The Role of Peroxisome Proliferator-Activated Receptor in Addiction: A Novel Drug Target.

The peroxisome proliferator activated receptors (PPARs) are a superfamily of well-recognized ligand-binding nuclear receptors comprising three isoforms: PPARα, PPARγ, and PPARß/δ. In response to endogenous lipid messengers, PPARs trigger the transcription of genes related to a wider spectrum of physiological phenomena, including fatty acid oxidation, inflammation, adipogenesis, among many others. Thus, the importance of PPARs as putative protective therapy in health issues has increased the interest of studying these nuclear receptors, including the management of neurodegenerative disorders, multiple sclerosis, and likely addiction. In recent years, several pieces of evidence from animal models have demonstrated the promising role of PPARs as a critical element for interventions in addictive behaviors by reducing the reinforcing properties of addictive substances such as alcohol. However, there is a lack of data in the scope and has so far been unexplored the function of PPARs in additional drugs such as cannabis, opioids, methamphetamine, or cocaine. A similar scenario has been found for the management of binge-type eating disorders. Thus, here we review recent advances in understanding the relevance of the PPAR controlling addiction.

Plants with Anti-Addictive Potential.

Drug addiction is prevalent among individuals of modern society, being a major cause of disability and premature loss of life. Although the drug addiction have profound social, economical and health impact in the world population, its management remains a challenge as available pharmacological treatments remains ineffective for most people. The limited efficacy and adverse effects have led to a search for alternative therapies to treat drug addiction. In this context, natural products are an important source for new chemical substances with a potential therapeutic applicability. Therefore, this chapter will present data obtained after an extensive literature search regarding the use of medicinal plants as a pharmacological alternative for drug addiction treatment.

Metabolite Profiling of Anti-Addictive Alkaloids from Four Mexican Tabernaemontana Species and the Entheogenic African Shrub Tabernanthe iboga (Apocynaceae).

Ibogaine and other ibogan type alkaloids present anti-addictive effects against several drugs of abuse and occur in different species of the Apocynaceae family. In this work, we used gas chromatography-mass spectrometry (GC/MS) and principal component analysis (PCA) in order to compare the alkaloid profiles of the root and stem barks of four Mexican Tabernaemontana species with the root bark of the entheogenic African shrub Tabernanthe iboga. PCA demonstrated that separation between species could be attributed to quantitative differences of the major alkaloids, coronaridine, ibogamine, voacangine, and ibogaine. While T. iboga mainly presented high concentrations of ibogaine, Tabernaemontana samples either showed a predominance of voacangine and ibogaine, or coronaridine and ibogamine, respectively. The results illustrate the phytochemical proximity between both genera and confirm previous suggestions that Mexican Tabernaemontana species are viable sources of anti-addictive compounds.

NAChR α4ß2 Subtype and their Relation with Nicotine Addiction, Cognition, Depression and Hyperactivity Disorder.

BACKGROUND: Neuronal α4ß2 nAChRs are receptors involved in the role of neurotransmitters regulation and release, and this ionic channel participates in biological process of memory, learning and attention. This work aims to review the structure and functioning of the α4ß2 nAChR emphasizing its role in the treatment of associated diseases like nicotine addiction and underlying pathologies such as cognition, depression and attention-deficit hyperactivity disorder. METHODS: The authors realized extensive bibliographic research using the descriptors "Nicotine Receptor α4ß2" and "cognition", "depression", "attention-deficit hyperactivity disorder", besides cross-references of the selected articles and after analysis of references in the specific literature. RESULTS: As results, it was that found 179 relevant articles presenting the main molecules with affinity to nAChR α4ß2 related to the cited diseases. The α4ß2 nAChR subtype is a remarkable therapeutic target since this is the most abundant receptor in the central nervous system. CONCLUSION: In summary, this review presents perspectives on the pharmacology and therapeutic targeting of α4ß2 nAChRs for the treatment of cognition and diseases like nicotine dependence, depression and attention-deficit hyperactivity disorder.

Systematic review of N-acetylcysteine in the treatment of addictions

Objective: To conduct the first systematic literature review of clinical trials of N-acetylcysteine (NAC) for the treatment of substance abuse disorders and addictive behaviors. Methods: A search of the MEDLINE, Embase and PsycINFO databases was conducted. The inclusion criteria for the review were clinical trials that used NAC in the treatment of a disorder related to substance use and/or addictive behaviors, limited to texts in English, Spanish, or French. The selected studies were evaluated with respect to type of trial, sample size, diagnostic input, intervention, length of follow-up, outcome variables, and results. Results: Nine studies analyzing a total of 165 patients met the eligibility criteria and were included in qualitative analysis. These studies evaluated the role of NAC in cocaine dependence (three studies), cannabis dependence (two studies), nicotine dependence (two studies), methamphetamine addiction (one study), and pathological gambling (one study). Five of these trials were double-blind, randomized, and placebo-controlled. Conclusions: The studies analyzed suggest a potential role for NAC in the treatment of addiction, especially of cocaine and cannabis dependence. These results are concordant with the hypothesis of the involvement of glutamatergic pathways in the pathophysiology of addiction. .

Systematic review of N-acetylcysteine in the treatment of addictions.

OBJECTIVE: To conduct the first systematic literature review of clinical trials of N-acetylcysteine (NAC) for the treatment of substance abuse disorders and addictive behaviors. METHODS: A search of the MEDLINE, Embase and PsycINFO databases was conducted. The inclusion criteria for the review were clinical trials that used NAC in the treatment of a disorder related to substance use and/or addictive behaviors, limited to texts in English, Spanish, or French. The selected studies were evaluated with respect to type of trial, sample size, diagnostic input, intervention, length of follow-up, outcome variables, and results. RESULTS: Nine studies analyzing a total of 165 patients met the eligibility criteria and were included in qualitative analysis. These studies evaluated the role of NAC in cocaine dependence (three studies), cannabis dependence (two studies), nicotine dependence (two studies), methamphetamine addiction (one study), and pathological gambling (one study). Five of these trials were double-blind, randomized, and placebo-controlled. CONCLUSIONS: The studies analyzed suggest a potential role for NAC in the treatment of addiction, especially of cocaine and cannabis dependence. These results are concordant with the hypothesis of the involvement of glutamatergic pathways in the pathophysiology of addiction.

Hypotheses regarding the mechanisms of ayahuasca in the treatment of addictions.

Ayahuasca is a medicinal plant mixture utilized by indigenous peoples throughout the Amazon River basin for healing purposes. The "vine of the soul" or "vine of death," as it is known in South America, contains a combination of monoamine oxidase inhibitors and N,N-dimethyltryptamine (DMT). When ingested together, these medicines produce profound alterations in consciousness. Increasingly, ayahuasca is being utilized to treat addictions. However, the mechanism of action by which ayahuasca treats addictions remains unclear. We offer four hypotheses to explain possible biochemical, physiological, psychological, and transcendent mechanisms by which ayahuasca may exert its anti-addiction effects.

Craving decrease with topiramate in outpatient treatment for cocaine dependence: an open label trial / Diminuição da fissura com topiramato no tratamento ambulatorial para dependência de cocaína: um ensaio clínico aberto

OBJECTIVE: To evaluate anticraving action and tolerability of topiramate in cocaine user treatment. METHOD: Male users of inhaled cocaine which met criteria for cocaine dependence (Diagnostic and Statistical Manual of Mental Disorders, fourth edition) were selected for outpatient 12-week, open label trial with topiramate; individual dosage ranged between 25-300 mg/day. Main clinical variables were abstinence rate, craving intensity, frequency and duration, adherence, dropouts, side effects and impulsivity measure through Barratt Impulsivity Scale. Patients received assertive strategic counseling for abstinence assistance and medication monitoring evaluation every two weeks. Comparative analysis was made with intention to treat, missing values were replaced (last observation carried forward), and significance level was 5 percent. RESULTS: Adherence to treatment was 57 percent (at least three evaluations), 32 percent dropped out (one evaluation). There were no severe side effects. Negative test average was 25.4 percent (31.2). Significant reduction in craving intensity and duration was observed in 25 percent of the sample. No statistical significant reduction in craving frequency was observed in 7.1 percent. Increase in frequency was observed in 10.7 percent and 82.1 percent did not present any variation. No significant statistical variations in Barratt Impulsivity Scale or in the total score were found in the final evaluation when compared to baseline. CONCLUSION: More randomized placebo-controlled trials with topiramate for cocaine dependants should be performed to evaluate preliminary evidence.

OBJETIVO: Avaliar a ação anticraving e tolerabilidade do topiramato em usuários de cocaína. MÉTODO: Homens usuários de cocaína inalada que preenchiam critérios para dependência de cocaína (Manual Diagnóstico e Estatístico de Desordens Mentais, quarta edição) foram selecionados para 12 semanas de tratamento ambulatorial, em ensaio clínico aberto com topiramato; dosagens escalonadas entre 25-300 mg/dia. As principais variáveis clínicas foram taxa de abstinência, intensidade, freqüência e duração do craving, aderência, perdas, efeitos colaterais e impulsividade medida por meio da Escala de Impulsividade Barratt. Os pacientes receberam estratégias assertivas de aconselhamento para manutenção da abstinência e monitoramento da medicação avaliada a cada duas semanas. Análises comparativas foram feitas com intenção de tratar, valores perdidos foram substituídos (última observação carregada ao final) e o nível de significância de 5 por cento. RESULTADOS: A aderência ao tratamento foi de 57 por cento (pelo menos três avaliações), 32 por cento de perdas (uma avaliação). Não houve efeitos colaterais graves. A média de testes negativos foi 25,4 por cento (31,2). Significante redução na intensidade e duração do craving foi observada em 25 por cento da amostra. Nenhuma redução significativa na freqüência do craving foi observada em 7,1 por cento. Aumento na freqüência foi observado em 10,7 por cento e 82,1 por cento não apresentaram nenhuma variação. Nenhuma variação estatisticamente significativa na Escala de Impulsividade Barratt ou na pontuação total foi encontrada no final da avaliação quando comparado à inicial. CONCLUSÃO: Mais ensaios clínicos placebo-controlados com o topiramato para dependentes de cocaína deveriam ser conduzidos a fim de avaliar a evidência preliminar.

Craving decrease with topiramate in outpatient treatment for cocaine dependence: an open label trial.

OBJECTIVE: To evaluate anticraving action and tolerability of topiramate in cocaine user treatment. METHOD: Male users of inhaled cocaine which met criteria for cocaine dependence (Diagnostic and Statistical Manual of Mental Disorders, fourth edition) were selected for outpatient 12-week, open label trial with topiramate; individual dosage ranged between 25-300 mg/day. Main clinical variables were abstinence rate, craving intensity, frequency and duration, adherence, dropouts, side effects and impulsivity measure through Barratt Impulsivity Scale. Patients received assertive strategic counseling for abstinence assistance and medication monitoring evaluation every two weeks. Comparative analysis was made with intention to treat, missing values were replaced (last observation carried forward), and significance level was 5%. RESULTS: Adherence to treatment was 57% (at least three evaluations), 32% dropped out (one evaluation). There were no severe side effects. Negative test average was 25.4% (31.2). Significant reduction in craving intensity and duration was observed in 25% of the sample. No statistical significant reduction in craving frequency was observed in 7.1%. Increase in frequency was observed in 10.7% and 82.1% did not present any variation. No significant statistical variations in Barratt Impulsivity Scale or in the total score were found in the final evaluation when compared to baseline. CONCLUSION: More randomized placebo-controlled trials with topiramate for cocaine dependants should be performed to evaluate preliminary evidence.