Neuroscience Newsletter - 2024 July

psylo_newsletters

3 Aug

Welcome to Psylo's Neuroscience Newsletter - July Edition!

Science in Sixty Seconds

The Science of MDMA

By August 11, the FDA will announce whether MDMA-assisted therapy will be approved, and therefore can be prescribed, as a treatment for post-traumatic stress disorder. In honor of this historic milestone in development of psychedelic therapies, here is a brief primer on the science behind MDMA, exploring its history, pharmacology, and therapeutic potential.

What is MDMA?
MDMA (3,4-methylenedioxymethamphetamine), commonly known as ecstasy or molly, is a psychoactive compound that produces prosocial and stimulant effects. It is structurally related to amphetamines and phenethylamine psychedelics (like mescaline) but elicits distinct subjective effects. While sometimes included in the broad class of psychedelics, it is more accurately classified as an empathogen-entactogen, known for enhancing empathy, introspection, and emotional connection.

A Brief History of MDMA
MDMA was first synthesized by Merck in 1912 as an intermediate product during the development of substances to stop abnormal bleeding but wasn’t studies. It wasn't until the late 1960s that its psychoactive properties were recognized by American chemist Alexander Shulgin. During the 1970s, MDMA gained popularity as a psychiatric tool, enhancing communication and emotional processing in psychotherapy. However, its non-medical use surged in the 1980s, leading to concerns about its safety. By 1985, MDMA was classified as a Schedule 1 drug, which severely hindered its scientific research for decades.

Reemergence and Evidence for PTSD Treatment
The resurgence of MDMA research can largely be attributed to the efforts of researchers and advocacy groups, notably the Multidisciplinary Association for Psychedelic Studies (MAPS). MDMA, when combined with psychotherapy, can facilitate the reprocessing of traumatic memories, improving or resolving PTSD symptoms. The first controlled clinical study on MDMA-assisted psychotherapy was launched in 2004. Since then, multiple Phase 2 and Phase 3 trials have demonstrated its safety and efficacy in treating PTSD, and in 2017, MDMA-assisted therapy received FDA Breakthrough Therapy designation. Remarkably, 67% of participants no longer met the diagnostic criteria for PTSD, compared to 32% in the placebo group, with benefits persisting for at least 12 months. These studies also suggest improvements in comorbid symptoms such as substance misuse, eating disorder symptoms and chronic pain.

Pharmacology of MDMA
MDMA exerts its effects by increasing brain levels of monoamines—serotonin, dopamine, and norepinephrine—through complex mechanisms. It inhibits monoamine transporters, preventing the removal of these neurotransmitters from the synapse, and promotes their release, together leading to elevated levels in the synapse. MDMA also binds directly to various receptors, including adrenergic, serotonergic, and histaminergic receptors, and notably the ‘psychedelic’ 5-HT2A receptor. [1,2]

Effects and Therapeutic Mechanisms
At doses of 75–150 mg, MDMA produces effects lasting several hours, including increased feelings of closeness, emotional openness, reduced social inhibition, positive mood, and heightened sensory perception. Physiological effects include increased heart rate, blood pressure, and body temperature. [3,4,5]

MDMA alters brain activity in regions involved in emotional regulation, decision-making, and social behavior. It promotes neuroplasticity and modulates emotional memory circuits, aiding in memory reconsolidation and fear extinction. These changes help reprocess traumatic memories and enhance therapeutic engagement. [6, 7, 8]

Safety and Concerns
In clinical settings, MDMA is generally safe with manageable side effects such as transient increases in heart rate, blood pressure, anxiety, and jaw tension. However, recreational use carries higher risks due to impure samples, overdose, and poly-drug use. While long-term use can lead to serotonin depletion, neurotoxicity, cognitive impairments, and mood disorders. Additionally, combining MDMA with other substances, like antidepressants, stimulants, depressants, alcohol, and cardiovascular medications can significantly amplify these risks, particularly in individuals with cardiovascular conditions. [9,10,11]

Controversies and Criticisms
The development of MDMA therapy has been controversial. On June 4, an FDA Advisory Committee reviewed but did not recommend its approval. Criticisms include small trial sizes, blinding difficulties, sample bias, safety concerns, therapist misconduct allegations, advocacy group influence, and lack of standardized protocols. For further details, refer to Harvard Law Professor Mason Marks' article and my summary thread on X.

Conclusion
MDMA is a unique molecule with a storied history that underscores the importance of robust scientific research, sufficient funding, and regulatory support in developing innovative mental health treatments. If approved, MDMA-assisted therapy could revolutionize PTSD treatment, offering hope to those who have not found relief through conventional methods. Next week, the FDA's decision will mark a pivotal moment in the evolution of psychedelic therapies, with significant implications for their future.

RESEARCH UPDATES

Clinical Research

Psilocybin Desynchronizes the Human Brain | A high-dose psilocybin caused over three times greater disruption in brain connectivity than the ADHD medication methylphenidate, driven by desynchronization across spatial scales. Psilocybin led to a strong decrease in the connection between the hippocampus and the brain's default mode network, with this effect lasted for weeks. This disruption might be linked to the long-term proplasticity and therapeutic effects of psychedelics. This imaging study involved 7 healthy participants, each undergoing approximately 18 MRI visits (before, during, and after drug administration). Nature

LSD Effects Depend on Baseline Cognition | Repeated low doses of LSD (15 mcg) produced stimulatory effects on arousal and pre-attentive processing, with responses varying based on participants' baseline cognitive states, and these effects were sustained beyond the treatment period; a randomized, placebo-controlled study comparing LSD to THC and methamphetamine (N=53). Transl Psychiatry

LSD Therapy has Lasting Anxiolytic Effects | A single dose of LSD combined with therapy significantly reduced anxiety and depression symptoms, with effects still present at the 12-month follow-up. Participants also reported positive long-term changes in personality traits. An open-label follow-up of a “double-blind”, placebo-controlled, crossover study (N=39). Br J Psychiatry

Psychedelic Experiences Reported to Poison Centers | Over half of psychedelic exposures reported to US poison centers from 2012-2022 (N= 54,605) required medical treatment, had severe symptoms, or resulted in death; cardiovascular effects were common; 41.1% were concomitant exposures and hallucinogenic mushroom exposures increased most over the study period from 593 in 2012 to 1,440 in 2022. Ann Emerg Med

[Case study] Psilocybin-Assisted therapy with Antidepressants| Serotonergic antidepressants need to be discontinued before Psilocybin-Assisted therapy. However, the combination of psilocybin with serotoninergic antidepressants was well-tolerated in a case study, with mild headaches being the main adverse effect. Discontinuation of antidepressants may not be necessary for the efficacy of psilocybin-assisted psychotherapy. Front Psychiatry

Survey of Canadians Receiving Compassionate Psilocybin Access | Significant improvements in anxiety, depression, pain, quality of life, and spiritual well-being were reported in a longitudinal survey of cancer patients receiving legal psilocybin-assisted psychotherapy through compassionate access (N=8). Most participants found the sessions meaningful despite some challenges. Sci Rep

Psychedelic Self-Treatment for Mental Health | In the Global Drug Survey 2020, 2,552 respondents reported using psychedelics to self-treat mental health issues. Significant self-reported benefits included Improved Mental Health, Improved Self-Awareness, and Neuro-Sensory. Notably, these benefits were associated with a reduced need for prescribed medications, particularly for depression or related conditions. J Psychopharmacol

Preclinical Research

5-MeO-DMT's Anxiolytic Effects in Mice | 5-MeO-DMT altered gene expression in brain regions related to neuroplasticity and exhibited both anxiolytic and anxiogenic effects in mice. Mol Psychiatry

Blood-Brain Barrier Modulation and Neuroplasticity | Neuronal activity increased BBB permeability in the somatosensory cortex, which was linked to long-term synaptic plasticity; study of rats combined with human MRI imaging. Elife

Predicting Hallucinogenic Potential with AI | AI models, trained on in vitro and in vivo data sets derived from Shulgin’s books, accurately predicted the hallucinogenic potential of molecules, with high performance metrics, and identified promising neuroplastogens without hallucinogenic effects. ACS Chem Neurosci

LSD Binding at Dopamine D1 Receptor | LSD binds uniquely to the dopamine D1 receptor, with its dissociation rate influenced by the receptor's extracellular loop 2 and G protein stabilization, offering detailed structural and kinetic insights into LSD's interaction with the dopamine D1 receptor. Neuron

Psychedelic Effects on Dopamine Signaling | DOI increased dopamine signaling in the nucleus accumbens (NAc) core (a region extensively linked to reward learning, motivation, and drug-seeking) in response to rewards and proximal reward cues, enhancing prediction error signaling in rats. Neuropsychopharmacology

Novel Tropanes with Reduced Side Effects | Several novel tropanes significantly increased cortical neuronal growth while showing reduced activity at muscarinic receptor subtypes in a structure-activity relationship study screening various tropane subclasses. J Med Chem

Mechanisms Behind Psilocybin's Antidepressant Effects | Psilocybin demonstrated significant pro-social and antidepressant effects in both Wistar-Kyoto and Wistar rats, with strain-specific variations in BDNF-related signaling and modulation of Arc expression. Psychopharmacology (Berl)

Psilocybin Enhances Fear Extinction | Psilocybin significantly enhanced fear extinction, retention, and reduced fear renewal in mice, with effects dependent on dose, context, and serotonin receptor activity. ACS Chem Neurosci

Psilocybin Effects on Metabolism | Psilocybin significantly increased body weight and lean mass in mice without affecting intake/output, and elevated certain metabolic markers. The effects were not influenced by 5-HT2A/2C receptor antagonism. Physiol Behav

Reviews and Commentaries

New and Emerging Treatments for Major Depressive Disorder | This review summarizes current research into new and emerging treatments for major depressive disorder, including psychedelics, antibiotics, opioid modulators, neuropeptides, and neuromodulatory therapies, highlighting their therapeutic potential and the need for further clinical research. BMJ

Emerging GPCR Targets For [Alcohol Use Disorder] AUD: Insights From Preclinical Studies | This review discusses recent preclinical studies on G protein-coupled receptor (GPCR) targets that have potential for reducing behaviors associated with excessive alcohol intake and highlights compounds with promising pharmacological profiles for future clinical investigation in treating alcohol use disorder (AUD). Curr Opin Neurobiol

Current Perspectives on the Clinical Research and Medicalization of Psychedelic Drugs for Addiction Treatments: Safety, Efficacy, Limitations and Challenges | This review discusses the current clinical research evidence, therapeutic potential, and safety of psychedelics such as psilocybin, LSD, ketamine, MDMA, and ibogaine for treating substance use disorders (SUDs), highlighting the need for more clinical research and addressing the limitations and challenges in this area. CNS Drugs

Pharmacological Properties of Psychedelics with a Special Focus on Potential Harms | This review provides an in-depth analysis of the pharmacology of classic psychedelics, highlighting their effects, interactions, potential risks, and side effects, emphasizing the importance of understanding the harms associated with their use. Curr Top Behav Neurosci.

Neurobiological Correlates of Psychedelic Experiences and Psychedelic-Associated Adverse Effects | This review comprehensively explores the neural mechanisms of psychedelic drugs, emphasizing human neuroimaging studies and potential adverse effects, and delves into prevailing models like the CSTC feedback loop, the entropic brain hypothesis, and the claustrum hypothesis. Curr Top Behav Neurosci.

Therapeutic Potential of Psychedelic Drugs: Navigating High Hopes, Strong Claims, Weak Evidence, and Big Money | This review critically examines the therapeutic claims of psychedelic drugs, emphasizing the need for rigorous research to validate promising findings, such as the potential benefits of ketamine, MDMA, and psilocybin for various mental health conditions, while cautioning against premature clinical use driven by profit motives rather than robust evidence. Annu Rev Psychol.

Psilocybin in Pharmacotherapy of Obsessive-Compulsive Disorder | This review discusses the potential of psilocybin as a novel and effective treatment for obsessive-compulsive disorder (OCD), highlighting its efficacy in managing symptoms and the need for more therapeutic options due to the limitations of current medications. Pharmacol Rep.

Esketamine in Depression: Putative Biomarkers from Clinical Research | This review explores the potential biomarkers associated with the antidepressant response to esketamine in treating treatment-resistant depression, highlighting the need for further clinical research to identify those most likely to benefit from this therapy. Eur Arch Psychiatry Clin Neurosci

Methylenedioxymethamphetamine Is a Connectogen with Empathogenic, Entactogenic, and Still Further Connective Properties: It Is Time to Reconcile "The Great Entactogen-Empathogen Debate" | This review argues for a reconciliation of the terms "empathogen" and "entactogen" to describe MDMA, emphasizing its broad connective properties and therapeutic potential. J Psychopharmacol.

Clinical Trials Update

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

Psilocybin (25 mg) with Psychological Support and transcutaneous auricular Vagus Nerve Stimulation (taVNS)| Depression (N=141) | An Investigation of Strategies to Understand and Optimize the Antidepressant Effects of Psilocybin (The OPTIMIZE Study) - NCT06512194

Psilocybin (25 mg) with supportive therapy | Treatment Resistant Depression, Chronic Pain (N=16) | Treatment With Psilocybin for Chronic Neuropathic Pain and Depression (TRANSCEND): An Open-Label Clinical Trial - NCT06518720

Psilocybin (25 mg) with supportive therapy, Risperidone, SV2A radiotracer | Feasibility of integrating PET imaging in to psilocybin trials, Treatment-resistant Depression (N=12) | | Imaging the Effects of Serotonin 2A Receptor Modulation on Synaptic Density in Treatment-resistant Depression (SYNVEST) - NCT06512220

Psilocybin (25 mg) with supportive therapy| Treatment-Resistant Bipolar Depression (N=30) | Neurobiological Effects [fMRI] of Psilocybin in Treatment Resistant Bipolar Depression (Psilo-BD) - NCT06506019

Psilocybin (15 mg) |Brain Synchrony in Healthy Volunteers (N=30) | Effects of Psilocybin on Shared Experience - NCT06529939

5-MeO-DMT as GH001 | Healthy Volunteers (N=52) | Pharmacokinetics of GH001 Delivered Via a Proprietary Aerosol Delivery Device in Healthy Subjects - NCT06511947

Ketamine | Methamphetamine Use Disorder, HIV (N=12) | Ketamine Therapy for Methamphetamine Use Disorder & HIV (KetaMet) - NCT06538285

Ketamine | Methamphetamine Use Disorder (N=120) | Randomized, Double-Blind, Active Placebo-Controlled Trial of Ketamine for Methamphetamine Use Disorder (KMD) - NCT06496750

IV Ketamine vs. IN Esketamine | Treatment Resistant Depression (N=80) | IV Ketamine Vs. IN Esketamine for MDD TRD - NCT06488586

PSYLO UPDATES

Our CEO Joshua Ismin had the pleasure of sitting down with Josh Hardman from Psychedelic Alpha for an insightful chat about our recent successful $8M seed financing round.

In this mini-interview, Josh discusses:

🚀 Plans to advance our neuroplastogen program, PSYLO-100X, into clinical trials.
🔬 Our unique target-based approach to non-hallucinogenic drug discovery.
🧠 Indication selection with a flexible, evidence-informed strategy.
📅 Timeline for entering clinical trials.
🤔 What makes a psychedelic a psychedelic and how Psylo is pioneering in the neuro space with our innovative neuroplastogens.

🙏 A big thank you to Josh Hardman and Psychedelic Alpha for the feature.

See the full interview to learn more about our groundbreaking work and future plans.

Sam Banister (CSO) and Krista Licata (Chief of Staff) at the new lab site, located at the University of Colorado Boulder, Colorado.

Sam Banister (CSO) and Dilara Bahceci (Head of Communications) had the pleasure of meeting with members of the KOLON Industries team from South Korea in Denver, Colorado.