White Matter Alterations in Military Service Members With Remote Mild Traumatic Brain Injury.

Importance: Mild traumatic brain injury (mTBI) is the signature injury experienced by military service members and is associated with poor neuropsychiatric outcomes. Yet, there is a lack of reliable clinical tools for mTBI diagnosis and prognosis. Objective: To examine the white matter microstructure and neuropsychiatric outcomes of service members with a remote history of mTBI (ie, mTBI that occurred over 2 years ago) using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI). Design, Setting, and Participants: This case-control study examined 98 male service members enrolled in a study at the National Intrepid Center of Excellence. Eligible participants were active duty status or able to enroll in the Defense Enrollment Eligibility Reporting system, ages 18 to 60 years, and had a remote history of mTBI; controls were matched by age. Exposures: Remote history of mTBI. Main Outcomes and Measures: White matter microstructure was assessed using a region-of-interest approach of skeletonized diffusion images, including DTI (fractional anisotropy, mean diffusivity, radial diffusivity and axial diffusivity) and NODDI (orientation dispersion index [ODI], isotropic volume fraction, intra-cellular volume fraction). Neuropsychiatric outcomes associated with posttraumatic stress disorder (PTSD) and postconcussion syndrome were assessed. Results: A total of 65 male patients with a remote history of mTBI (mean [SD] age, 40.5 [5.0] years) and 33 age-matched male controls (mean [SD] age, 38.9 [5.6] years) were included in analysis. Compared with the control cohort, the 65 service members with mTBI presented with significantly more severe PTSD-like symptoms (mean [SD] PTSD CheckList-Civilian [PCL-C] version scores: control, 19.0 [3.8] vs mTBI, 41.2 [11.6]; P < .001). DTI and NODDI metrics were altered in the mTBI group compared with the control, including intra-cellular volume fraction of the right cortico-spinal tract (ß = -0.029, Cohen d = 0.66; P < .001), ODI of the left posterior thalamic radiation (ß = -0.006, Cohen d = 0.55; P < .001), and ODI of the left uncinate fasciculus (ß = 0.013, Cohen d = 0.61; P < .001). In service members with mTBI, fractional anisotropy of the left uncinate fasciculus was associated with postconcussion syndrome (ß = 5.4 × 10-3; P = .003), isotropic volume fraction of the genu of the corpus callosum with PCL-C (ß = 4.3 × 10-4; P = .01), and ODI of the left fornix and stria terminalis with PCL-C avoidance scores (ß = 1.2 × 10-3; P = .02). Conclusions and Relevance: In this case-control study of military-related mTBI, the results suggest that advanced magnetic resonance imaging techniques using NODDI can reveal white matter microstructural alterations associated with neuropsychiatric symptoms in the chronic phase of mTBI. Diffusion trends observed throughout widespread white matter regions-of-interest may reflect mechanisms of neurodegeneration as well as postinjury tissue scarring and reorganization.

Ethical considerations for psychedelic-assisted therapy in military clinical settings.

Psychedelic treatments, particularly 3,4-methylenedioxymethamphetamine (MDMA)-assisted and psilocybin-assisted therapies, have recently seen renewed interest in their clinical potential to treat various mental health conditions. Clinical trials for both MDMA-assisted and psilocybin-assisted therapies have shown to be highly efficacious for post-traumatic stress disorder and major depression. Recent research trials for psychedelic-assisted therapies (PAT) have demonstrated that although they are resource-intensive, their effects are rapid-acting, durable and cost-effective. These results have generated enthusiasm among researchers seeking to investigate psychedelic therapies in active-duty service members of the US military, particularly those with treatment refractory mental health conditions. At the same time, psychedelics remain in early stages of clinical investigation, have not yet achieved regulatory approval for general clinical use and may confer unique psychological and neurobiological effects that could raise novel ethical considerations when treating active-duty service members. Should psychedelics achieve regulatory approval, military relevant considerations may include issues of access to these treatments, appropriate procedures for informed consent, confidentiality standards, and possible unanticipated mental health risks and other psychological sequelae. A service member's deployability, as well as their ability to return to full military duty following PAT, may also be of unique concern. The authors argue that MDMA-assisted therapy currently represents a promising treatment that should be more rapidly investigated as a clinical therapy for service members while still taking a measured approach that accounts for the many military-specific uncertainties that remain.

Opioid-Related Trends in Active Duty Service Members During the Coronavirus Disease 2019 Pandemic.

INTRODUCTION: The USA is experiencing an opioid epidemic. Active duty service members (ADSMs) are at risk for opioid use disorder (OUD). The Coronavirus disease 2019 (COVID-19) pandemic has disrupted health care and introduced additional stressors. METHODS: The Military Healthcare System Data Repository was used to evaluate changes in diagnosis of OUD, medications for OUD (MOUD), opioid overdose (OD), and opioid rescue medication. ADSMs ages 18-45 years enrolled in the Military Healthcare System between February 2019 and April 2022 were included. Joinpoint Trend Analysis Software calculated the average monthly percent change over the study period, whereas Poisson regression compared outcomes over three COVID-19 periods: Pre-lockdown (pre-COVID-19 period 0) (February 2019-February 2020), early pandemic until ADSM vaccination initiation (COVID-19 period 1 [CP1]) (March 2020-November 2020), and late pandemic post-vaccination initiation (COVID-19 period 2 [CP2]) (December 2020-April 2022). RESULTS: A total of 1.86 million eligible ADSMs received care over the study period. Diagnoses of OUD decreased 1.4% monthly, MOUD decreased 0.6% monthly, diagnoses of opioid OD did not change, and opioid rescue medication increased 8.5% monthly.Diagnoses of OUD decreased in both COVID-19 time periods: CP1 and CP2: Rate ratio (RR) = 0.74 (95% CI, 0.68-0.79) and RR = 0.72 (95% CI, 0.67-0.76), respectively. MOUD decreased in both CP1 and CP2: RR = 0.77 (95% CI, 0.68-0.88) and RR = 0.86 (95% CI, 0.78-0.96), respectively. Adjusted rates for diagnoses of opioid OD did not vary in either COVID-19 time period. Opioid rescue medication prescriptions increased in CP1 and CP2: RR = 1.09 (95% CI, 1.02-1.15) and RR = 6.02 (95% CI, 5.77-6.28), respectively. CONCLUSIONS: Rates of OUD and MOUD decreased, whereas rates of opioid rescue medication increased during the study period. Opioid OD rates did not significantly change in this study. Changes in the DoD policy may be affecting rates with greater effect than COVID-19 pandemic effects.

Psychedelic-Assisted Therapy in Military and Veterans Healthcare Systems: Clinical, Legal, and Implementation Considerations.

PURPOSE OF REVIEW: This review discusses the current and projected landscape of psychedelic-assisted therapy (PAT), with a focus on clinical, legal, and implementation considerations in Department of Defense (DoD) and Department of Veterans Affairs (VA) healthcare systems. RECENT FINDINGS: 3,4-Methylenedioxymethamphetamine (MDMA)- and psilocybin-assisted therapy have shown promising outcomes in efficacy, safety, tolerability, and durability for PTSD and depression, respectively. MDMA-assisted therapy is already approved by the Food and Drug Administration (FDA) on an Expanded Access ("compassionate use") basis for PTSD, with full approval projected for 2024. Psilocybin-assisted therapy is projected to be FDA-approved for depression soon thereafter. Other psychedelics are in earlier stages of development. The VA is currently conducting PAT clinical trials. Although there are clear legal pathways for the VA and DoD to conduct PAT trials, a number of implementation barriers exist, such as the very high number of clinical hours necessary to treat each patient, resource requirements to support treatment infrastructure, military-specific considerations, and the high level of evidence necessary for PAT to be recommended in clinical practice guidelines. Ongoing considerations are whether and how PAT will be made available to VA and DoD beneficiaries, feasibility and cost-effectiveness, and ethical safeguards that must be implemented to prioritize access to PAT given the likelihood of extremely limited initial availability. However, with imminent FDA approval of PATs and considerable national interest in these treatments, DoD and VA policymakers must be prepared with clearly delineated policies and plans for how these healthcare systems will approach PAT.

Cannabis and Cannabinoids for Pain and Posttraumatic Stress Disorder in Military Personnel and Veterans.

This Viewpoint reviews the evidence for using cannabis and cannabinoids to treat pain and PTSD in military and veteran populations.

Beliefs and Perceived Barriers Regarding Psychedelic-assisted Therapy in a Pilot Study of Service Members and Veterans With a History of Traumatic Brain Injury.

INTRODUCTION: Posttraumatic stress disorder (PTSD) and depression are common in service members and veterans, and the response to currently available treatments is often modest at best. Recent studies suggest potential benefit with psychedelic-assisted therapies (PATs), particularly 3,4-methylenedioxymethamphetamine-assisted therapy for PTSD and psilocybin-assisted therapy for depression. This study examined beliefs and perceived barriers regarding PAT among service members and veterans to inform the delivery of these treatments if they are approved by the FDA. MATERIALS AND METHODS: Twenty-one service members and veterans (67% male, 81% White, and 43% active duty) with a history of traumatic brain injury and co-occurring cognitive and psychological symptoms completed a measure assessing baseline knowledge and views of PAT, read a brief psychoeducation regarding PAT, and then responded to questions related to their beliefs and perceived barriers to PAT. RESULTS: Before psychoeducation, participants reported a neutral view of psychedelic drugs (M = 2.76; range: 1-5), PAT (M = 3.33), and interest in PAT (M = 3.10). After psychoeducation, participants reported a significantly more positive view of psychedelic drugs (M = 3.24, P = .014) and interest in PAT (M = 3.67, P = .016). Overall, participants indicated that they would support PAT availability in medical settings if proven beneficial (M = 4.52; 5 = "agree strongly") and they would support a loved one engaging in PAT (M = 4.29). The most frequently reported health concerns were concern of long-term effects (43%), fear of losing their mind (33%), fear of personality changes (33%), and fear of traumatic brain injury complications (24%). The most frequently endorsed barriers were time commitment, transportation, financial concerns, work, and childcare (33%-19%), with 48% reporting no barriers. CONCLUSIONS: This is the first study to explore beliefs and perceived barriers regarding PAT among service members and veterans. These results indicate that military populations may be interested in PAT, particularly if psychoeducation and outreach regarding these treatments occurred. If FDA approved, it will be important to facilitate command support and address logistical barriers to ensure appropriate access within military contexts.

3,4-Methylenedioxymethamphetamine (MDMA)-Assisted Therapy in Hawaii: A Brief Review.

The Food and Drug Administration (FDA) granted breakthrough therapy status to 3,4-methyl​enedioxy​methamphetamine-assisted therapy (MDMA-AT) in 2017 due to preliminary evidence supporting its efficacy and safety in treating post-traumatic stress disorder (PTSD). A series of six phase-II clinical trials studying MDMA-AT for treatment-resistant PTSD found that 54% of MDMA-AT full-dose participants no longer met the diagnosis of PTSD after two MDMA sessions, compared to 23% in the control group. In the first phase-III clinical trial, 67% no longer met the criteria for PTSD after three sessions. The effects are durable, with 67% no longer diagnosable after one year and 74% at nearly four years. The MDMA-AT is being fast-tracked for potential FDA approval by 2023. In 2021, Hawaii's Senate Bill 738 unsuccessfully proposed that psilocybin be removed from the Schedule I controlled substances list due to its clinical efficacy for major depressive disorder. Methyl​enedioxy​methamphetamine is also a Schedule I controlled substance and has proven to be a treatment option that could potentially benefit the people of Hawaii.

Depression and/or PTSD Comorbidity Affects Response to Antidepressants in Those With Alcohol Use Disorder.

Objective: Depression and post-traumatic stress disorder (PTSD) highly co-occur with alcohol use disorder (AUD). The comparative effects of noradrenergic vs. serotonergic antidepressants on drinking and depressive outcomes for those with AUD and co-occurring depression and/or PTSD are not well known. Methods: This study was an analysis of a randomized control trial of 128 patients with AUD who had co-occurring depression and/or PTSD. They were randomized to treatment with paroxetine vs. desipramine and naltrexone vs. placebo leading to four groups: paroxetine plus naltrexone, paroxetine plus placebo, desipramine plus naltrexone, and desipramine plus placebo. Outcomes were percent of drinking days, percent heavy drinking days, drinks per drinking day (Time Line Follow-back Method), and depressive symptoms (Hamilton Depression Scale). Groups compared were (1) depression without PTSD (depression group; n = 35), (2) PTSD without depression (PTSD group; n = 33), and (3) both depression and PTSD (comorbid group; n = 60). Results: There were no overall significant differences in drinking outcomes by medication in the entire sample, and no significant interaction when diagnostic groups were not considered. However, when diagnostic groups were included in the model, the interactions between time, diagnostic group, and medication (desipramine vs. paroxetine) were significant for percent drinking days (p = 0.042), and percent heavy drinking days (p = 0.036); paroxetine showed better drinking outcomes within the depression group, whereas desipramine showed better drinking outcomes in the PTSD and comorbid groups. Regarding depressive symptoms, paroxetine was statistically superior to desipramine in the total sample (p = 0.007), but there was no significant interaction of diagnostic group and medication. Naltrexone led to a decrease in craving but no change in drinking outcomes. Conclusions: The results of this study suggest that drinking outcomes may respond differently to desipramine and paroxetine depending on comorbid MDD and/or PTSD.