S ex; biological and physiologic traits characterizing males and females; and gender, a continuum of socioculturally constructed roles and behaviors associated with men, women, and gender-spectrum diversity, are among the most important determinants of health and disease outcomes. However, these fundamental factors are often ignored in biomedical research and are rarely incorporated into clinical care. We call for sex-and gender-specific and differentiating factors to be urgently included in the research, prevention, and therapeutics implementation response to the coronavirus disease 2019 (COVID-19) pandemic.Although available sex-disaggregated data for COVID-19 show equal numbers of cases between sexes, current evidence indicates that fatality rates are higher in men than in women. A recent report (23 April 2020) from the Italian National Institute of Health shows that of 23 188 deaths from COVID-19 infection in Italy, approximately 70% were in men. In the United States, provisional death counts for COVID-19 from February to April 2020 similarly indicate a sex bias in fatality rates: Of 37 308 deaths reported by the National Center for Health Statistics, 59% were in men. Similar trends have been reported in China (1) and South Korea (2).

Post-traumatic stress disorder (PTSD) is a common, debilitating condition with limited treatment options. Extinction of fear memories through prolonged exposure therapy, the primary evidence-based behavioral treatment for PTSD, has only partial efficacy. In mice, pharmacological inhibition of fatty acid amide hydrolase (FAAH) produces elevated levels of anandamide (AEA) and promotes fear extinction, suggesting that FAAH inhibitors may aid fear extinction-based treatments. A human FAAH 385C->A substitution encodes an FAAH enzyme with reduced catabolic efficacy. Individuals homozygous for the FAAH 385A allele may therefore offer a genetic model to evaluate the impact of elevations in AEA signaling in humans, helping to inform whether FAAH inhibitors have the potential to facilitate fear extinction therapy for PTSD. To overcome the challenge posed by low frequency of the AA genotype (appr. 5%), we prospectively genotyped 423 individuals to examine the balanced groups of CC, AC, and AA individuals (n = 25/group). Consistent with its loss-of-function nature, the A allele was dose dependently associated with elevated basal AEA levels, facilitated fear extinction, and enhanced the extinction recall. Moreover, the A-allele homozygotes were protected against stress-induced decreases in AEA and negative emotional consequences of stress. In a humanized mouse model, AA homozygous mice were similarly protected against stress-induced decreases in AEA, both in the periphery, and also in the amygdala and prefrontal cortex, brain structures critically involved in fear extinction and regulation of stress responses. Collectively, these data suggest that AEA signaling can temper aspects of the stress response and that FAAH inhibition may aid the treatment for stress-related psychiatric disorders, such as PTSD.

Extensive preclinical data implicate corticotropin-releasing hormone (CRH), acting through its CRH1 receptor, in stress-and dependence-induced alcohol seeking. We evaluated pexacerfont, an orally available, brain penetrant CRH1 antagonist for its ability to suppress stress-induced alcohol craving and brain responses in treatment seeking alcohol-dependent patients in early abstinence. Fiftyfour anxious alcohol-dependent participants were admitted to an inpatient unit at the NIH Clinical Center, completed withdrawal treatment, and were enrolled in a double-blind, randomized, placebo-controlled study with pexacerfont (300 mg/day for 7 days, followed by 100 mg/day for 23 days). After reaching steady state, participants were assessed for alcohol craving in response to stressful or alcoholrelated cues, neuroendocrine responses to these stimuli, and functional magnetic resonance imaging (fMRI) responses to alcohol-related stimuli or stimuli with positive or negative emotional valence. A separate group of 10 patients received open-label pexacerfont following the same dosing regimen and had cerebrospinal fluid sampled to estimate central nervous system exposure. Pexacerfont treatment had no effect on alcohol craving, emotional responses, or anxiety. There was no effect of pexacerfont on neural responses to alcohol-related or affective stimuli. These results were obtained despite drug levels in cerebrospinal fluid (CSF) that predict close to 90% central CRH1 receptor occupancy. CRH1 antagonists have been grouped based on their receptor dissociation kinetics, with pexacerfont falling in a category characterized by fast dissociation. Our results may indicate that antagonists with slow offset are required for therapeutic efficacy. Alternatively, the extensive preclinical data on CRH1 antagonism as a mechanism to suppress alcohol seeking may not translate to humans.

Addictive disorders are a major public health concern, associated with high relapse rates, significant disability and substantial mortality. Unfortunately, current interventions are only modestly effective. Preclinical studies as well as human neuroimaging studies have provided strong evidence that the observable behaviours that characterize the addiction phenotype, such as compulsive drug consumption, impaired self-control, and behavioural inflexibility, reflect underlying dysregulation and malfunction in specific neural circuits. These developments have been accompanied by advances in neuromodulation interventions, both invasive as deep brain stimulation, and non-invasive such as repetitive transcranial magnetic stimulation and transcranial direct current stimulation. These interventions appear particularly promising as they may not only allow us to probe affected brain circuits in addictive disorders, but also seem to have unique therapeutic applications to directly target and remodel impaired circuits. However, the available literature is still relatively small and sparse, and the long-term safety and efficacy of these interventions need to be confirmed. Here we review the literature on the use of neuromodulation in addictive disorders to highlight progress limitations with the aim to suggest future directions for this field.

BACKGROUND A common single nucleotide polymorphism (C385A) in the human fatty acid amide hydrolase (FAAH) gene has been associated with decreased distress responses in healthy volunteers, but its role in psychiatric disorders remains unknown. Here, we obtained genotypes and carried out a secondary analysis of subjects from a trial of comorbid posttraumatic stress disorder (PTSD) and alcohol dependence (AD). We evaluated the effects of C385A variation on behavioral and biochemical biomarkers of distress responses. METHODS Forty-nine patients with PTSD and AD were admitted for 4 weeks to an experimental medicine unit at the NIH Clinical Center. Following detoxification, stress reactivity and peripheral endocannabinoid levels were assessed in response to a challenge session using personalized auditory guided imagery. Over the course of the study, subjects were also evaluated for changes in PTSD symptom severity. RESULTS FAAH 385A allele carriers showed a marked increase in serum anandamide levels throughout the stress challenge procedure compared with C allele homozygotes, while levels of endocannabinoids primarily metabolized through other enzymatic activity, such as 2-AG, did not differ between genotype groups. FAAH 385A carriers also had decreased subjective anxiety responses to the stress challenge. Similar effects of FAAH C385A genotype were found at the level of clinical PTSD symptom severity, in particular in the arousal domain. CONCLUSIONS This is to our knowledge the first study showing that FAAH 385A variation modulates stress responses in subjects with disorders characterized by increased stress reactivity. These findings point to the endocannabinoid pathway as a promising target for future anti-stress therapeutics.

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The endocannabinoid system plays an important role in reward and addiction. One of the two main endocannabinoid neurotransmitters, anandamide, is metabolized by fatty acid amide hydrolase, an enzyme with a functional genetic polymorphism (FAAH Pro129Thr, rs324420). The Thr129 allele has been linked to problem drug and alcohol use, but the association has not been widely replicated and may be stronger for clinical measures of severity rather than categorical diagnosis. In the present study, we sought to determine whether the Thr129 allele was associated with both alcohol dependence (AD) diagnosis and severity in a sample of 1434 European American and African American individuals, 952 of whom were diagnosed with lifetime AD. Participants were genotyped for FAAH rs324420, and ancestry was determined via a genome-wide panel of ancestry informative markers. Subjects participated in Structured Clinical Interviews for psychiatric disorders and 90-day Timeline Followback interviews to assess recent alcohol use. European American participants with current AD had a higher Thr129 allele frequency than non-dependent controls. In European Americans with lifetime AD, there were significantly different distributions of drinking days and binge drinking days between the two genotype groups, with Thr129 carriers reporting a median of 10 fewer abstinent days and 13 more binge drinking days than Pro129/Pro129 homozygotes. In African American participants, there were no significant differences between Thr129 allele frequency in cases and controls and no significant differences in measures of AD severity by genotype. These findings provide evidence that the Pro129Thr missense variant is associated with AD severity in European Americans.

Unfortunately for mariners, the total amount of wave energy in a storm doesn't rise linearly with wind speed, but to its fourth power. The seas generated by a forty-knot wind aren't twice as violent as those from a twenty-knot wind, they're seventeen times as violent.