Review: Cannabinoids as Medicinals.

Purpose of review: There have been many debates, discussions, and published writings about the therapeutic value of cannabis plant and the hundreds of cannabinoids it contains. Many states and countries have attempted, are attempting, or have already passed bills to allow legal use of cannabinoids, especially cannabidiol (CBD), as medicines to treat a wide range of clinical conditions without having been approved by a regulatory body. Therefore, by using PubMed and Google Scholar databases, we have reviewed published papers during the past 30 years on cannabinoids as medicines and comment on whether there is sufficient clinical evidence from well-designed clinical studies and trials to support the use of CBD or any other cannabinoids as medicines. Recent findings: Current research shows that CBD and other cannabinoids currently are not ready for formal indications as medicines to treat a wide range of clinical conditions as promoted except for several exceptions including limited use of CBD for treating two rare forms of epilepsy in young children and CBD in combination with THC for treating multiple-sclerosis-associated spasticity. Summary: Research indicates that CBD and several other cannabinoids have potential to treat multiple clinical conditions, but more preclinical, and clinical studies and clinical trials, which follow regulatory guidelines, are needed to formally recommend CBD and other cannabinoids as medicines.

Cocaethylene, simultaneous alcohol and cocaine use, and liver fibrosis in people living with and without HIV.

BACKGROUND: The simultaneous consumption of cocaine and alcohol results in the production of cocaethylene (CE) in the liver, a highly toxic metabolite. Prior research suggests that cocaine use contributes to liver disease and its concomitant use with alcohol may increase its hepatotoxicity, but studies in humans are lacking. We evaluated the role of cocaine, its simultaneous use with alcohol, and CE on liver fibrosis. METHODS: We performed a cross-sectional analysis of the Miami Adult Studies on HIV (MASH) cohort. Cocaine use was determined via self-report, urine screen, and blood metabolites, using liquid chromatography with tandem mass spectrometry. Hazardous drinking was determined with the AUDIT-C and liver fibrosis with the Fibrosis-4 Index (FIB-4). RESULTS: Out of 649 participants included in this analysis, 281 (43.3%) used cocaine; of those, 78 (27.8%) had CE in blood. Cocaine users with CE had higher concentrations of cocaine metabolites in blood and were more likely to drink hazardously than cocaine users without CE and cocaine non-users. Overall, cocaine use was associated with liver fibrosis. CE in blood was associated with 3.17 (95% CI: 1.61, 6.23; p = 0.0008) times the odds of liver fibrosis compared to cocaine non-users, adjusting for covariates including HIV and HCV infection. The effect of CE on liver fibrosis was significantly greater than that of cocaine or alcohol alone. CONCLUSIONS: CE is a reliable marker of simultaneous use of cocaine and alcohol that may help identify individuals at risk of liver disease and aid in the prevention of its development or progression.

Cocaine use associated gut permeability and microbial translocation in people living with HIV in the Miami Adult Study on HIV (MASH) cohort.

OBJECTIVE: Determine if cocaine use impacts gut permeability, promotes microbial translocation and immune activation in people living with HIV (PLWH) using effective antiretroviral therapy (ART). METHODS: Cross-sectional analysis of 100 PLWH (ART ≥6 months, HIV-RNA <200 copies/mL) from the Miami Adult Studies on HIV (MASH) cohort. Cocaine use was assessed by self-report, urine screen, and blood benzoylecgonine (BE). Blood samples were collected to assess gut permeability (intestinal fatty acid-binding protein, I-FABP), microbial translocation (lipopolysaccharide, LPS), immune activation (sCD14, sCD27, and sCD163) and markers of inflammation (hs-CRP, TNF-α and IL-6). Multiple linear regression models were used to analyze the relationships of cocaine use. RESULTS: A total of 37 cocaine users and 63 cocaine non-users were evaluated. Cocaine users had higher levels of I-FABP (7.92±0.35 vs. 7.69±0.56 pg/mL, P = 0.029) and LPS (0.76±0.24 vs. 0.54±0.27 EU/mL, P<0.001) than cocaine non-users. Cocaine use was also associated with the levels of LPS (P<0.001), I-FABP (P = 0.033), and sCD163 (P = 0.010) after adjusting for covariates. Cocaine users had 5.15 times higher odds to exhibit higher LPS levels than non-users (OR: 5.15 95% CI: 1.89-13.9; P<0.001). Blood levels of BE were directly correlated with LPS (rho = 0.276, P = 0.028), sCD14 (rho = 0.274, P = 0.031), and sCD163 (rho = 0.250, P = 0.049). CONCLUSIONS: Cocaine use was associated with markers of gut permeability, microbial translocation, and immune activation in virally suppressed PLWH. Mitigation of cocaine use may prevent further gastrointestinal damage and immune activation in PLWH.

HIV, psychological resilience, and substance misuse during the COVID-19 pandemic: A multi-cohort study.

OBJECTIVE: The COVID-19 pandemic has dramatically impacted mental health, increasing rates of substance misuse. Resilience is a positive adaptation to stress that may act as a buffer against adverse mental health outcomes. Based on prior knowledge, we hypothesized that PLWH would display higher resilience than HIV-uninfected peers, and that high resilience would be associated with lower risk of substance misuse. METHODS: This analysis of the Collaborating Consortium of Cohorts Producing NIDA Opportunities (C3PNO) included data from six USA cohorts that administered a COVID-19-related survey with a 3-month follow-up during May 2020 and March 2021. All data was self-reported. The Brief Resilience Scale and General Anxiety Disorder-7 were utilized. Primary analyses consisted of multivariate generalized linear mixed models with random intercepts using binary logistic regression. RESULTS: A total of 1430 participants completed both surveys, of whom 670 (46.9%) were PLWH. PLWH had lower odds of anxiety (OR=0.67, 95% CI: 0.51-0.89) and higher odds of high resilience (OR=1.21, 95% CI: 1.02-1.44) than HIV-uninfected participants, adjusted for covariates. The presence of anxiety was associated with higher risk of misuse of all substances. High resilience was associated with lower risk of anxiety and misuse of substances, adjusted for covariates. CONCLUSIONS: Psychological resilience was associated with lower risk of anxiety and substance misuse, potentially serving as a buffer against poor mental and behavioral health during the COVID-19 pandemic. Further research is needed to identify pathways of resilience in the context of substance misuse and comprehensive resilience-focused interventions.

Hepatitis C Virus Infection in Persons Who Inject Drugs in the Middle East and North Africa: Intervention Strategies.

There is a high incidence and prevalence of hepatitis C viral infection in persons with or without substance use disorders (SUDs) in the Middle East and North Africa (MENA) region, but only a small number receive comprehensive care. Highly effective direct-acting antiviral (DAA) medications are available at substantially lower costs; however, complete elimination of the hepatitis C virus (HCV) can only be achieved if integrated care strategies target those at highest risk for HCV infection and transmission and improve access to care. Due to the high prevalence of SUD in the MENA region, strategies to eliminate HCV must focus on integrated healthcare across multiple subspecialties, including addiction medicine, psychiatry, infectious diseases, hepatology, and social work. In this invited manuscript, we review the epidemiology of HCV in the MENA region and highlight intervention strategies to attain the WHO's goal of HCV eradication by 2030.

The Link between Cannabis Use, Immune System, and Viral Infections.

Cannabis continues to be the most used drug in the world today. Research shows that cannabis use is associated with a wide range of adverse health consequences that may involve almost every physiological and biochemical system including respiratory/pulmonary complications such as chronic cough and emphysema, impairment of immune function, and increased risk of acquiring or transmitting viral infections such as HIV, HCV, and others. The review of published research shows that cannabis use may impair immune function in many instances and thereby exerts an impact on viral infections including human immune deficiency virus (HIV), hepatitis C infection (HCV), and human T-cell lymphotropic type I and II virus (HTLV-I/II). The need for more research is also highlighted in the areas of long-term effects of cannabis use on pulmonary/respiratory diseases, immune dysfunction and the risk of infection transmission, and the molecular/genetic basis of immune dysfunction in chronic cannabis users.

Cannabis/Cannabinoids for Treating COVID-19 Associated Neuropsychiatric Complications.

COVID-19 epidemic has resulted in devastating mortality and morbidity consisting of socioeconomic and health effects that have included respiratory/pulmonary, cardiovascular, mental health and neurological consequences such as anxiety, depression, and substance use. Several effective vaccines have been developed and extensive efforts are underway to develop therapeutics to treat COVID-19. Cannabis and/or its product-cannabidiol (CBD) are being advertised for the treatment of COVID-19 associated mental/neurological complications and substance use disorders. However, research reviewed shows that there is insufficient data from clinical studies to support the use of cannabis or CBD for the treatment of COVID-19 associated mental health and neurological complications. Additional basic and clinical research is suggested to develop cannabis or cannabidiol for the treatment of mental health problems associated with coronavirus infection and or substance use disorders. In the meantime, it is important that the addiction physician/psychiatrist must caution while prescribing or recommending cannabis or CBD for treating such clinical indications. Research shows that currently there is no clinical evidence to support the use of cannabis or any of its compounds including CBD for treating any of the neuropsychiatric complications of COVID-19. Thus, it is important that the addiction physicians/psychiatrists caution their patients from using cannabis or cannabis products for treating any such complications.

COVID-19 and Cannabidiol (CBD).

COVID-19 pandemic has resulted in devastating mortality and morbidity consisting of socioeconomic and health effects that have included respiratory/pulmonary, cardiovascular, mental health and neurological consequences such as anxiety, depression, and substance use. Extensive efforts are underway to develop preventive vaccines and therapeutics such as remdesivir, dexamethasone, convalescent plasma, and others to treat COVID-19 but many report residual mental health problems after recovery. Cannabis products such as cannabidiol (CBD) are being advertised for the treatment of COVID-19 associated mental health problems and substance use disorders. This commentary will briefly clear the myth that CBD can ameliorate a wide range of COVID-19 associated health effects including anxiety, depression, or any substance use disorder, and show that there is a clear lack of sufficient unbiased clinical evidence from well-designed double-blind, placebo-controlled clinical trials to prove the antianxiety or antidepression therapeutic properties of CBD and support its wide use as medicine to treat COVID-19- associated mental health conditions or substance use disorders. Finally, we suggest that addiction physicians must play an important role in dealing with their patients requesting CBD prescription for treating any of these conditions.

Interventions for HIV and hepatitis C virus infections in recreational drug users.

Recreational drug use and infections are 2 of the major problems in the world today. Both cause serious health problems, such as immunologic impairment leading to opportunistic infections and medical comorbidity, including medical complications associated with, for example, human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections. Effective and safe interventions (prevention and pharmacologic treatment) are possible for drug-dependent patients with single or dual infections with HIV and HCV if patients in drug treatment programs are closely monitored for adherence and compliance to treatment regimens.

Drug interactions between antiretroviral medications and medications used in the treatment of drug addiction: research needs.

Today substance dependence is one of the major public health problems in the world with millions of people abusing legal and illegal drugs. In addition, almost one-third of the world's population suffers with one or more infections. Both drugs of abuse and infections are associated with serious medical and health consequences, some of which may be exacerbated by the occurrence of pharmacokinetic and/or pharmacodynamic interactions between medications used in the treatment of these conditions when they co-occur. This review briefly discusses issues surrounding clinical management related to drug interactions experienced by substance abusing patients. The emphasis of this paper is on the research needed to further study the extent, nature, and underlying molecular/genetic mechanism(s) of interactions between drugs of abuse, medications used in the treatment of drug addiction, and co-occurring infections.

Clinical management of drug addicts infected with human immunodeficiency virus and hepatitis C virus.

Substance abuse and infections remain two of the major problems in the world today. Both are associated with serious morbidity and mortality, including immunological impairment leading to opportunistic infections, mental and neuropsychiatric complications of HIV and HCV infections, and liver damage of chronic HCV infection. Clinical management of substance abusers with infections is possible, available, and effective if individuals in drug treatment programs are closely monitored for adherence and compliance to HIV/HCV treatment regimens.

Addiction Medicine Physicians and Medicinal Cannabinoids.

This Viewpoint communicates the importance of clinicians, particularly addiction clinicians, to be educated about both harmful and beneficial effects of cannabis and related products before making therapeutic recommendations.

Drug-Drug Interactions and Diagnostics for Drug Users With HIV and HIV/HCV Coinfections: Introduction.

Substance use and pharmacologic treatment of co-occurring infections such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are associated with many adverse consequences including pharmacokinetic and pharmacodynamic drug-drug interactions (DDIs). The National Institute on Drug Abuse sponsored a 2-day conference on DDIs at which clinicians/scientists from government, academia, and the pharmaceutical industry presented the most current research findings to formulate a comprehensive overview of DDIs. Specific topics discussed included drug metabolism; drug interactions between medications used in the treatment of HIV, HCV, and substance use disorders; intrahepatic concentrations and methods of assessment of drugs in liver disease of varying etiologies and degrees of impairment; and minimally invasive sampling techniques for the assessment of intrahepatic drug concentrations, viral replication, and changes in gene expression in response to treatment. Finally, the speakers identified research targets and priorities on DDIs. Areas of emphasis included development of diagnostic assays for drug concentration assessment in different organs, an enhanced understanding of factors responsible for alterations in drug metabolism and excretion, and establishment of clinical trials and work groups to study DDIs. Our long-term objective is to broaden investigation in the field of DDIs in substance users.

Medical management of HIV-hepatitis C virus coinfection in injection drug users.

Several million people inject drugs of abuse and, as a result, are coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). The treatment of this coinfected drug-abusing population is fraught with many problems such that clinicians and other health care providers have to determine whether patients should be treated first for drug addiction, for HIV/AIDS, or for HCV infection or simultaneously treated. These proceedings present the incidence and prevalence of coinfections with HIV and HCV in high-risk populations and discuss the underlying pathophysiology of coinfections and the problems and strategies of managing the treatment of coinfections among people who also inject illicit drugs. In addition, the expert panel recommended further research to determine the best possible treatment regimens applicable to injection drug users coinfected with HIV and HCV.

Bloodborne and sexually transmitted infections in drug abusers in the United States, Latin America, the Caribbean, and Spain.

In the United States, approximately 1 million Americans are infected with human immunodeficiency virus (HIV), and several thousand new infections are reported each year. More than one-third of cases of acquired immunodeficiency syndrome (AIDS) are associated with injection drug use. An estimated 1.8 million adults and children are currently living with HIV in Latin America and the Caribbean, and injection drug abuse remains a major factor in initial exposures to HIV in these parts of the world. Although only 3 cases of AIDS related to drug abuse have been reported in Bolivia, a country with a nascent epidemic, >19,000 cases of AIDS have been reported in Argentina and >22,000 in Brazil, with a significant number associated with injection drug use. Extensive epidemiological and clinical research has been conducted in the United States and elsewhere to determine the extent and nature of the problem and to design and develop interventions (prevention and treatment) for drug abusers infected with HIV. The articles in this supplement present a current view of the nature and extent of the bloodborne and sexually transmitted infections in drug abusers and their partners in the Western Hemisphere.

Interventions for metabolic and endocrine complications of human immunodeficiency virus/acquired immune deficiency syndrome and illicit drug use.

Illicit drug use and concurrent infection with human immunodeficiency virus (HIV) are associated with metabolic and endocrine complications that may include lipid, carbohydrate, and endocrine metabolism disorders and nutritional deficiencies. Interventions for these metabolic and endocrine complications range from micronutrient supplementation to hormone-replacement therapy. We present the current strategies for the management of metabolic and endocrine disorders of HIV/acquired immunodeficiency virus and drug use. In addition, the panel members (contributing authors of the present supplement) recommend further research to determine the nature and extent of problems and to design better and effective therapies.

Do drugs of abuse impact on HIV disease?

Drug abuse, certain lifestyles, access and adherence to drug abuse treatment, and medical consequences of drug abuse remain as important factors that impact on HIV disease among AIDS patients worldwide. Most in vitro and in vivo studies show a significant impact on HIV disease. Epidemiological studies in the past have failed to support these observations. However, new and limited evidence shows that drug abuse may accelerate HIV disease in humans. Research is needed to design new or refine known techniques that more closely mimic natural conditions of HIV disease, and perform additional assessments of basic laboratory, clinical, and epidemiological data to determine whether drug abuse significantly impacts on HIV disease.