Psychedelic Law, Science & Policy

The Drug Enforcement Administration (DEA) is issuing this temporary order to schedule three 7-hydroxymitragynine-related substances (mitragynine pseudoindoxyl, MGM-15, and MGM-16), including their isomers, esters, ethers, salts, and salts of isomers, esters, and ethers, whenever the existence of such isomers, esters, ethers, and salts is possible, in schedule I of the Controlled Substances Act. DEA bases this action on a finding that placing mitragynine pseudoindoxyl, MGM-15, and MGM-16 in schedule I is necessary to avoid an imminent hazard to public safety. This order imposes the regulatory controls and administrative, civil, and criminal sanctions applicable to schedule I controlled substances on persons who handle (manufacture, distribute, reverse distribute, import, export, engage in research, conduct instructional activities or chemical analysis with, or possess) or propose to handle these three 7-hydroxymitragynine-related substances.

Major depressive disorder (MDD) has a widespread heterogeneity as per the psychiatric nosology, and traditional symptom-based diagnosis frameworks do not offer many clues regarding tailored therapy techniques. The recent development of multi-omics and data-driven solutions has now provided evidence for pathophysiologically different subtypes of MDD, moving the field toward precision psychiatry. The systematic review aggregates multimodal studies that combing neuroimaging, genomics, transcriptomics, epigenomics, metabolomics, and proteomics to define MDD subtypes. There are two to four candidate clusters that have been formed across these heterogeneous modalities, and each has a neurobiological and clinical profile. Cognitive subtypes are characterized by executive failure and loss of prefrontal and temporal gray matter. Neuroimaging-derived subtypes show specific patterns of functional connectivity that may predict response to selective serotonin reuptake inhibitors (SSRIs) or repetitive transcranial magnetic stimulation (rTMS) in preliminary studies. There are immune-metabolic subtypes characterized by increased inflammatory cytokines and dysregulation of metabolic pathways. Molecular subtypes appear to be differentiated by cellular mechanisms such as mitophagy and pyroptosis. Taken together, these results indicate that multi-omics integration, in addition to explaining the molecular architecture of MDD, also characterizes patient subgroups with pathophysiological mechanisms, dimensions of symptoms, and disease treatment. The growing body of literature demonstrates that there is a shift in psychiatry toward a more mechanistic approach and that biomarker-based diagnostics and personalized treatment regimens are urgently needed to improve clinical outcomes in depressive diseases.

Animals use their sense of smell for survival and well-being. Any disruption to olfactory perception, such as in the case of olfactory hallucinations, can lead to devastating consequences and decreased quality of life. Psychedelics interrupt and distort accurate perception, yet little is known about the impact of psychedelics on olfactory behaviors. Using an olfactory search task, we investigated the impact of the psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) on olfactory search behavior of mice. We found that DOI decreases search accuracy, alters movement, and increases sniff rate. These findings suggest that the olfactory behaviors are altered by DOI, elucidating psychedelic-induced changes to olfactory processes.

Treatment-resistant depression (TRD) remains a major clinical challenge, yet the biological processes distinguishing TRD from non-treatment-resistant depression (nTRD) are incompletely defined. While circulating serum proteomes reflect broad systemic alterations associated with depression, extracellular vesicles (EVs) could provide a more selective representation of intercellular signaling relevant to treatment resistance. Here, we carried out a pilot study to evaluate the extent that parallel proteomic profiling of serum and serum-derived EVs could distinguish healthy controls (CON), nTRD, and TRD individuals. In this exploratory and hypothesis-generating study, serum proteomes exhibited robust global differences between depression groups and controls, largely reflecting shared systemic biology across nTRD and TRD. In contrast, EV proteomes showed limited global separation but revealed subtype-associated pathway differences. Relative to controls, nTRD EVs were enriched for immune and inflammatory pathways. By contrast, TRD EVs were characterized by enrichment of mitochondrial metabolism, oxidative phosphorylation, translational initiation, and MYC-regulated pathways, together with depletion of synaptic signalling, membrane trafficking, and cytoskeletal pathways. Comparative analysis of pathways significant in both contrasts revealed that these bioenergetic and translational signatures were selectively amplified in TRD relative to nTRD. Our exploratory analyses identified that the circulating EV cargo may reflect a treatment-resistance-specific reorganization of biological pathways not apparent in bulk serum proteomics. This study highlights parallel serum and EV proteomics as a complementary approach for molecular stratification in antidepressant resistance.

Antiepileptic drugs (AEDs) are commonly prescribed to treat epilepsy and other neurodegenerative disorders (NDs). Gabapentin (GBP) is a newer, off-label antiepileptic/anticonvulsant for NDs that remains underexplored. Recent evidence indicates that prolonged, frequent, and high-dose use of GBP may be associated with an increased risk of various types of dementia and cognitive impairment. GBP has become 1 of the top 20 most prescribed drugs for NDs. GBP modulates voltage-gated calcium channels by binding to the alpha2delta subunit. One possible mechanism is oxidative stress, which can damage neuronal structures, impair synaptic function, and cause mitochondrial dysfunction, all of which are strongly implicated in the pathogenesis of several NDs and contribute to cognitive decline. Another factor is excitotoxicity, where abnormal glutamatergic activity causes excessive calcium influx and neuronal injury, thereby exacerbating mood problems and memory deficits. Long-term use of GBP interferes with SIRT1 (neuroprotective), CaMKII (calcium regulator), and tau phosphorylation regulation, damaging downstream signalling, disrupting central pain pathways in the spinal cord and brain (central sensitisation), damaging neuronal survival pathways, and promoting neurodegeneration. This literature review aims to synthesise current insights on GBP neurotoxic effects, including changes at the gene and protein levels, neuronal structure, function, and network connectivity, as well as strategies for managing GBP-associated NDs. Further research is needed to clarify the exact mechanisms and to develop protective strategies to reduce neurodegenerative risks, optimise seizure control, and evaluate the risks of GBP in clinical settings.