of the DA transporter, increasing synaptic DA availability, and inhibiting DA nigrostriatal and mesolimbocortical reuptake. MDMA induces DA release in the striatum, and repeated administration decreases DA concentration. MDMA also possesses weak D1 and D2 receptor affinity, and these effects are involved in MDMA-induced hyperlocomotion and dopaminergic toxicity.

MDMA increases available 5-HT and DA levels, which is partially responsible for the increased release of DA. However, at clinically relevant doses, the increase in DA levels is minimal, suggesting that abuse concerns are not so relevant at clinical doses.

Ayahuasca, DMT, and 5-MeO-DMT increase dopamine levels and decrease dopamine turnover in the amygdala and whole brain, respectively, which might be involved in the amelioration of suicidality and addiction behaviors by modulating reward-related circuitries.

Psychedelics and entactogens involve the DA system in mediating reward responses and developing addiction. Future studies must clarify whether psychedelics affect reward-related pathways and whether this represents a concrete danger for abuse.

D. Glutamate

Glutamate is involved in excitatory neurotransmission, synaptogenesis, synaptic plasticity, memory, mood, and cognition. It can act via NMDA receptors, AMPA receptors, or metabotropic receptors, and dysfunction of the glutamatergic ionotropic receptor NMDA can be triggered by repeated stress.

The glutamatergic system drives the frontal hypermetabolic state induced by psychedelics, which also correlates to therapeutic efficacy and enhanced neurotrophic activity. NMDA receptor hypofunctioning is thought to be involved in the pathogenesis of SCZ.

LSD elevates glutamate via stimulating postsynaptic 5-HT2A receptors on pyramidal cells in deep cortical layers, and this effect is reversed by 5-HT2A receptor antagonists, AMPA receptor antagonists, selective antagonists of the NR2B subunit of NMDA receptors, and positive mGluR2 allosteric modulators.

Psilocybin administration causes a region-specific hypermetabolic state, especially in the frontolateral and frontomedial cortices. Psilocybin and ketamine together can cause antidepressant-like effects comparable to those of fluoxetine.

Ketamine and its metabolite norketamine act via NMDA receptor antagonism to elicit antidepressant effects and to enhance synaptogenesis in the PFC. It is likely that the increase of AMPA receptors over NMDA receptors in cortical circuits is responsible for the onset of antidepressant effects.

Ketamine increases cortical excitability and glutamate release, and this action correlates with improvement of psychiatric symptoms. Ketamine is metabolized to hydroxynorketamine, which has antidepressant effects mediated by early and sustained activation of AMPA receptor, independently from NMDA receptor. Ketamine administration increases firing and bursting in the locus coeruleus and VTA, decreases firing activity in PFC GABAergic interneurons, and enhances striatal dopamine release. Ketamine also blocks NMDA receptor – mediated burst firing in the lateral habenula, disinhibiting monoaminergic reward centers and rapidly relieving depression.

3,4-Methylenedioxymethamphetamine increases glutamate release in the anteromedial striatum and dorsal hippocampus, and inhibits neuronal firing in the NAc similarly to 5-HT and DA.

MDMA use during adolescence leads to neuroadaptive changes in glutamatergic-related gene expression in corticolimbic structures, which may be involved in the neurotoxic effects of MDMA binge use and repeated use in individuals of young age.

Ayahuasca, DMT, and 5-MeO-DMT have been shown to decrease glutamate levels in the hippocampus and amygdala in rats, and this may be why people who ingest psychedelics multiple times during their lifetime have a lower incidence of alcohol and substance use disorder.

E. GABA

GABA is the main inhibitory neurotransmitter in the adult brain, and it is involved in many physiological processes such as pain modulation and serotonergic modulation of cortical networks. It is also involved in the acute and potentially long-term effects of psychedelic compounds.

Ketamine has been shown to modulate GABAergic populations within the CSTC circuit, including a disruption of RT activity. The antidepressant effects of ketamine require the modulation of GABAA and GABAB receptors in discrete networks of cortical PV+ GABAergic interneurons. Ketamine affects neurotransmission in the thalamocortical circuit via NMDA receptor blockade, which leads to increased DA release and decreased burst activity, which is reminiscent of SCZ.

This circuit is implicated in the generation of consciousness, dysfunctional in psychiatric conditions, and targeted by psychedelics, suggesting that it is at the therapeutic core of psychedelics.

LSD and DOI are partial agonists at 5-HT2A receptors in cortical interneurons and activate cortical GABAergic interneurons. DOI also upregulates PV expression in cFOS+ GABAergic interneurons in the mPFC and somatosensory cortex.

MDMA increases GABA efflux in the VTA and decreases GABA efflux in the substantia nigra, and modulates GABA-related gene expression in a specific spatiotemporal fashion. This effect is attenuated by pretreatment with the anti-inflammatory ketoprofen.

Psilocybin might act on 5-HT2A receptors on GABAergic interneurons in the striatum and NAc to modulate psychedelic-induced, 5-HT mediated dopaminergic effects, as is the case for DOI and LSD.

Ayahuasca increases GABA levels in the hippocampus and amygdala, which could be involved in the retrieval of repressed traumatic memories experienced by some individuals who ingest ayahuasca.

F. Norepinephrine

The neuromodulatory NE system, which regulates crucial functions such as cognition, emotions, stress responses, learning, memory, behavioral flexibility, sleep/wake cycle, heart rate, digestion, respiration, and sexual arousal, might play an important role in both the acute effects of psychedelics, dissociative anesthetics, and entheogens.

The LC contains the majority of NE neurons and plays an important role in determining stimuli salience and optimizing performance. The NE system is dysfunctional in stress-induced psychiatric disorders and can be treated with tricyclics or serotonin-norepinephrine reuptake inhibitors.

Ketamine and PCP increase NE release and inhibit its reuptake, and ketamine potentiates the contraction-inducing effects of NE on vascular adrenergic neurons. Ketamine also attenuates the cardiodepressant effects of the a2-adrenoceptor agonist dexmedetomidine.

Ketamine and PCP were shown to inhibit NE reuptake in NE neurons of the rat cortex, but ketamine had a lower inhibitory activity. Ketamine may affect NET through a direct action at the desipramine binding site of NET or an indirect effect through NMDA receptors over NET.

MDMA is an a2-adrenergic receptor agonist and interacts with NET, inhibiting NE reuptake, and increasing NE release. The b-adrenergic receptor antagonist propranolol and the a1- and b-adrenergic receptor antagonist carvedilol attenuate the cardiostimulatory effects of MDMA.

A study found a weak correlation between NET polymorphisms and the cardiostimulatory effects of MDMA, including greater heart rate elevations in subjects carrying the GG genotype and decreased arterial pressure elevations in subjects carrying the AA genotype.

LSD is an a2-adrenoceptor agonist and increases the firing rate of some, but not all, LC/NE neurons. It also potentiates the response to stimuli that normally excite LC/NE neurons and attenuates the vascular and cardiac responses mediated by a- and b-adrenoceptor activation. LSD was reported to facilitate neuronal excitation in the rat facial motor nucleus and to decrease brainstem NE levels, suggesting that NE projections from the LC may indeed be relevant for the behavioral effects of LSD.

Psilocybin, an a2-adrenoceptor agonist, decreases available NE levels by up to 25% in the rat brain in the 4 hours after administration, and increases normetanephrine, a product of NE turnover, by over 2-fold 1 hour after psilocybin administration.

DMT was reported to potentiate the effects of 5-HT and NE in the facial nucleus in rats, but no effect was found on NE turnover. Ayahuasca administration increased NE levels in the amygdala but not the hippocampus. Ayahuasca administration increased the urinary excretion of normetanephrine, and 5-MeO-DMT was shown to suppress NE reuptake and increase its turnover, suggesting that 5-MeO-DMT might elicit analgesic effects via modulating the NEergic system.

G. Oxytocin

Although beyond the scope of this work, oxytocin is a neurotransmitter hormone involved in sociability and anxiety that is dysregulated across psychiatric disorders. It is thought to mediate at least partially the empathogenic, antidepressant, and anxiolytic effects elicited by psychedelic compounds and SSRIs.

MDMA, LSD, and DOI increase OT levels, and may benefit patients with ASD. Clinical studies are investigating the utility of these compounds on ASD. OT augmentation in psychotherapeutic settings is beneficial for depression and PTSD, and it has been reported that MDMA leads to an OT-dependent reopening of long-term depression in the NAc. Moreover, OT may be useful for migraine headaches and cluster headaches.

Several lines of evidence suggest that ligands can stabilize different receptor active states, leading to different interactions with cellular signaling proteins, thus leading to the selective activation of some signaling pathways over others.

A therapeutic point of view, it is important to identify molecules that selectively activate a specific therapeutic pathway, avoiding side effects. For example, opioids like morphine are commonly used to treat pain, but prolonged treatment leads to tolerance and related opioid use disorder. Recent in vitro studies evaluated novel and promising MOR-biased ligands and found that they display improved safety profiles compared to existing opioid compounds. However, the potential clinical use of these compounds remains uncertain. TRV027, a biased ligand of the angiotensin II type 1 receptor, was tested in patients with acute heart failure, but did not improve the clinical status.

LSD binding to 5-HT2A and 5-HT2B receptors causes conformational changes that contribute to the long half-life and slow dissociation rate of LSD, as well as to the strong functional selectivity for b-arrestin signaling over Gq signaling. A study conducted in mouse embryonic fibroblast derived from wild-type and b-arrestin knockout mice demonstrated that serotonin produces 5-HT2A receptor internalization via b-arrestin coupled to protein kinases 1 and 2 (Erk1/2) phosphorylation activation. However, DOI and LSD do not promote phosphoinositide hydrolysis signaling. A stable HEK 293 T-cell based bioassay was developed to monitor b-arrestin 2 recruitment to the 5-HT2A receptor, and was used to characterize 30 phenylalkylamine psychedelics.

B. Psychedelics and Homo- and Heteroreceptor Complexes

Biased signaling occurs at individual receptors, but also at homo- and heteroreceptor complexes, where multiple GPCRs interact and alter the repertoire of potential ligands and affinity for intracellular signal transduction proteins.

The mechanism for the functional interaction between 5-HT2A and mGluR2 receptor signaling is not completely understood, and the existence of a heterodimer complex between these two receptors in a recombinant system is not necessarily an evidence and justification for its occurrence in vivo.

Psychedelic compounds interact with heteroreceptor complexes in the cortical sensory gating and trigger psychedelic-specific patterns of gene expression. These gene expression changes differ profoundly from those elicited by non-psychedelic 5-HT2A receptor agonists.

Psychedelics interact with the 5-HT2A receptor of a 5-HT2A-D2L complex, which favors D2 receptor signaling to canonical Gi/o-mediated 5-HT2A receptor signaling. A 5-HT2A-D3 heteroreceptor complex may also exist, and antipsychotic drugs favor this signaling pathway.

5-HT1A-5-HT2A isoreceptor complexes have been described in the pyramidal cell layer of the dorsal hippocampus and in the ACC. These complexes are stress-responsive and represent a potential driving mechanism in psychiatry disorders and a candidate therapeutic target for drug discovery.

Other 5-HT isoreceptor complexes have been characterized, including the heterodimers 5-HT2A-5-HT2C and 5-HT1A-5-HT7 and the homodimers 5-HT1A-5-HT1A and 5-HT7-5-HT7. Whether psychedelics bind to these complexes remains to be determined.

C. Psychedelic-Induced Biased Phosphoproteomics

Psychedelic-specific phosphoproteomic changes have been reported, including a hyperphosphorylated intracellular residue relevant for 5-HT2A receptor desensitization and internalization elicited by psychedelic (as opposed to nonpsychedelic)

The psychedelic-stabilized 5-HT2A receptor conformation might modulate protein kinase C access, leading to a psychedelic-specific phosphorylation fingerprint. This could be a key molecular interaction mediating the psychedelic crosstalk between these two receptors and might be involved in psychedelic-initiated therapeutic improvements.

Although the full pharmacological profile of psychedelic compounds is far more complex than previously thought, the knowledge generated is creating a unique opportunity for the development of novel, more efficacious designer drugs with structural analogy to psychedelic compounds.

VI. Going Beyond Receptors: Neuronal Circuits Activated by Psychedelic Drugs

Research on the effects of psychedelics has mostly focused on the single effects of a compound on specific neurotransmitters and neuroplastic or neuroinflammatory mediators. However, the complex psychological effects triggered by psychedelics suggest that psychedelics can activate specific neuronal circuits in the brain.

Several neural circuits have been suggested that may drive the therapeutic improvements elicited by psychedelics, and it is likely that a combination of the circuits so far proposed coupled with purely immunomodulatory and neurotrophic actions and subjective meaningful experiences concur to elicit the observed clinical improvements.

A. Effects on the Default Mode Network Hub Functioning, and the “Reset” Model

The DMN is a circuit involving several brain regions, including the ventromedial and dorsal PFC, the PCC, and discrete regions of the hippocampal formation. It is thought to be involved in introspection, autobiographical memory retrieval, internal mentation, and time travel.

Psychedelics decrease DMN activity and induce effects similar to the psychedelic state, including ego dissolution, visual imagery, and detachment from the surrounding world. It has been suggested that a “reset” mechanism might take place in which the acute disintegration of canonical information processing within DMN substrates allows for subsequent resumption and reintegration of normal brain function.

B. The Cortico-Striato-Thalamo-Cortical Model

LSD and other serotonergic psychedelics activate presynaptic 5-HT2A receptors in deep-layer cortical neurons, which in turn excite thalamocortical relay neurons while disynaptically inhibiting them. This interaction is thought to be the driver of the cortico-striato-thalamo-cortical (CSTC) feedback loop modulation observed in imaging studies.

Psychedelic compounds might “open the gate” of consciousness via allowing the transfer of information from the thalamus to the cortex. LSD decreases serotonergic firing in the DRN, which leads to a hyperpolarization of RT neurons that express 5-HTRs, decreasing bursting activity and ultimately decreasing the inhibitory influence of the RT on thalamocortical relay cells and thereby “opening the gate”. This results in increased thalamocortical connectivity and decreased cortico-striato-thalamo connectivity.

SSRIs and psychedelics increase thalamic functional connectivity, and thalamocortical activation is required for memory retrieval and the formation of new memories. This mechanism might be involved in the therapeutic improvements observed in populations with PTSD.

C. The Claustrum

The claustrum is an area rich in 5-HT2A receptors, and it has extensive inhibitory functional connectivity with cortical areas related to the top-down control of cognitive function and emotions. The claustrum could be one of the areas where psychedelics activate neural information for altered states of consciousness and awareness.

A recent study reported that psilocybin decreases activity and connectivity in the claustrum, which is involved in emotions, memory, and attention.

The organization of the claustrum resembles that of the thalamus, suggesting that it might serve similar functions in terms of information processing and gating. It might also be involved in cognitive plasticity and adaptability, and may be involved in sleep via feedforward inhibition of the cortex.

Psychedelics modulate the DMN, CSTC, and claustral circuits, which are closely related to experiencing mystical-type experiences, emotional breakthrough episodes, psychological flexibility, creative thinking, and increased acceptance. These states might mediate the anxiolytic and antidepressant effects of psychedelic compounds.

VII. Effects of Psychedelics on Sleep

Only a few studies investigated the effects of psychedelics on sleep. Ayahuasca administration decreased the percentage and duration of rapid eye movement (REM) sleep and increased non-REM sleep and the number of sleep cycles, but not subjective measures of sleep quality.

LSD administered just before bedtime increased the duration of the first or second REM periods in some patients, with a rebound effect in the rest of the REM periods.

LSD administration during sleep causes an increase in wakefulness, a dose-dependent increase in REM sleep onset latency, a large decrease in REM sleep, and a smaller decrease in non-rapid eye movement sleep.

Studies investigating the effects of ketamine and PCP on the RT suggest that these drugs might affect sleep, and that some therapeutic benefits of psychedelics might be mediated by their effects over sleep.

VIII. Long-Term Neurobiological and Psychological Effects of Psychedelic Compounds

Although there is a paucity of studies investigating the long-term outcomes of psychedelic use in the general population, the evidence suggests that repeated lifetime exposure to psychedelic compounds may reduce the incidence of psychiatric conditions and increase several behavioral, social, and cognitive domains.

A. N,N-Dimethyltryptamine, 5-Methoxy-N,N-dimethyltryptamine, and Ayahuasca

The most studied psychedelic compound in terms of long-term effects arising from repeated ingestion is probably ayahuasca. This is because many people in the Amazon Basin use ayahuasca in religious ceremonies. Ayahuasca administration can improve depression scores, decrease suicidality, increase acceptance capacities, reduce neuroticism, and increase agreeableness, and these effects are still appreciable at 6-month follow-up. Adolescents who regularly ingest ayahuasca score lower for psychiatric symptoms such as anxiety, body dysmorphism, and attentional problems compared with controls.

Long-term ayahuasca users showed increased ACC and decreased PCC thickness, and these changes were positively correlated with greater consumption. These changes were also associated with decreased alcohol use and abuse, and increased spirituality. Ayahuasca consumption during pregnancy and lactation results in decreased anxiety and decreased the interest for social interactions in the offspring, suggesting potential neuromodulatory effects in the fetus, and long-term psychedelic use might induce plasticity mechanisms in the serotonergic system.

LSD improves mood, life attitude, and well-being/life satisfaction in the long term, and does not affect negative attitude, anti-social effects, or negative behaviors. LSD affects the 5-HT2A receptor in the mPFC, which might be involved in the anxiolytic and antidepressant mechanism of action of LSD. In preclinical studies, LSD elicited antidepressant-like effects in a rodent model of depression. Repeated administration elicited antidepressant-like effects without affecting controls. Preclinical models of SCZ show that chronic administration of high doses of LSD induces deleterious neurobiological changes, but no evidence of neuronal damage is available.

C. 3,4-Methylenedioxymethamphetamine

MDMA has a higher risk of abuse and long-term adverse neurobiological outcomes when used chronically. However, at clinical doses, the toxicity arising from MDMA administration seems low, and repeated administration of MDMA during adolescence leads to extensive neuroadaptive changes in glutamatergic-related gene expression in corticolimbic structures.

MDMA abuse at a young age in recreational settings is associated with changes in gene expression in the glutamatergic system. These changes may be relevant to the deleterious effects of MDMA in clinical settings.

D. Psilocybin

Psilocybin has been widely studied for its mystical and peak experiences, which seem to mediate and predict at least partially clinical improvements after administration. Psilocybin induces sustained antidepressant and anxiolytic effects in preclinical models, which are detectable up to 6 months after administration. Patients with treatment-resistant MDD showed increased brain-measured emotional responses after psilocybin treatment, suggesting that neuroadaptive processes take place in response to psilocybin treatment, which might help patients reconnect with their emotions.

Long-term improvements have been observed after psilocybin, which is indicative of potential usefulness of this approach for the abuse of alcohol, tobacco, and other substances.

E. Ketamine

Ketamine elicits rapid, sustained, and long-lasting antidepressant effects in adolescents and adults diagnosed with treatment-refractory MDD, and also improves suicidality. It may be useful in patients with suicidal ideation and behavior, but greater adverse events can be encountered when ketamine is used instead of other anesthetics for electroconvulsive therapy. Ketamine has been shown to decrease cue-induced craving and risk of relapse, and to decrease levels of oxytocin in the early phases of abstinence. It may also have deleterious effects on the opioidergic system.

IX. Side Effects of Psychedelic Compounds

Psychedelics administered in controlled clinical settings appear nonaddictive and present mild, transient side effects. However, there are several concerns that need to be considered in the drug development of psychedelics, including the possibility of negative acute or long-term effects.

Mild to moderate acute physical side effects have been reported by individuals receiving human-grade psychedelic compounds in controlled clinical settings. These side effects may be more severe in patients with pre-existing cardiac conditions or a family history of cardiovascular disease.

Medical-grade psychedelics induce a transient psychosis-like state in healthy patients, which can be accompanied by hallucinations, sense of unity and transcendence, mystical experiences, feelings of bliss and boundlessness, dissociation, derealization, revelations, and the re-experiencing of traumatic memories.

Given the psychological rather than physiological effects of psychedelics, interpersonal support should be available during clinical administration to address psychological distress that might arise. Psychological guidance to facilitate integration should also be available before, during, and after administration.

Uncontrolled Settings

Medical-grade psychedelic compounds are considered psychologically and physically safe when administered in controlled clinical settings, but the use of these compounds in uncontrolled clinical settings is potentially less safe.

Serious psychological side effects can occur after the ingestion of LSD, ayahuasca, DMT, and psilocybin, including fear, dangerous and disordered behavior, and the manifestation of latent psychiatric conditions such as schizophrenia, bipolar disorders, and anxiety.

Patients diagnosed with acute LSD- and PCP-induced psychoses have been successfully treated with the antipsychotics haloperidol and chlorpromazine. However, 5-HT antagonist antipsychotics like olanzapine are also used in emergency settings.

Bipolar disorder patients may switch to mania after the administration of psychedelic compounds. It is important to assess the likelihood that patients with BD might switch to mania if receiving psychedelic therapy and to identify the most suited antimanic pharmacological approaches to treat such patients should the switch take place.

Psychotic episodes can occur after the ingestion of psychedelic compounds in uncontrolled settings, and are more likely to occur in individuals with a history of SCZ, BD, or personality disorder, or those more inclined to mistrustfulness, fearfulness, and susceptibility on projection as defense.

Psychedelic compounds appear to have a considerable margin of safety, although rare, conspicuous physiological adverse reactions such as vasoconstriction, coronary artery spasms, and rhabdomyolysis have been reported after the consumption of high doses of psychedelic compounds in unsupervised settings.

Serotonin syndrome can occur due to excessive stress on central and peripheral postsynaptic serotonin receptors, and can lead to severe side effects such as rhabdomyolysis, metabolic acidosis, seizures, renal failure, intravascular coagulopathy, and death.

Several approved serotonergic psychiatric drugs, including SSRIs, have been associated with serotonin syndrome, including the combined use of pharmaceutical amphetamines and MDMA, and the ingestion of serotonergic psychedelics by patients who medicate with SSRIs.

Although no cases of serotonin syndrome have been reported after the administration of medical-grade psychedelic compounds in clinical settings, the use of SSRIs and SNRIs should be carefully taken into consideration prior to psychedelic therapy.

MDMA is neurotoxic to neurotransmitter systems, and catechols derived from MDMA metabolism appear to be responsible for the neurotoxic effects. Other metabolites, such as 6-HO-MDMA, are nontoxic, and quinone-thioethers, orto-quinones, and glutathione conjugates might contribute to the neurotoxic properties of MDMA.

Acute injections of 5-GSyla-MeDA increase dopamine (DA) and 5-HT levels and increase long-term dopamine (but not 5-HT) turnover, while multiple intrastriatal and intracortical administrations of 2,5-Bis-(glutathion-S-yl)-aMeDA significantly deplete striatal and cortical 5-HT (but not hippocampal) 5-HT.

Codependence with other substances is linked to several psychoses induced by psychedelics, especially cannabis and alcohol.

LSD, psilocybin, and mescaline have weak abuse potential profiles, and repeated LSD administration at high doses tends to attenuate the rewarding effects of methamphetamine and the depressant k-opioid receptor agonist U69,593, although only findings for the latter were statistically significant.

In another study, no self-administration of DMT or psilocybin was observed in comparison with saline, and none self-administered DOI. In nonhuman primates, minimal rates of LSD self-injection were observed after a daily access procedure.

Hallucinogen-persisting perception disorder occurs in patients with alcoholism, military personnel, and individuals with a long-term history of psychedelic use/abuse. It can be treated with high-potency serotonergic benzodiazepines such as clonazepam.

Cardiovascular side effects can arise after microdosing psychedelics, including cardiac 5-HT2B receptor overstimulation, valvular fibrosis, and valvular regurgitation. These effects are accompanied by increased cardiac 5-HT2B receptor and decreased SERT expression. Pulmonary hypertension was observed after the repeated administration of serotonergic psychedelics, including fenfluramine, dexfenfluramine, and aminorex.

One individual experienced severe cardiovascular side effects after frequent ingestion of Psilocybe semilanceata mushrooms for 1 month. Further efforts should be devoted to identifying biological biomarkers and psychological predictors of psychedelic-induced subjective side effects.

X. Recommendations for Future Research

Psychedelics modulate pathways involved in the improvement and remission of psychiatric disorders. These effects are compound- and dosage-specific, and long-term neurobiological side effects need to be systematically assessed.

Studies should investigate whether microdosing can elicit clinical improvement and/or remission of psychiatric symptoms, and whether long-term microdosing regimens would be necessary to reach remission. Pharmacogenomics and pharmacoepigenomics could be applied in this endeavor to address biological variability underlying different responses to psychedelics.

If psychedelics are approved as therapeutics, certain individuals may be excluded from accessing this type of treatment. Another challenge is to design a novel selective 5-HT2A receptor agonist with enhanced therapeutic potential.

Psychedelics might be useful for other neuroinflammatory and systemic conditions, such as high-fat diet-induced obesity and diabetes, gut inflammatory challenges, and asthma.

Clinical studies may boost the acceptance of this approach by legislative, funding, and academic bodies, leading to the implementation of necessary policy shifts that will allow this therapy to reach the bedside. Lastly, compounds with structural analogy might represent an alternative to natural and semisynthetic psychedelics. 1Acetyl-LSD (ALD-52), 1-propanoyl-LSD (1P-LSD), and 1-butanoyl-LSD (1B-LSD) are 1-acyl substituted LSD derivatives that produce psychedelic effects in humans. These derivatives are weak agonists at 5-HT2A receptors, but induce head twitches in mice with relatively high potency.

XI. Conclusion

Given the available evidence to date, psychedelic compounds are challenging the current paradigm in psychiatry. They may soon be developed in clinical trials and approved by pharmaceutical regulatory governmental authorities.