Biobehavioral effects of topiramate on cannabis-related outcomes in adolescents

描述（由申请人提供）：大麻使用障碍是一个重大的公共卫生问题，不成比例地影响青年。虽然正在制定有希望的心理社会干预措施，但大多数青年并不单单受益于这些干预措施。鉴于对改善青少年治疗的临床需求，NIDA最近确定了对青少年药物耐受性和潜在疗效数据的迫切需求（RFA-DA-09- 001）。本申请的主要目的是测试托吡酯（TPM），一种正在紧张研究中用于治疗几种滥用药物的抗惊厥药物，是否会影响青少年的大麻使用和相关表型。TPM促进γ-氨基丁酸（GABA）神经传递并阻断AMPA/红藻氨酸盐谷氨酸受体。由于中皮质边缘多巴胺（DA）的释放，这有助于急性药物使用的奖励作用，是通过GABA能神经元的紧张性抑制控制和兴奋性控制通过多巴胺能神经元，TPM的并发GABA能激动和多巴胺能拮抗作用被认为是减少药物使用，部分是通过减弱渴望。事实上，TPM可以减少酒精、尼古丁和可卡因的使用。虽然TPM对大麻滥用的影响未经测试，但大麻通过激活与大多数滥用药物相同的中脑边缘DA途径来发挥其增强作用，因此也可能受到TPM的影响。我们建议将滥用或依赖大麻的非寻求治疗的青少年（n = 132;年龄15-18）随机分为TPM（200 mg/天）或安慰剂组，为期6周。青少年将使用手持电子日记监测他们的大麻使用，渴望，吸食大麻的急性主观影响以及6周内的戒断症状。此外，参与者将完成对大麻相关线索反应的实验室评估。这种全面而有效的分析将提供有关TPM对青少年大麻使用影响的急需数据，同时增加有关TPM对大麻使用作用的生物行为机制的重要新信息。 公共卫生相关性：这项研究将有助于确定药物托吡酯是否减少大麻滥用或依赖青少年的大麻使用。它也将有助于回答这个问题，“托吡酯如何减少大麻的使用？“了解托吡酯如何减少青少年中的大麻使用将有助于更有针对性的药物治疗方法，并有助于确定可能改善青少年大麻治疗结果的其他药物。

DESCRIPTION (provided by applicant): Cannabis use disorders are a significant public health concern that disproportionately affect youth. Although promising psychosocial interventions are being developed, most youth do not benefit from these interventions alone. In light of the clinical demand for improved treatments for youth, NIDA recently identified the critical need for data on the tolerability and potential efficacy of medications in adolescents (RFA-DA-09- 001). The major objective of this application is to test whether topiramate (TPM), an anticonvulsant medication under intense study for treating several drugs of abuse, affects cannabis use and related phenotypes in youth. TPM facilitates gamma aminobutyric acid (GABA) neurotransmission and blocks AMPA/kainite glutamate receptors. Because mesocorticolimbic dopamine (DA) release, which contributes to the rewarding effects of acute drug use, is under tonic inhibitory control via GABAergic neurons and excitatory control via glutamatergic neurons, TPM's concurrent GABAergic agonism and glutamatergic antagonism is thought to reduce drug use, in part, by attenuating craving. Indeed, TPM reduces alcohol, nicotine, and cocaine use. Although the effects of TPM on cannabis abuse are untested, cannabis exerts its reinforcing effects by activating the same mesolimbic DA pathways as most abused drugs and therefore is also likely to be influenced by TPM. We propose to randomize nontreatment seeking youth (n = 132; ages 15-18) with cannabis abuse or dependence to TPM (200 mg/day) or placebo for 6 weeks. Youth will monitor their cannabis use, craving, acute subjective effects of smoked cannabis, and withdrawal symptoms for the 6-week period using handheld electronic diaries. In addition, participants will complete a laboratory assessment of reactivity to cannabis-related cues. This comprehensive yet efficient analysis will provide much needed data on the effects of TPM on cannabis use in adolescents while adding important new information about the biobehavioral mechanisms of TPM action on cannabis use. PUBLIC HEALTH RELEVANCE: This study will help to determine whether the medication, topiramate, reduces cannabis use among adolescents with cannabis abuse or dependence. It also will help answer the question, "How does topiramate reduce cannabis use?" Understanding how topiramate may reduce cannabis use among adolescents would allow for a more targeted pharmacotherapeutic approach to treatment and help to identify additional medications that may hold promise for improving cannabis treatment outcomes for youth.