Abstract Purpose of Review This commentary summarizes how the intense and distinctive subjective effects of psychedelics complicate tests of the efficacy and mechanisms of action (MOAs) of psychedelic-assisted treatments (PATs) for mental-health conditions. Specifically, we discuss (a) how estimates of PAT efficacy are confounded under functional unblinding and (b) uncertainty surrounding whether subjective or neurobiological effects are causal therapeutic MOAs of PATs. We then review methodological solutions to address these challenges. Recent Findings Several novel methodologies have been discussed in the literature. For testing PAT efficacy under functional unblinding, potential solutions include improved active placebo conditions, expectancy-focused recruitment and consent procedures, better measurement of expectancies and blinding, and more rigorous statistical modeling. For testing whether subjective effects are causal MOAs in PATs, strategies that disentangle the subjective and neurobiological effects of psychedelics are needed. Potential methods include administering psychedelics under general anesthesia, developing non-psychoactive psychedelic analogues, leveraging Mendelian randomization, and studying psychedelic microdosing. Participant safety and ethical considerations are critical for many of these strategies. Ultimately, combining multiple innovative methods may offer the most robust insights. Summary Future empirical efforts to develop these strategies will be crucial for advancing our limited understanding of whether and how PATs achieve clinical benefits in psychiatry.

Abstract Purpose of Review Lifetime exposure to trauma is extremely common, affecting ~ 70% of global population, whereas lifetime prevalence of PTSD is ~ 6%. FDA-approved medications for PTSD have small-medium effect sizes. Trauma-focused psychotherapies are considered first-line treatments and have large effect sizes, but also high rates of dropout and refusal, and most patients retain PTSD diagnosis. Mindfulness-Based Interventions (MBIs) as treatments for PTSD have high levels of engagement, retention, and patient satisfaction. Here we briefly describe MBIs and review empirical support for MBIs in the treatment of trauma and PTSD in military veterans, survivors of intimate partner violence and childhood maltreatment, and among substance users with trauma. Recent Findings Meta-analyses of MBIs for PTSD symptoms have mixed findings, with low to medium-high effect sizes, and quality of studies and range of MBIs vary greatly. MBIs with well-established protocols have medium-high effects for PTSD in some populations and promote acceptance and emotion regulation, and reduce self-blame, avoidance, and hyperarousal. Summary MBIs may target specific mechanisms leading to overall improvements in symptoms and quality of life. Trauma-specific adaptations to MBIs must be made to maximize acceptability, safety, and efficacy. MBIs may be most effective as adjunctive treatments for PTSD, for those unwilling to do trauma-focused empirically supported treatments (ESTs), who drop out or have high residual symptoms. Clinical Opinion In my opinion, informed client treatment preference to the extent feasible is ethically imperative and empirically supported for optimal outcomes in persons with PTSD. I would first discuss and recommend “first line” ESTs for PTSD that have the largest effect sizes and best quality of empirical support, including exposure-based psychotherapies (e.g. PE) and CPT (both of which I am trained in) as well as EMDR, and also refer for a medication consult. I would describe MBIs such as “trauma sensitive” MBCT and MBSR as interventions that are often helpful as adjunctive treatments useful for improving grounding and physiological and emotional self-regulation skills, and can themselves lead to moderate improvements in PTSD symptoms without trauma exposure. For clients with PTSD who decline trauma-focused therapy, drop out early, or do not benefit from empirically supported treatments (ESTs) I would recommend a trauma sensitive MBI, optimally one led by a trauma therapist as a second-line therapy to gain skills and stabilization, or as an adjunct to medication, ongoing cognitive therapy, present-centered therapy, or IPT. I would not recommend a MBI (i.e. community mindfulness group) delivered by a person who does not have experience in trauma therapy as a stand-alone treatment in the absence of other treatment or support.

BackgroundTreatment-resistant schizophrenia (TRS) affects approximately 30% of patients with schizophrenia, with clozapine remaining the most effective treatment despite its limitations. Recent evidence suggests that neuroinflammation plays a crucial role in TRS pathophysiology, with altered immune responses and elevated inflammatory markers contributing to disease progression. Understanding these mechanisms may open new avenues for therapeutic interventions.ObjectiveThis review aims to consolidate the current knowledge on neuroinflammation in TRS and explore emerging immune-modulating treatment options.MethodsA systematic literature review was conducted, including studies published between 2000 and 2024 on neuroinflammation and treatment strategies for TRS. Databases such as PubMed and SCOPUS were searched using key terms including “schizophrenia,” “treatment-resistant schizophrenia,” “inflammation,” “neuroinflammation,” and “therapy.” Only studies involving human subjects and demonstrating clinical improvement were considered.ResultsSeveral immune-modulating treatments show promise for TRS. N-acetylcysteine (NAC) may reduce oxidative stress and modulate glutamatergic transmission, improving negative symptoms. Celecoxib, a COX-2 inhibitor, has shown mixed results, with some studies reporting symptom improvement, particularly in acute psychosis. Aspirin, a non-selective COX inhibitor, demonstrated benefits in early-stage schizophrenia. Minocycline, an antibiotic with anti-inflammatory properties, exhibited improvements in negative symptoms and cognitive function. Biological therapies such as tocilizumab (IL-6 receptor inhibitor), rituximab (B-cell depleting antibody), and canakinumab (IL-1β inhibitor) have shown variable efficacy, with limitations due to blood–brain barrier penetration.ConclusionNeuroinflammation plays a key role in TRS, and immune-modulating treatments may offer alternative therapeutic strategies. While preliminary findings are promising, larger, well-controlled studies are necessary to determine their clinical relevance and long-term effects. Future research should focus on personalized approaches targeting inflammatory pathways in TRS patients.