Neuroscience Newsletter - 2024 September

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8 Oct

Welcome to Psylo's Neuroscience Newsletter - September Edition!

Science in Sixty Seconds

Beyond 5-HT2A: Exploring the Broader Molecular Targets of Psychedelics

Classic psychedelics like psilocin, LSD, DMT, and mescaline are primarily recognized for their potent effects on the 5-HT_2A receptor, which plays a central role in modulating perception, mood, and therapeutic potential. However, these compounds also interact with a broader range of receptor targets. Additionally, there are compounds often referred to as "neuroplastogens", which engage similar receptor systems without producing the profound perceptual changes typically associated with psychedelics. The roles of these receptors in shaping both hallucinogenic and non-hallucinogenic psychedelic experiences are still being explored.

Key Molecular Targets

In addition to the 5-HT_2Areceptor, both hallucinogenic and non-hallucinogenic psychedelics engage with other serotonergic and non-serotonergic targets such as dopamine, adrenergic, and neurotrophic receptors. Notable examples include:

Psilocin binds with high affinity to 5-HT_2B and 5-HT₇ receptors, and with moderate affinity to serotonin 5-HT_1A, 5-HT_1B, 5-HT_2A, and 5-HT_2C receptors. Psilocin may also interact with TrkB, a neurotrophic receptor implicated in neuroplasticity.
LSD has a broad profile, binding with high affinity to 5-HT_1A, 5-HT_1B, 5-HT_2A, 5-HT_2C, and 5-HT₇ receptors, and with moderate to low affinity to other serotonergic (5-HT_2B, 5-HT_1D), dopaminergic, adrenergic and TAAR₁ receptors. LSD may also bind to TrkB, with an affinity much higher than that of many traditional antidepressants.
DMT binds with moderate affinity to 5-HT_1D and Sigma₁ receptors, and with lower affinity to other serotonergic receptors.
Mescaline binds primarily to 5-HT_2A receptors with moderate affinity and shows weak affinity for alpha-2 adrenergic receptors.
5-MeO-DMT binds with relatively high affinity to 5-HT_1A, 5-HT_1D, and 5-HT₇ receptors, and with lower affinity for other serotonergic and dopaminergic receptors.
DOI has a high affinity for both 5-HT_2A and 5-HT_2C receptors, with moderate affinity for 5-HT_2B and lower affinity for other serotonergic receptors.

Table 1. Binding affinities of psychedelics to various molecular targets. High affinity corresponds to Ki values <10 nM, moderate affinity to Ki values between 10–100 nM, and low affinity to Ki values between 100–1000 nM. Data are from Holze et al., 2024, Jaster et al., 2023, Moliner et al., 2023, Berry et al., 2017, Rickli et al., 2016.

Potential Implications of Receptor Targets

The receptor functions of the targets engaged by psychedelics may contribute to their therapeutic and subjective outcomes:

5-HT_1A receptors modulate mood regulation, particularly anxiety.
5-HT_1D receptors modulate pain and migraine pathophysiology and are targets for some antimigraine drugs.
5-HT_2B receptors pose a significant cardiac safety risk when overstimulated, particularly in the form of heart valve damage, as seen with drugs like fenfluramine. While psychedelics such as LSD and psilocin also bind to 5-HT2B, they do so at much lower levels, which likely reduces this risk. Developing compounds that avoid 5-HT2B activation altogether could further minimize any potential long-term cardiovascular concerns.
5-HT_2C receptors regulate mood, anxiety, and impulsivity, with therapeutic potential for treating substance use disorders.
5-HT₇ receptors are involved in circadian rhythm, mood, and cognitive function.
Dopamine receptors play a significant role in motor control, mood, motivation, reward, memory and cognition. Dopamine receptors have been implicated in LSD's hallucinogenic effects, such as disembodiment, self-awareness and impaired cognition.
TAAR (Trace Amine-Associated Receptors) are involved in neurotransmitter release and LSD was shown to decrease dopaminergic activity through TAAR1 receptors.
Sigma₁ receptor are linked to cellular functions like calcium signaling and neuronal excitability, potentially contributing to DMT’s effects.
TrkB is a receptor for BDNF that regulates neuroplasticity, synaptogenesis, and neuronal survival, and plays a key role in the therapeutic effects of antidepressants. Their involvement in psychedelic activity is still being studied.

Clinical Evidence: Are the Targets Relevant?

Despite their diverse molecular engagements, clinical trials have not demonstrated significant therapeutic differences between psychedelics. Psilocybin and LSD, for example, have shown similar efficacy in treating conditions such as depression and anxiety, reinforcing the central role of 5-HT2A activation in therapeutic outcomes. However, these compounds have not been directly compared in head-to-head trials. Additionally, participants in trials often struggle to distinguish between substances like LSD, psilocybin, mescaline, and 2C-B (Holze et al., 2022, Ley et al., 2023, Mallaroni et al., 2023). Key differences typically arise from dose and duration rather than qualitative effects, suggesting that receptor engagement beyond 5-HT2A may not drastically alter the core psychedelic experience.

Conclusion

While 5-HT2A activation remains the primary driver of the effects of classic psychedelics, their interactions with other receptor targets add layers of complexity to their pharmacological profiles. These additional targets are associated with known biological effects, though their contributions to the therapeutic effects of psychedelics remain unclear. Continued research into highly selective 5-HT2A agonists, as well as non-hallucinogenic compounds, may help optimize the safety and therapeutic potential of psychedelic treatments in the future.

RESEARCH UPDATES

Clinical Research

Psychedelics For Anxiety and Depression in Life-Threatening Illness | Psychedelic-assisted therapy using psilocybin or LSD may reduce anxiety and depression in people with life-threatening diseases, but the evidence is of low to very low in certainty; a meta-analysis of six RCTs with 149 participants. Cochrane Database Syst Rev

Adverse Events in Classic Psychedelics Studies | Classic psychedelics were generally well-tolerated, though some serious adverse events were reported in participants with neuropsychiatric disorders; a meta-analysis involving 214 studies with 3504 participants. JAMA Psychiatry

Brain Connectivity Changes with LSD and Amphetamines | LSD produced distinct connectivity changes in the brain, particularly increasing global connectivity in the basal ganglia and thalamus, compared to amphetamines; a double-blind, placebo-controlled trial (N=28 healthy volunteers). Mol Psychiatry

Relaxation Predicts Antidepressant Effect in Psychedelic Therapy | Relaxation during psychedelic-assisted therapy with LSD or psilocybin was the strongest predictor of reduced depressive symptoms, rather than mystical experiences; a naturalistic study with 28 patients and 28 healthy volunteers. J Psychopharmacol

Heart Activity Predicts Well-Being After DMT | Sympathovagal coactivation during DMT was positively related to peak experiences and predicted improved well-being two weeks later; a placebo-controlled trial (N=17). J Psychopharmacol

Psilocybin with Midazolam: Effects on Memory | Co-administration of midazolam with psilocybin impaired memory of the psychedelic experience but maintained subjective quality, suggesting that memory may contribute to psilocybin’s therapeutic effects; a clinical trial (N=8 healthy participants). Transl Psychiatry

Assessing Adverse Events in Psychedelic Therapy | This study developed a new framework for systematically assessing adverse events in psychedelic-assisted therapies, addressing significant gaps in current reporting methods. J Psychopharmacol

DMT and Meditation Synergy Explored | DMT combined with harmine enhanced mystical-type experiences, non-dual awareness, and psychological insight in experienced meditators during a mindfulness retreat; a randomized, placebo-controlled study (N=40). J Psychopharmacol

LSD Microdosing and Creativity Assessment | LSD microdosing (10 µg doses of LSD or placebo every third day for six weeks) did not lead to measurable improvements in creativity, despite participants feeling more creative; a randomized controlled trial (N=80). Psychopharmacology (Berl)

Predictors of LSD Experience in Healthy Adults | LSD dose and pre-drug mental states were significant predictors of subjective effects, with higher doses leading to stronger experiences and personality traits like "Openness to Experience" enhancing mystical effects; a randomized, double-blind, placebo-controlled study (N=213 healthy participants). Transl Psychiatry

Psychedelic Use and Psychological Distress by Sexual Identity | Psychedelic use was associated with reduced odds of psychological distress in heterosexual individuals but not in sexual minority groups; data from the 2021 National Survey on Drug Use and Health (N = 253,824,662 US adults). J Psychopharmacol

Psilocybin for Veterans with Severe Depression | Psilocybin-assisted therapy (single dose, 25 mg) resulted in a 60% response rate and 53% remission in veterans with severe treatment-resistant depression at Week 3; an open-label pilot study (N = 15 veterans) who received. J Affect Disord

Preclinical Research

Psychedelic DOI Reduces Heroin Motivation in Rats | DOI reduced heroin motivation in a rat model of heroin and alcohol co-use, an effect blocked by a 5-HT2A antagonist but not a 5-HT2C antagonist. Neuropharmacology

Psilocybin Increases Optimistic Behavior in Rats | Psilocybin increased optimistic engagement in rats by modifying forgetting rates and reducing loss aversion, leading to more rewards; behavior was analyzed using active inference and reinforcement learning models. Transl Psychiatry

Novel Tool To Study Biased Agonism at the 5-HT2A Receptor | A photoswitchable ligand for the 5-HT2A receptor, based on TCB-2, was developed, enabling light-controlled switching between G protein and β-arrestin pathways to study biased agonism. Chem Commun (Camb)

How DOI Affects Anxiety via Hippocampal Neurons | DOI produced acute anxiolytic effects in rodent models by enhancing the firing rate of parvalbumin-positive interneurons in the ventral hippocampus through 5-HT2A receptor activation. Neuron

Chotosan Reduces Inflammation-Induced Anxiety in Mice | A traditional Japanese botanical drug, chotosan, and its active component Uncaria hook reduced anxiety-like behavior in mice by inhibiting 5-HT2A receptor hyperfunction caused by inflammation. Front Pharmacol

Mirtazapine Reduces Pain and Improves Movement After SCI | Mirtazapine alleviated neuropathic pain and improved locomotor recovery in rats following spinal cord injury by modulating neuroinflammatory pathways and upregulating 5-HT2A receptor expression. Neurochem Res

5-HT2A Receptor Controls Visual Input Gain | Activating 5-HT2A receptors in distinct cell types in the mouse visual cortex modulated sensory input gain, influencing excitatory and inhibitory neuron firing without affecting baseline activity. Nat Commun

LSD Activates the TrkB Pathway | LSD activated TrkB signaling in neural stem cells (NSCs), similar to BDNF, but did not promote the proliferation of NSCs, suggesting a specific effect on neurons rather than stem cells; in vitro study on human NSCs. Stem Cell Res Ther

Effects of Tryptamines in Psilocybin Mushrooms | Norbaeocystin, a tryptamine found in psilocybin mushrooms, was shown to activate the 5-HT2A receptor and exhibit antidepressant-like effects without causing hallucinations, similar to psilocybin. Br J Pharmacol

Psilocybin Does Not Reduce Cocaine Relapse in Rodents | Psilocybin administration following extinction training did not affect cue-induced reinstatement of cocaine-seeking behavior in male and female rats and mice. Neuroscience

Sex Differences in DOI's Effect on Fentanyl Use | DOI reduced fentanyl consumption in female rats but increased it in male rats, highlighting sex-dependent effects of 5-HT2A activation on opioid reinforcement. Drug Alcohol Depend

Serotonin Receptors Modulate Claustrum Neuron Excitability | Serotonin inhibited, and the psychedelic DOI stimulated, excitatory currents in claustrum neurons from mice through 5-HT2C receptors, not 5-HT2A, suggesting serotonin receptor subtype-specific modulation of brain excitability. Prog Neurobiol

Reviews and Commentaries

Psychedelics And Schizophrenia: A Double-Edged Sword | This review explores the controversial potential of psychedelics in treating schizophrenia, highlighting both their therapeutic promise for improving negative symptoms and social cognition, and the risks of worsening positive symptoms, while suggesting careful, low-dose applications in future clinical trials. Mol Psychiatry

Neurobiological Research On N,N-Dimethyltryptamine (DMT) and its Potentiation by Monoamine Oxidase (MAO) Inhibition: From Ayahuasca to Synthetic Combinations of DMT and MAO Inhibitors | This review summarizes the pharmacological and neurobiological effects of DMT, highlighting how its combination with MAO inhibitors, such as in ayahuasca, enhances its psychoactivity and therapeutic potential for neuropsychiatric disorders, based on emerging research and neuroimaging studies. Cell Mol Life Sci

Classical Psychedelics' Action On Brain Monoaminergic Systems | This review explores the neurochemical effects of classical psychedelics on serotonergic, dopaminergic, and noradrenergic neurons, revealing complex, state-dependent, and region-specific effects on brain monoaminergic systems with no clear, consistent neuronal signature. Int J Biochem Cell Biol

Chemistry/Structural Biology of Psychedelic Drugs and Their Receptor(s) | This review examines the structure-activity relationships of classic serotonergic psychedelics, focusing on their molecular mechanisms of action through the 5-HT2A receptor and the atomistic basis for their pharmacological effects, particularly in research to determine causality and specific mechanisms. Transl Psychiatry

Less Is More? A Review of Psilocybin Microdosing | This review highlights the current evidence on psilocybin microdosing, identifying research gaps and emphasizing the need for more rigorous, randomized placebo-controlled trials to draw definitive conclusions on its efficacy. J Psychopharmacol

An Integrated Theory of False Insights and Beliefs Under Psychedelics | This perspective proposes a model explaining how psychedelics may induce false insights and beliefs by altering brain and subjective experiences, offering directions for future research to minimize potential risks while leveraging their therapeutic potential. Commun Psychol

Evaluating the Potential for Psilocybin as a Treatment for Post-Traumatic Stress Disorder | This review explores psilocybin’s potential as a treatment for PTSD, discussing its antidepressant and anxiolytic effects, proposed mechanisms of action, and the challenges facing future research on its therapeutic use. J Pharmacol Exp Ther

Clinical Trials Update

A round-up of the latest registered clinical trials investigating psychedelics:

CYB003 [Psilocybin Analog] | Major Depressive Disorder (N=220) | Phase III Long-term Extension Trial to Assess Safety and Efficacy of CYB003 in MDD (EXTEND) - NCT06605105

Psilocybin (25 mg vs. 1 mg) | Persistent Post-Concussive Symptoms (N=40) | Treatment of Persistent Post-concussive Symptoms With Psilocybin Assisted Therapy (PatACT) - NCT06615908

Psilocybin + (Pimavanserin [2A antagonist] vs. placebo) | Major Depressive Disorder, Mechanism of Action (N=60) | Psilocybin Mechanism of Action (MOA) - NCT06592833

Any Serotonergic Psychedelic vs. Placebo | Neural Processing (N=200) | Computer Game, Qualitative, and MEG/EEG Assessment of Serotonergic Psychedelics - NCT06624137

Ketamine-Assisted Psychotherapy | Depression (N=10) | A Ketamine-assisted Group Therapy Intervention for Spanish-speaking Adults With Depression - NCT06597695

Ketamine | Bipolar Depression, fMRI (N=20) | FMRI of Patients Receiving IV Ketamine for Treatment Resistant Bipolar Depression - NCT06620042

PSYLO UPDATES

Sam Banister (CSO) and Dilara Bahceci (Head of Communications) attended the 7th Neuropsychiatric Drug Development Summit in Boston from September 24-26. Dilara participated in a panel discussion on the challenges of reimbursement and market access for psychiatric therapeutics. The conference offered valuable opportunities for networking and knowledge exchange.

Psylo is proud to be featured in SmartCompany alongside Enosis Therapeutics for our efforts to revolutionize neuropsychiatric treatment with innovative technologies. Read the full article here.