Psychedelic Law, Science & Policy

The Food and Drug Administration (FDA or Agency) is announcing the publication of FDA's Strategy Document on Facilitating Chemistry, Manufacturing, and Controls Readiness for Products With Accelerated Clinical Development (Strategy Document), which outlines actions FDA has taken and the Agency's plans for fiscal years 2026-2027 to facilitate chemistry, manufacturing, and controls (CMC) readiness for products with accelerated clinical development timelines. As part of the Prescription Drug User Fee Act (PDUFA) Reauthorization Performance Goals and Procedures Fiscal Years 2023-2027 (PDUFA VII), FDA committed to advance its capability to facilitate CMC development for sponsors of CDER- and CBER-regulated drugs and biologics intended to diagnose, treat, or prevent a serious disease or condition where there is an unmet medical need. The actions described in the Strategy Document are based on lessons learned from FDA's experience with submissions for products on accelerated clinical development timelines as well as other public input.

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Cancer is rarely one button pressed; it is a series of small steps, which is why drug combinations beat single drugs. This paper proposes that this shape, many small steps adding up with no single one in control, is the shared form behind a whole group of conditions. It is a framework-theoretic account of compound disease progression and intervention, applying the Friction Theory architecture (Pødenphant Lund 2026b, Paper 1) to cancer, autoimmune disease, ME/CFS and long COVID, and treatment-resistant depression as instances of compound multi-scale race pathology. Target venue: Cell Reports Medicine (primary); fallbacks PLOS Medicine, Nature Communications. Abstract. Several major chronic and progressive diseases share a clinical signature that single-mechanism explanations have struggled to capture: chronic multi-system dysregulation that responds poorly to single-target therapy, presents with substantial inter-individual heterogeneity, and produces episodic exacerbations or treatment-failure patterns that cannot be reduced to any one pathway. We propose that these conditions are framework-distinct instances of compound race pathology: disease progression produced by coupled multi-scale RACE-architectures where each contributing scale resolves its own race under commit-pressure, hysteretic trace accumulates across scales, and the compound mechanism cannot be addressed by intervention bounded at any single scale's control coefficient. Central formal apparatus. The paper extends Metabolic Control Analysis (Kacser & Burns 1973; Heinrich & Rapoport 1974) — established for steady-state biochemical pathways — to multi-scale disease progression under explicit assumption-set transfer. Heinrich & Rapoport's general distributed-linear-control formulation applies to any system with a conserved scalar under specifiable assumptions; the framework specifies (a) progression-rate as the conserved scalar additive by hysteretic-trace deposition, (b) control coefficients per scale operationalised via factorial design where data permit, (c) linear-response approximation valid in the linear regime, with (d) modified formalism (non-linear interaction terms; cascade percolation per Buldyrev et al. 2010; Hill-equation saturation) for the three non-linear regimes specified in §2.3. Worked-example operationalisation candidates: rheumatoid arthritis (RA, O'Dell triple-DMARD anchor) and heart failure with reduced ejection fraction (HFrEF, included as an applicability-mapping case outside the framework's construction-set in §3.5, with COPD triple-therapy and T2DM combination-therapy registered as the genuinely adversarial forward tests). Hysteresis-fighting taxonomy. Three categories distinguish wholesale attractor-perturbation interventions by durability profile, with sub-classification by substrate-reversibility: A1 cellular reversible (HSCT MS, FMT for recurrent C. difficile, CAR-T SLE drug-free remission); A2 mixed (HSCT SSc, CAR-T IIM); A3 fibrotic halt-only (CAR-T SSc no-progression). Empirically anchored on the CASTLE 2026 SLE/IIM/SSc gradient (Müller et al. 2026, Nature Medicine). Category B (substrate-modification with consolidation requirement): ketamine + CBT (Wilkinson 2017/2021), psilocybin-assisted TRD (Carhart-Harris 2021), HBOT for long COVID. Category C (state-perturbation requiring maintenance): SSRI/SNRI, esketamine, ECT without continuation. Ten empirical predictions plus R1–R10 falsification set with explicit framework-pivotal vs component-test distinction. R3 (substrate-vector predicts response in compound disease) and R5 (CAR-T SLE/IIM/SSc substrate-reversibility gradient at n ≥ 100) are pre-committed as framework-pivotal: their joint disconfirmation refutes the framework's central compound-multi-scale-RACE mechanism; no graceful-degradation clause permits joint survival. R1, R2, R4, R6–R10 are component-tests: their disconfirmation forces revision of specific framework components while the central mechanism is preserved. Substrate

Since the introduction of disulfiram in 1951 (the first ever Food and Drug Administration (FDA)-approved medication for substance use disorders (SUDs)) (1), only seven other individual medications have been approved for the treatment of SUDs. While the repurpose of medications and different formulations increase the total number of FDA-approved medicines (Table 1 and(2)), the arsenal of pharmacological approaches remains limited for the group of diseases that affect 16.8% of individuals aged 12 or older (3), are linked to more than 700,000 deaths annually (4)(5)(6), and cost more than 700 billion dollars yearly (7). Notable progress in public health has been achieved with certain current medications (such as buprenorphine for opioid use disorder (8) or varenicline for nicotine use disorder ( 9)). In contrast, attempts to identify successful, off-label treatment for other SUDs (topiramate for cocaine use disorder (10), bupropion with naltrexone for methamphetamine use disorder (11), or gabapentin for cannabis use disorder (12)) have yielded only relatively modest results.The current Research Topic is an effort to highlight emerging pharmacological and psychosocial treatments for SUDs. In recent years, several hallmark papers have discussed the potential use of psychedelics in the treatment of SUDs (e.g. psilocybin for alcohol use disorder (13) or ketamine for cocaine use disorder ( 14)). In this Collection, a study by Qeadan et al. analyzed a national cohort of patients with SUDs and found that psychedelic treatment (primarily ketamine) significantly improved outcomes, including relapse, overdose, and hospitalization, especially when combined with outpatient services, supporting the need for research on further integrated treatment. Shen et al. conducted a scoping review, which suggests that ketamine could be considered as a therapeutic agent in the management of opioid withdrawal as well as in reducing cravings in patients with opioid use disorder. In a case-study, Brett et al. described a patient who underwent psilocybinassisted therapy for methamphetamine use disorder, with favorable outcomes on abstinence and overall mental health. Finally, in a large cross-sectional study, Glynos et al. found that more than two-thirds of participants with SUDs reported improved outcomes following the naturalistic use of psychedelics. These studies highlight the importance of future research evaluating the feasibility and efficacy of psychedelics in the treatment of SUDs. Outside of the realm of psychedelics, Alshehri, in a systematic review, proposes that valproic acid can reduce alcohol use, stabilize mood, and manage withdrawal in patients with co-occurring alcohol use disorder and psychiatric conditions.Non-pharmacological interventions have also been employed to address SUDs, including cognitive behavioral therapy (CBT) (15), community reinforcement approach ( 16), motivational interviewing (17), and contingency management (18), with varying degrees of efficacy. In 2017, the FDA approved reSET®, a first-of-its-kind, prescription-only, 12-week digital course of CBT delivered directly to the patient's smartphone for the treatment of SUDs (19). In 2018, reSET-O®, specifically designed for patients with opioid use disorder, was approved (20). In 2020, the FDA cleared Transcranial Magnetic Stimulation for short-term smoking cessation (21). In this collection, Seok et al. conducted a meta-analysis on the effects of eye movement desensitization and reprocessing (EMDR) therapy on addictionrelated symptoms, reporting the reduction of short-term cravings as well as a decrease in co-occurring symptoms such as depression and anxiety. Ssentongo et al. discussed how combining inpatient education and counseling with pharmacotherapy reduced readmission risk for patients with SUDs, advocating for the integration of addiction consultation services in hospitals.To conclude, a thought-provoking series of articles explores emerging approaches to treating S

INTRODUCTION: Neurofilament light chain (NfL) is a structural axonal protein measurable in CSF and blood, increasingly investigated as a biomarker of neuroaxonal injury in clinical and research contexts. This review aims to explore the use of blood-based NfL as an endpoint in clinical trials of neurodegenerative conditions. METHOD: A database search of MEDLINE and EMBASE was conducted to identify interventional clinical trials and/or related post hoc analyses for neurodegenerative diseases, published between 2013 and 2024 that reported the use of serum or plasma NfL as an endpoint. Additional studies from reference lists of included trials were manually considered for inclusion where relevant. Data were charted descriptively by disease type and summarised. RESULTS: 49 studies were included, 29 in multiple sclerosis (MS), eight in amyotrophic lateral sclerosis (ALS), six in Alzheimer's disease (AD), and six in other diseases. Across studies, reductions in NfL often paralleled improvements in primary efficacy outcomes, supporting its use as a biomarker of disease activity and treatment response. However, several studies demonstrated a lack of concordance between change in NfL and in clinical outcomes, some of which may be related to the non-disease-modifying mechanisms of the interventions studied. This necessitates careful consideration when applying blood-based NfL as a biomarker endpoint for studies involving such interventions. CONCLUSION: Blood NfL is a promising biomarker with potential utility as a surrogate endpoint in neurological clinical trials, particularly for diseases with active axonal injury. Further validation, particularly around disease- and intervention-specific interpretation, is needed before blood NfL can be incorporated more routinely as a clinical endpoint.

Substance use disorders (SUD) involving ketamine, cocaine, and alcohol present significant clinical challenges, often characterized by high relapse rates and limited pharmacological options. This case report details a 30-year-old male with a five-year history of severe polysubstance dependence, including daily intranasal ketamine use (2–3 g/day), cocaine, and alcohol, comorbid with recurrent depressive disorder. Despite conventional psychiatric treatment, the patient experienced severe cravings and sought ibogaine-assisted treatment. The patient underwent a structured 13-day residential program in Mexico, receiving an 800 mg ibogaine HCl flood dose (10.1 mg/kg), followed by two supplementary booster doses of 300 mg (3.8 mg/kg) under continuous medical and ECG monitoring. Following treatment, the patient reported an immediate cessation of cravings for all substances. Over approximately 17 months of follow-up including a medically supervised fractionated ibogaine intervention approximately 11 months after the initial treatment, serial toxicology and psychometric assessments were consistent with continued abstinence from ketamine, cocaine, alcohol and other previously misused substances, and significant improvements in depression (PHQ-9: 0–3), anxiety, and quality of life (WHOQOL-BREF: 55 to 71). This report represents the first longitudinally documented case of sustained abstinence in severe ketamine use disorder following ibogaine treatment, supported by serial toxicology and standardized psychometric outcomes. It adds objective, time-resolved evidence to a literature that has largely focused on ibogaine for opioid use disorder, and it highlights ketamine use disorder as a specific target for future controlled trials. The therapeutic outcome is hypothesized to arise from ibogaine’s unique polypharmacology. This includes acute NMDA antagonism, which may disrupt compulsive circuits, as well as noribogaine’s (the principal long-acting metabolite of ibogaine, with an elimination half-life of approximately 28–49 hours) kappa opioid receptor agonism and serotonin transporter inhibition, which stabilize reward pathways. Additionally, enhanced neuroplasticity via GDNF/BDNF expression may facilitate long-term behavioral changes. This case provides rare, rigorously documented evidence for ibogaine’s potential in treating chronic ketamine dependence and highlights the urgent need for controlled clinical trials within regulated frameworks to further investigate its safety and efficacy.