No abstract

Our results suggest that ondansetron (particularly the 4 microg/kg twice per day dosage) is an effective treatment for patients with early-onset alcoholism, presumably by ameliorating an underlying serotonergic abnormality. JAMA. 2000;284:963-971

Objective-Severe alcohol consumption can cause serious morbidity and death. Because the serotonin transporter (5-HTT) is an important regulator of neuronal 5-HT function, allelic differences at that gene may modulate the severity of alcohol consumption and predict therapeutic response to the 5-HT 3 receptor antagonist, ondansetron.Method-We randomized 283 alcoholics by genotype in the 5′-regulatory region of the 5-HTT gene (LL/LS/SS), with additional genotyping for another functional single nucleotide polymorphism (T/G), rs1042173, in the 3′-untranslated region, in a controlled double-blind trial. Subjects received ondansetron (4 μg/kg twice daily) or placebo for 11 weeks, plus standardized cognitive behavioral therapy.Results-LL subjects who received ondansetron vs. placebo had fewer mean drinks per drinking day (DDD) and a higher percentage of days abstinent (PDA) (−1.62; p=0.007 and 11.27%; p=0.023). Within ondansetron recipients, DDD was lower and PDA higher in LL vs. LS/SS subjects (−1.53; p=0.005 and 9.73%; p=0.03). Ondansetron LL subjects also had fewer DDD and greater PDA than all other genotype and treatment groups combined (−1.45; p=0.002 and 9.65%; p=0.013). For both DDD and PDA, 5′-HTTLPR and rs1042173 variants interacted significantly (p=0.023 and 0.009). Ondansetron LL/TT had fewer DDD and a greater PDA than all other genotype and treatment groups combined (−2.63; p<0.0001 and 16.99%; p=0.002). Conclusions-We propose a new pharmacogenetic approach using ondansetron to reduce the severity of alcohol consumption and improve abstinence in alcoholics.

Cannabis, the most commonly used illicit substance, exerts its primary psychoactive effect via delta-9 tetrahydrocannabinol (Δ(9) -THC) agonism of cannabinoid receptor type 1 (CB1). Some users develop a cannabis use disorder and physical dependence manifested by withdrawal symptoms during abstinence. Hence, there is growing public health concern about increasing use of a new generation of synthetic cannabinoid (SC) agonists (eg, JWH-018, CP 47,497) marketed as natural herbal incense mixtures under brand names such as "Spice" and "K2." Anecdotal reports suggest overlapping effects with marijuana when the mixtures are smoked, however, systematic evaluation of SC-related psychoactive properties and adverse effects is lacking. We conducted a systematic review of published reports on SC clinical effects in humans. Most highlight potential toxicity such as acute anxiety and psychosis. In addition, we carefully document three cases in which experienced marijuana users meeting criteria for cannabis dependence with physiologic dependence smoked SC products regularly. The SC mixture effects were reportedly similar to marijuana and well tolerated. The individuals all reported that SC product use effectively alleviated cannabis withdrawal. Biopsychosocial factors associated with SC initiation and usage by the cases help to shed light on psychopharmacologic, clinical, and public health aspects of SC product consumption.

Background Despite growing concern about the increased rates of synthetic cannabinoid (SC) use and their effects, only limited data are available that addresses these issues. This study assessed the extent of SC product use and reported effects among a cohort of adult marijuana and tobacco users. Methods A brief telephone interview was conducted with individuals who had given permission to be contacted for future research while screening for a cannabis/nicotine dependence medication development study (NCT01204723). Results Respondents (N= 42: 88% participation rate) were primarily young adults, male, racially diverse, and high school graduates. Nearly all currently smoked tobacco and cannabis, with 86% smoking cannabis on 5 or more days per week. Nearly all (91%) were familiar with SC products, half (50%) reported smoking SC products previously, and a substantial minority (24%) reported current use (i.e., past month). Despite a federal ban on five common SCs, which went into effect on March 1, 2011, a number of respondents reported continued SC product use. Common reasons reported for use included, but were not limited to, seeking a new “high” similar to that produced by marijuana and avoiding drug use detection via a positive urine screen. The primary side effects were trouble thinking clearly, headache, dry mouth, and anxiety. No significant differences were found between synthetic cannabinoid product users (ever or current) and non-users by demographics or other characteristics. Conclusions Among current marijuana and tobacco users, SC product consumption was common and persisted despite a Federal ban. The primary reasons for the use of SC-containing products seem to be to evade drug detection and to experience a marijuana-like high. (Support: DA027131)

In this trial, topiramate (up to 300 mg/d) showed potential as a safe and promising medication for the treatment of cigarette smoking in alcohol-dependent individuals.

As an adjunct to medication compliance enhancement treatment, topiramate (up to 300 mg/d) was superior to placebo at not only improving drinking outcomes but increasing overall well-being and quality of life and lessening dependence severity and its harmful consequences.

Preclinical studies have exploded our knowledge about the behavioral and biological underpinnings of alcoholism. These studies suggest that certain neurotransmitters, particularly those interacting with the opioid, N-methyl-D-aspartate, and monoamine systems, may play a critical role in the expression of alcohol-drinking and other behaviors associated with its abuse liability. Built upon this foundation, important advances have been made in the development of therapeutic medications for the treatment of alcoholism. Of the medications reviewed, acamprosate's potential appears to be the most widely established. In the USA, naltrexone was approved by the Food and Drug Administration in 1995 for the treatment of alcoholism; however, the results of some studies have been less encouraging. Naltrexone's reliance on high compliance rates for efficacy may, eventually, limit its potential in clinical settings offering generic treatment for alcoholism. The relative paucity of dose-response studies on naltrexone's effects in treating alcoholics is an important gap in the literature. Recent data from a large clinical trial suggests that ondansetron, a serotonin3 antagonist, offers new hope for the treatment of early onset alcoholics; a type of alcoholism most difficult to manage with psychosocial measures alone. Different subtypes of alcoholic may, therefore, have varying treatment responses to serotonergic agents. Matching subtypes of alcoholic to effective treatment medications based upon their different biologies remains an important therapeutic goal. Combinations of effective pharmacological agents need exploration as they may prove to be synergistic, and could shepherd in a new era of treatments aimed at multiple neurotransmitter targets associated with the alcoholism disease. The coming decade promises more powerful tools for characterizing drug effects on alcohol drinking, thereby closing the gap between animal models of addiction and the human condition.