Integrative Pharmacology in the Treatment of Substance Use Disorders.

The detrimental physical, mental, and socioeconomic effects of substance use disorders (SUDs) have been apparent to the medical community for decades. However, it has become increasingly urgent in recent years to develop novel pharmacotherapies to treat SUDs. Currently, practitioners typically rely on monotherapy. Monotherapy has been shown to be superior to no treatment at all for most substance classes. However, many randomized controlled trials (RCTs) have revealed that monotherapy leads to poorer outcomes when compared with combination treatment in all specialties of medicine. The results of RCTs suggest that monotherapy frequently fails since multiple dysregulated pathways, enzymes, neurotransmitters, and receptors are involved in the pathophysiology of SUDs. As such, research is urgently needed to determine how various neurobiological mechanisms can be targeted by novel combination treatments to create increasingly specific yet exceedingly comprehensive approaches to SUD treatment. This article aims to review the neurobiology that integrates many pathophysiologic mechanisms and discuss integrative pharmacology developments that may ultimately improve clinical outcomes for patients with SUDs. Many neurobiological mechanisms are known to be involved in SUDs including dopaminergic, nicotinic, N-methyl-D-aspartate (NMDA), and kynurenic acid (KYNA) mechanisms. Emerging evidence indicates that KYNA, a tryptophan metabolite, modulates all these major pathophysiologic mechanisms. Therefore, achieving KYNA homeostasis by harmonizing integrative pathophysiology and pharmacology could prove to be a better therapeutic approach for SUDs. We propose KYNA-NMDA-α7nAChRcentric pathophysiology, the "conductor of the orchestra," as a novel approach to treat many SUDs concurrently. KYNA-NMDA-α7nAChR pathophysiology may be the "command center" of neuropsychiatry. To date, extant RCTs have shown equivocal findings across comparison conditions, possibly because investigators targeted single pathophysiologic mechanisms, hit wrong targets in underlying pathophysiologic mechanisms, and tested inadequate monotherapy treatment. We provide examples of potential combination treatments that simultaneously target multiple pathophysiologic mechanisms in addition to KYNA. Kynurenine pathway metabolism demonstrates the greatest potential as a target for neuropsychiatric diseases. The investigational medications with the most evidence include memantine, galantamine, and N-acetylcysteine. Future RCTs are warranted with novel combination treatments for SUDs. Multicenter RCTs with integrative pharmacology offer a promising, potentially fruitful avenue to develop novel therapeutics for the treatment of SUDs.

High-Frequency Transcranial Magnetic Stimulation Combined With Functional Magnetic Resonance Imaging Reveals Distinct Activation Patterns Associated With Different Dorsolateral Prefrontal Cortex Stimulation Sites.

OBJECTIVES: Transcranial magnetic stimulation (TMS) has been extensively used for the treatment of depression, obsessive-compulsive disorder, and certain neurologic disorders. Despite having promising treatment efficacy, the fundamental neural mechanisms of TMS remain understudied. MATERIALS AND METHODS: In this study, 15 healthy adult participants received simultaneous TMS and functional magnetic resonance imaging to map the modulatory effect of TMS when it was applied over three different sites in the dorsolateral prefrontal cortex. Independent component analysis (ICA) was used to identify the networks affected by TMS when applied over the different sites. The standard general linear model (GLM) analysis was used for comparison. RESULTS: ICA showed that TMS affected the stimulation sites as well as remote brain areas, some areas/networks common across all TMS sites, and other areas/networks specific to each TMS site. In particular, TMS site and laterality differences were observed at the left executive control network. In addition, laterality differences also were observed at the dorsal anterior cingulate cortex and dorsolateral/dorsomedial prefrontal cortex. In contrast with the ICA findings, the GLM-based results mainly showed activation of auditory cortices regardless of the TMS sites. CONCLUSIONS: Our findings support the notion that TMS could act through a top-down mechanism, indirectly modulating deep subcortical nodes by directly stimulating cortical regions. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT03394066.

Effects of metformin on apoptosis and α-synuclein in a rat model of pentylenetetrazole-induced epilepsy.

The present study was designed to examine the possible neuroprotective and antiepileptic effects of metformin (Metf) in a rat model of pentylenetetrazole (PTZ)-induced epilepsy and its possible underlying mechanisms. Forty male albino rats were assigned to 4 groups of equal size: (1) normal control (NC) group, (2) Metf group: daily treatment with Metf (200 mg/kg, i.p.) for 2 weeks, (3) PTZ group: treatment with PTZ (50 mg/kg, i.p.) every other day for 2 weeks, and (4) Metf + PTZ group: daily treatment with PTZ and metformin (200 mg/kg, i.p.) for 2 weeks. Administration of PTZ caused a significant increase in seizure score and duration, induced a state of oxidative stress (high malondialdehyde, low reduced glutathione and catalase activity), and led to the upregulation of ß-catenin, caspase-3, and its cleavage products, Hsp70 and α-synuclein, in hippocampal regions as well as a significant reduction in seizure latency. While Metf treatment significantly ameliorated PTZ-induced seizures, attenuated oxidative stress, and upregulated α-synuclein and ß-catenin expression, it also inhibited caspase-3 activation and the release of the cleavage product and caused more upregulation in Hsp70 expression in hippocampal regions (p < 0.05). In conclusion, the antiepileptic and neuroprotective effects of Metf in PTZ-induced epilepsy might be due to the inhibition of apoptosis, attenuation of oxidative stress and α-synuclein expression, and upregulation of Hsp70.

The Impact of Mirth-Inducing Ventral Striatal Deep Brain Stimulation on Functional and Effective Connectivity.

Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) is an investigational therapy for treatment-resistant obsessive-compulsive disorder. The ability of VC/VS DBS to evoke spontaneous mirth in patients, often accompanied by smiling and laughter, is clinically well documented. However, the neural correlates of DBS-evoked mirth remain poorly characterized. Patients undergoing VC/VS DBS surgery underwent intraoperative evaluation in which mirth-inducing and non-mirth-inducing stimulation localizations were identified. Using dynamic causal modeling (DCM) for fMRI, the effect of mirth-inducing DBS on functional and effective connectivity among established nodes in limbic cortico-striato-thalamo-cortical (CSTC) circuitry was investigated. Both mirth-inducing and non-mirth-inducing VC/VS DBS consistently resulted (conjunction, global null, family-wise error-corrected P < 0.05) in activation of amygdala, ventral striatum, and mediodorsal thalamus. However, only mirth-inducing DBS resulted in functional inhibition of anterior cingulate cortex. Dynamic causal modeling revealed that mirth-inducing DBS enhanced effective connectivity from anterior cingulate to ventral striatum, while attenuating connectivity from thalamus to ventral striatum relative to non-mirth-inducing stimulation. These results suggest that DBS-evoked mood elevation is accompanied by distinct patterns of limbic thalamocortical connectivity. Using the novel combination of DBS-evoked mood alteration and functional MRI in human subjects, we provide new insights into the network-level mechanisms that influence affect.

Cannabis Edibles: Blood and Oral Fluid Cannabinoid Pharmacokinetics and Evaluation of Oral Fluid Screening Devices for Predicting Δ9-Tetrahydrocannabinol in Blood and Oral Fluid following Cannabis Brownie Administration.

BACKGROUND: Roadside oral fluid (OF) Δ9-tetrahydrocannabinol (THC) detection indicates recent cannabis intake. OF and blood THC pharmacokinetic data are limited and there are no on-site OF screening performance evaluations after controlled edible cannabis. CONTENT: We reviewed OF and blood cannabinoid pharmacokinetics and performance evaluations of the Draeger DrugTest®5000 (DT5000) and Alere™ DDS®2 (DDS2) on-site OF screening devices. We also present data from a controlled oral cannabis administration session. SUMMARY: OF THC maximum concentrations (Cmax) were similar in frequent as compared to occasional smokers, while blood THC Cmax were higher in frequent [mean (range) 17.7 (8.0-36.1) µg/L] smokers compared to occasional [8.2 (3.2-14.3) µg/L] smokers. Minor cannabinoids Δ9-tetrahydrocannabivarin and cannabigerol were never detected in blood, and not in OF by 5 or 8 h, respectively, with 0.3 µg/L cutoffs. Recommended performance (analytical sensitivity, specificity, and efficiency) criteria for screening devices of ≥80% are difficult to meet when maximizing true positive (TP) results with confirmation cutoffs below the screening cutoff. TPs were greatest with OF confirmation cutoffs of THC ≥1 and ≥2 µg/L, but analytical sensitivities were <80% due to false negative tests arising from confirmation cutoffs below the DT5000 and DDS2 screening cutoffs; all criteria were >80% with an OF THC ≥5 µg/L cutoff. Performance criteria also were >80% with a blood THC ≥5 µg/L confirmation cutoff; however, positive OF screening results might not confirm due to the time required to collect blood after a crash or police stop. OF confirmation is recommended for roadside OF screening.ClinicalTrials.gov identification number: NCT02177513.

Effects of ferulic acid on oxidative stress, heat shock protein 70, connexin 43, and monoamines in the hippocampus of pentylenetetrazole-kindled rats.

The present study investigated the effects of ferulic acid (FA) on pentylenetetrazole (PTZ)-induced seizures, oxidative stress markers (malondialdehyde (MDA), catalase, and reduced glutathione (GSH)), connexin (Cx) 43, heat shock protein 70 (Hsp 70), and monoamines (serotonin (5-HT) and norepinephrine (NE)) levels in a rat model of PTZ-induced kindling. Sixty Sprague Dawley rats were divided into 5 equal groups: (a) normal group; (b) FA group: normal rats received FA at a dose of 40 mg/kg daily; (c) PTZ group: normal rats received PTZ at a dose of 50 mg/kg i.p. on alternate days for 15 days; (d) FA-before group: treatment was the same as for the PTZ group, except rats received FA; and (e) FA-after group: rats received FA from sixth dose of PTZ. PTZ caused a significant increase in MDA, Cx43, and Hsp70 along with a significant decrease in GSH, 5-HT, and NE levels and CAT activity in the hippocampus (p < 0.05). Pre- and post-treatment with FA caused significant improvement in behavioral parameters, MDA, CAT, GSH, 5-HT, NE, Cx43 expression, and Hsp70 expression in the hippocampal region (p < 0.05). We conclude that FA has neuroprotective effects in PTZ-induced epilepsy, which might be due to attenuation of oxidative stress and Cx43 expression and upregulation of neuroprotective Hsp70 and neurotransmitters (5-HT and NE).

Evaluation of divided attention psychophysical task performance and effects on pupil sizes following smoked, vaporized and oral cannabis administration.

Establishing science-based driving per se blood Δ9 -tetrahydrocannabinol (THC) limits is challenging, in part because of prolonged THC detection in chronic, frequent users. Therefore, documenting observable signs of impairment is important for driving under the influence of drugs. We evaluated frequent and occasional cannabis smokers' performance on the modified Romberg balance, one leg stand (OLS), and walk and turn (WAT) tasks, and pupil size effects following controlled placebo (0.001% THC), smoked, vaporized and oral (6.9% [~50.4 mg] THC) cannabis administration. Significant effects following inhaled doses were not observed due to delayed tasks administration 1.5 and 3.5 h post-dose, but significant impairment was observed after oral dosing (blood THC concentrations peaked 1.5-3.5 h post-dose). Occasional smokers' odds of exhibiting ≥2 clues on the OLS or WAT following oral dosing were 6.4 (95% CI 2.3-18.4) times higher than after placebo, with THC and 11-hydroxy-THC blood concentrations individually producing odds ratios of 1.3 (1.1-1.5) and 1.5 (1.3-1.8) for impairment in these tasks, respectively. Pupil sizes after oral dosing under the direct lighting condition were significantly larger than after placebo by mean (SE, 95% CI) 0.4 (0.1, 0.2-0.6) mm at 1.5 h and 0.5 (0.2, 0.2-0.8) mm at 3.5 h among all participants. Oral cannabis administration impaired occasional cannabis users' performance on the OLS and WAT tasks compared to placebo, supporting other reports showing these tasks are sensitive to cannabis-related impairment. Occasional smokers' impairment was related to blood THC and 11-hydroxy-THC concentrations. These are important public health policy findings as consumption of edible cannabis products increases. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

Free and Glucuronide Whole Blood Cannabinoids' Pharmacokinetics after Controlled Smoked, Vaporized, and Oral Cannabis Administration in Frequent and Occasional Cannabis Users: Identification of Recent Cannabis Intake.

BACKGROUND: There is increasing interest in markers of recent cannabis use because following frequent cannabis intake, Δ9-tetrahydrocannabinol (THC) may be detected in blood for up to 30 days. The minor cannabinoids cannabidiol, cannabinol (CBN), and THC-glucuronide were previously detected for ≤2.1 h in frequent and occasional smokers' blood after cannabis smoking. Cannabigerol (CBG), Δ9-tetrahydrocannabivarin (THCV), and 11-nor-9-carboxy-THCV might also be recent use markers, but their blood pharmacokinetics have not been investigated. Additionally, while smoking is the most common administration route, vaporization and edibles are frequently used. METHODS: We characterized blood pharmacokinetics of THC, its phase I and phase II glucuronide metabolites, and minor cannabinoids in occasional and frequent cannabis smokers for 54 (occasional) and 72 (frequent) hours after controlled smoked, vaporized, and oral cannabis administration. RESULTS: Few differences were observed between smoked and vaporized blood cannabinoid pharmacokinetics, while significantly greater 11-nor-9-carboxy-THC (THCCOOH) and THCCOOH-glucuronide concentrations occurred following oral cannabis. CBG and CBN were frequently identified after inhalation routes with short detection windows, but not detected following oral dosing. Implementation of a combined THC ≥5 µg/L plus THCCOOH/11-hydroxy-THC ratio <20 cutoff produced detection windows <8 h after all routes for frequent smokers; no occasional smoker was positive 1.5 h or 12 h following inhaled or oral cannabis, respectively. CONCLUSIONS: Vaporization and smoking provide comparable cannabinoid delivery. CBG and CBN are recent-use cannabis markers after cannabis inhalation, but their absence does not exclude recent use. Multiple, complimentary criteria should be implemented in conjunction with impairment observations to improve interpretation of cannabinoid tests. Clinicaltrials.gov Identifier: NCT02177513.

Stimulation-Induced Transient Nonmotor Psychiatric Symptoms following Subthalamic Deep Brain Stimulation in Patients with Parkinson's Disease: Association with Clinical Outcomes and Neuroanatomical Correlates.

BACKGROUND: The clinical and neurobiological underpinnings of transient nonmotor (TNM) psychiatric symptoms during the optimization of stimulation parameters in the course of subthalamic nucleus deep brain stimulation (STN-DBS) remain under intense investigation. METHODS: Forty-nine patients with refractory Parkinson's disease underwent bilateral STN-DBS implants and were enrolled in a 24-week prospective, naturalistic follow-up study. Patients who exhibited TNM psychiatric manifestations during DBS parameter optimization were evaluated for potential associations with clinical outcome measures. RESULTS: Twenty-nine TNM+ episodes were reported by 15 patients. No differences between TNM+ and TNM- groups were found in motor outcome. However, unlike the TNM- group, TNM+ patients did not report improvement in subsyndromal depression or quality of life. TNM+ episodes were more likely to emerge during bilateral monopolar stimulation of the medial STN. CONCLUSIONS: The occurrence of TNM psychiatric symptoms during optimization of stimulation parameters was associated with the persistence of subsyndromal depression and with lower quality of life ratings at 6 months. The neurobiological underpinnings of TNM symptoms are investigated yet remain difficult to explain.

N-acetylaspartate normalization in bipolar depression after lamotrigine treatment.

OBJECTIVES: The aim of the present study was to examine N-acetylaspartate (NAA), a general marker of neuronal viability, and total NAA (tNAA), the combined signal of NAA and N-acetylaspartylglutamate, in bipolar depression before and after lamotrigine treatment. Given that NAA is synthesized through direct acetylation of aspartate by acetyl-coenzyme A-l-aspartate-N-acetyltransferase, we hypothesized that treatment with lamotrigine would be associated with an increase in NAA level. METHODS: Patients with bipolar depression underwent two-dimensional proton magnetic resonance spectroscopy of the anterior cingulate at baseline (n = 15) and after 12 weeks of lamotrigine treatment (n = 10). A group of age-matched healthy controls (n = 9) underwent scanning at baseline for comparison. RESULTS: At baseline, patients with bipolar depression had significantly lower NAA [mean standard deviation (SD) = 1.13 (0.21); p = 0.02] than controls [mean (SD) = 1.37 (0.27)]. Significant increases in NAA [mean (SD) = 1.39 (0.21); p = 0.01] and tNAA [mean (SD) = 1.61 (0.25); p = 0.02] levels were found after 12 weeks of lamotrigine treatment. CONCLUSIONS: These data suggest an NAA deficit in bipolar depression that is normalized after lamotrigine treatment. Future research is warranted to evaluate whether baseline NAA level is a potential biomarker for identifying lamotrigine response patterns and whether this functional brain change has an associated clinical response.

Mood stability in Parkinson disease following deep brain stimulation: a 6-month prospective follow-up study.

BACKGROUND: Deep brain stimulation for Parkinson disease has been associated with psychiatric adverse effects including anxiety, depression, mania, psychosis, and suicide. OBJECTIVE: The purpose of this study was to evaluate the safety of deep brain stimulation in a large Parkinson disease clinical practice. METHODS: Patients approved for surgery by the Mayo Clinic deep brain stimulation clinical committee participated in a 6-month prospective naturalistic follow-up study. In addition to the Unified Parkinson's Disease Rating Scale, stability and psychiatric safety were measured using the Beck Depression Inventory, Hamilton Depression Rating Scale, and Young Mania Rating scale. Outcomes were compared in patients with Parkinson disease who had a psychiatric history to those with no co-morbid psychiatric history. RESULTS: The study was completed by 49 of 54 patients. Statistically significant 6-month baseline to end-point improvement was found in motor and mood scales. No significant differences were found in psychiatric outcomes based on the presence or absence of psychiatric comorbidity. CONCLUSIONS: Our study suggests that patients with Parkinson disease who have a history of psychiatric co-morbidity can safely respond to deep brain stimulation with no greater risk of psychiatric adverse effect occurrence. A multidisciplinary team approach, including careful psychiatric screening ensuring mood stabilization and psychiatric follow-up, should be viewed as standard of care to optimize the psychiatric outcome in the course of deep brain stimulation treatment.

Association of GATA4 sequence variation with alcohol dependence.

To further explore reports of association of alcohol dependence and response to acamprosate treatment with the GATA4 rs13273672 single nucleotide polymorphism (SNP), we genotyped this and 10 other GATA4 SNPs in 816 alcohol-dependent cases and 1248 controls. We tested for association of alcohol dependence with the 11 SNPs individually and performed a global test for association using a principle components analysis. Our analyses demonstrate significant association between GATA4 and alcohol dependence at the gene level (P = 0.009) but no association with rs13273672. Further studies are needed to identify potential causal GATA4 variation(s) and the functional mechanism(s) contributing to this association.

Melatonin: a ferroptosis inhibitor with potential therapeutic efficacy for the post-COVID-19 trajectory of accelerated brain aging and neurodegeneration.

The unprecedented pandemic of COVID-19 swept millions of lives in a short period, yet its menace continues among its survivors in the form of post-COVID syndrome. An exponentially growing number of COVID-19 survivors suffer from cognitive impairment, with compelling evidence of a trajectory of accelerated aging and neurodegeneration. The novel and enigmatic nature of this yet-to-unfold pathology demands extensive research seeking answers for both the molecular underpinnings and potential therapeutic targets. Ferroptosis, an iron-dependent cell death, is a strongly proposed underlying mechanism in post-COVID-19 aging and neurodegeneration discourse. COVID-19 incites neuroinflammation, iron dysregulation, reactive oxygen species (ROS) accumulation, antioxidant system repression, renin-angiotensin system (RAS) disruption, and clock gene alteration. These events pave the way for ferroptosis, which shows its signature in COVID-19, premature aging, and neurodegenerative disorders. In the search for a treatment, melatonin shines as a promising ferroptosis inhibitor with its repeatedly reported safety and tolerability. According to various studies, melatonin has proven efficacy in attenuating the severity of certain COVID-19 manifestations, validating its reputation as an anti-viral compound. Melatonin has well-documented anti-aging properties and combating neurodegenerative-related pathologies. Melatonin can block the leading events of ferroptosis since it is an efficient anti-inflammatory, iron chelator, antioxidant, angiotensin II antagonist, and clock gene regulator. Therefore, we propose ferroptosis as the culprit behind the post-COVID-19 trajectory of aging and neurodegeneration and melatonin, a well-fitting ferroptosis inhibitor, as a potential treatment.

Sex-difference in the association between social drinking, structural brain aging and cognitive function in older individuals free of cognitive impairment.

Background: We investigated a potential sex difference in the relationship between alcohol consumption, brain age gap and cognitive function in older adults without cognitive impairment from the population-based Mayo Clinic Study of Aging. Methods: Self-reported alcohol consumption was collected using the food-frequency questionnaire. A battery of cognitive testing assessed performance in four different domains: attention, memory, language, and visuospatial. Brain magnetic resonance imaging (MRI) was conducted using 3-T scanners (Signa; GE Healthcare). Brain age was estimated using the Brain-Age Regression Analysis and Computational Utility Software (BARACUS). We calculated the brain age gap as the difference between predicted brain age and chronological age. Results: The sample consisted of 269 participants [55% men (n=148) and 45% women (n=121) with a mean age of 79.2 ± 4.6 and 79.5 ± 4.7 years respectively]. Women had significantly better performance compared to men in memory, (1.12 ± 0.87 vs 0.57 ± 0.89, P<0.0001) language (0.66 ± 0.8 vs 0.33 ± 0.72, P=0.0006) and attention (0.79 ± 0.87 vs 0.39 ± 0.83, P=0.0002) z-scores. Men scored higher in visuospatial skills (0.71 ± 0.91 vs 0.44 ± 0.90, P=0.016). Compared to participants who reported zero alcohol drinking (n=121), those who reported alcohol consumption over the year prior to study enrollment (n=148) scored significantly higher in all four cognitive domains [memory: F3,268 = 5.257, P=0.002, Language: F3,258 = 12.047, P<0.001, Attention: F3,260 = 22.036, P<0.001, and Visuospatial: F3,261 = 9.326, P<0.001] after correcting for age and years of education. In addition, we found a significant positive correlation between alcohol consumption and the brain age gap (P=0.03). Post hoc regression analysis for each sex with language z-score revealed a significant negative correlation between brain age gap and language z-scores in women only (P=0.008). Conclusion: Among older adults who report alcohol drinking, there is a positive association between higher average daily alcohol consumption and accelerated brain aging despite the fact that drinkers had better cognitive performance compared to zero drinkers. In women only, accelerated brain aging is associated with worse performance in language cognitive domain. Older adult women seem to be vulnerable to the negative effects of alcohol on brain structure and on certain cognitive functions.

Association of the PDYN gene with alcohol dependence and the propensity to drink in negative emotional states.

Synthetic κ-opioid receptor (KOR) agonists induce dysphoric and pro-depressive effects and variations in the KOR (OPRK1) and prodynorphin (PDYN) genes have been shown to be associated with alcohol dependence. We genotyped 23 single nucleotide polymorphisms (SNPs) in the PDYN and OPRK1 genes in 816 alcohol-dependent subjects and investigated their association with: (1) negative craving measured by a subscale of the Inventory of Drug Taking Situations; (2) a self-reported history of depression; (3) the intensity of depressive symptoms measured by the Beck Depression Inventory-II. In addition, 13 of the 23 PDYN and OPRK1 SNPs, which were previously genotyped in a set of 1248 controls, were used to evaluate association with alcohol dependence. SNP and haplotype tests of association were performed. Analysis of a haplotype spanning the PDYN gene (rs6045784, rs910080, rs2235751, rs2281285) revealed significant association with alcohol dependence (p = 0.00079) and with negative craving (p = 0.0499). A candidate haplotype containing the PDYN rs2281285-rs1997794 SNPs that was previously associated with alcohol dependence was also associated with negative craving (p = 0.024) and alcohol dependence (p = 0.0008) in this study. A trend for association between depression severity and PDYN variation was detected. No associations of OPRK1 gene variation with alcohol dependence or other studied phenotypes were found. These findings support the hypothesis that sequence variation in the PDYN gene contributes to both alcohol dependence and the induction of negative craving in alcohol-dependent subjects.

A retrospective study of gender differences in depressive symptoms and risk of relapse in patients with alcohol dependence.

BACKGROUND AND OBJECTIVES: The aim of this study was to investigate potential gender differences in situations associated with heavy alcohol drinking. METHODS: Data from 395 alcohol dependent patients participating in the Mayo Clinic Intensive Addiction Program were evaluated. Each participant completed the inventory of drug taking situations (IDTS), Penn alcohol craving scale (PACS), patient health questionnaire (PHQ-9), and/or Beck depression inventory (BDI). Gender differences in IDTS scores representing three domains (negative, positive, and temptation) of situations associated with heavy alcohol use were examined. RESULTS: Women with alcohol dependence report a higher frequency of heavy drinking in unpleasant emotional (IDTS negative scores mean ± SD women vs. men: 52.3 ± 22.1 vs. 43.8 ± 21.8; p = .0006), and as a result of temptation (IDTS temptation scores mean ± SD women vs. men: 40.4 ± 23.0 vs. 35.3 ± 20.8; p = .035). Upon admission, women also scored significantly higher on depressive symptoms as measured by the BDI (23.4 ± 11.4 vs. 18.2 ± 9.8, p < .001). After controlling for depressive symptom severity as a covariate, the IDTS gender differences were no longer significant. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: Our results suggest that unpleasant or temptation based emotional situations are a vulnerability risk factor for heavy drinking particularly in females. This risk appears to be at least partially driven by depressive symptom burden. Future research is needed to further investigate this finding.

Sex difference in the association between blood alcohol concentration and serum ferritin.

Introduction: The sex difference in alcohol use disorder (AUD) is ingrained in distinctive neurobiological responses between men and women, which necessitates further investigation for a more tailored management. Methods: Minding the findings of iron dysregulation in AUD and the sex difference in iron homeostasis in multiple physiological and pathological settings, we examined the sex difference in the association between serum ferritin and blood alcohol concentration (BAC) in intoxicated males (n = 125) and females (n = 59). We included patients with both serum ferritin tested of any value and a BAC above the level of detection during the same hospital admission period. We investigated sex difference in the relationship between BAC, serum ferritin and liver enzymes in intoxicated critically ill and noncritically ill patients. Results: We found a negative association between serum ferritin and BAC in critically ill, intoxicated females [R2 = 0.44, F(1,14) = 11.02, p = 0.005], with much attenuated serum ferritin in females compared to their male counterparts (194.5 ± 280.4 vs. 806.3 ± 3405.7 ng/L, p = 0.002). We found a positive association between serum ferritin and liver enzymes [alanine transaminase (ALT) and aspartate transferase (AST)] in critically ill intoxicated females [ALT: R2 = 0.48, F(1,10) = 9.1, p = 0.013; AST: R2 = 0.68, F(1,10) = 21.2, p = 0.001] and in noncritically ill intoxicated males [ALT: R2 = 0.1, F(1,83) = 9.4, p = 0.003; AST: R2 = 0.1, F(1,78) = 10.5, p = 0.002]. The effect of BAC on serum ferritin was not mediated by ALT [indirect effect: (B = 0.13, p = 0.1)]. We also found a significant effect of sex, anemia, intensive care unit (ICU) admission and mortality on serum ferritin. Discussion: Our results suggest that high BAC in intoxicated female patients is associated with attenuated serum ferritin levels, questioning the role of low serum ferritin in female vulnerability to alcohol.

Attenuation of ferroptosis as a potential therapeutic target for neuropsychiatric manifestations of post-COVID syndrome.

Coronavirus disease-19 (COVID-19), caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), is associated with the persistence of pre-existing or the emergence of new neurological and psychiatric manifestations as a part of a multi-system affection known collectively as "post-COVID syndrome." Cognitive decline is the most prominent feature among these manifestations. The underlying neurobiological mechanisms remain under intense investigation. Ferroptosis is a form of cell death that results from the excessive accumulation of intracellular reactive iron, which mediates lipid peroxidation. The accumulation of lipid-based reactive oxygen species (ROS) and the impairment of glutathione peroxidase 4 (GPX4) activity trigger ferroptosis. The COVID-19-associated cytokine storm enhances the levels of circulating pro-inflammatory cytokines and causes immune-cell hyper-activation that is tightly linked to iron dysregulation. Severe COVID-19 presents with iron overload as one of the main features of its pathogenesis. Iron overload promotes a state of inflammation and immune dysfunction. This is well demonstrated by the strong association between COVID-19 severity and high levels of ferritin, which is a well-known inflammatory and iron overload biomarker. The dysregulation of iron, the high levels of lipid peroxidation biomarkers, and the inactivation of GPX4 in COVID-19 patients make a strong case for ferroptosis as a potential mechanism behind post-COVID neuropsychiatric deficits. Therefore, here we review the characteristics of iron and the attenuation of ferroptosis as a potential therapeutic target for neuropsychiatric post-COVID syndrome.

Natural Polyphenols-Resveratrol, Quercetin, Magnolol, and ß-Catechin-Block Certain Aspects of Heroin Addiction and Modulate Striatal IL-6 and TNF-α.

We have examined the effects of four different polyphenols in attenuating heroin addiction using a conditioned place preference (CPP) paradigm. Adult male Sprague Dawley rats received heroin (alternating with saline) in escalating doses starting from 10 mg/kg, i.p. up to 80 mg/kg/d for 14 consecutive days. The rats were treated with distilled water (1 mL), quercetin (50 mg/kg/d), ß-catechin (100 mg/kg/d), resveratrol (30 mg/kg/d), or magnolol (50 mg/kg/d) through oral gavage for 7 consecutive days, 30 min before heroin administration, starting on day 8. Heroin withdrawal manifestations were assessed 24 h post last heroin administration following the administration of naloxone (1 mg/kg i.p). Heroin CPP reinstatement was tested following a single dose of heroin (10 mg/kg i.p.) administration. Striatal interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) were quantified (ELISA) after naloxone-precipitated heroin withdrawal. Compared to the vehicle, the heroin-administered rats spent significantly more time in the heroin-paired chamber (p < 0.0001). Concomitant administration of resveratrol and quercetin prevented the acquisition of heroin CPP, while resveratrol, quercetin, and magnolol blocked heroin-triggered reinstatement. Magnolol, quercetin, and ß-catechin blocked naloxone-precipitated heroin withdrawal and increased striatal IL-6 concentration (p < 0.01). Resveratrol administration was associated with significantly higher withdrawal scores compared to those of the control animals (p < 0.0001). The results of this study show that different polyphenols target specific behavioral domains of heroin addiction in a CPP model and modulate the increase in striatal inflammatory cytokines TNF-α and IL-6 observed during naloxone-precipitated heroin withdrawal. Further research is needed to study the clinical utility of polyphenols and to investigate the intriguing finding that resveratrol enhances, rather than attenuates naloxone-precipitated heroin withdrawal.

No difference in COVID-19 treatment outcomes among current methamphetamine, cannabis and alcohol users.

BACKGROUND: Poor outcomes of COVID-19 have been reported in older males with medical comorbidities including substance use disorder. However, it is unknown whether there is a difference in COVID-19 treatment outcomes between patients who are current cannabis users, excessive alcohol drinkers and those who use a known hazardous stimulant such as methamphetamine (METH). METHODS: Electronic medical records (EMR) of COVID-19 patients with current METH (n = 32), cannabis (n = 46), and heavy alcohol use (n = 44) were reviewed. COVID-19 infection was confirmed by positive SARS-CoV-2 PCR test, current drug use was confirmed by positive urine drug testing, and alcohol use was identified by a blood alcohol concentration greater than 11 mg/dl. Multivariate linear regression models as well as the firth logistic regression models were used to examine the effect of substance use group (METH, cannabis, or alcohol) on treatment outcome measures. RESULTS: A total of 122 patients were included in this analysis. There were no significant differences found between drug groups in regards to key SARS-CoV-2 outcomes of interest including ICU admission, length of stay, interval between SARS-CoV-2 positive test and hospital discharge, delirium, intubation and mortality after adjusting for covariates. About one-fifth (21.9% in METH users, 15.2% in cannabis users, and 20.5% in alcohol users) of all patients required ICU admission. As many as 37.5% of METH users, 23.9% of cannabis users, and 29.5% of alcohol users developed delirium (P = 0.4). There were no significant differences between drug groups in COVID-19 specific medication requirements. Eight patients in total died within 10 months of positive SARS-CoV-2 PCR test. Two patients from the METH group (6.3%), two patients from the cannabis group (4.3%), and four patients from the alcohol group (9.1%) died. DISCUSSION: The study outcomes may have been affected by several limitations. These included the methodology of its retrospective design, relatively small sample size, and the absence of a COVID-19 negative control group. In addition, there was no quantification of substance use and many covariates relied on clinical documentation or patient self-report. Finally, it was difficult to control for all potential confounders particularly given the small sample size. CONCLUSION: Despite these limitations, our results show that current METH, cannabis, and heavy alcohol users in this study have similar treatment outcomes and suffer from high morbidity including in-hospital delirium and high mortality rates within the first-year post COVID-19. The extent to which co-morbid tobacco smoking contributed to the negative outcomes in METH, cannabis, and alcohol users remains to be investigated.