Biobehavioral effects of topiramate on cannabis-related outcomes in adolescents

说明(申请人提供)：大麻使用障碍是一个严重的公共卫生问题，对年轻人的影响不成比例。尽管正在制定有希望的心理社会干预措施，但大多数青年并不能仅从这些干预措施中受益。鉴于改善青少年治疗的临床需求，NIDA最近确定迫切需要有关青少年对药物的耐受性和潜在疗效的数据(RFA-DA-09-001)。这一应用的主要目的是测试托吡酯(TPM)是否影响青少年的大麻使用和相关表型。托吡酯是一种正在紧张研究中的抗惊厥药物，用于治疗几种滥用药物。TPM促进γ-氨基丁酸(GABA)神经传递，并阻断AMPA/海人藻氨酸谷氨酸受体。由于中皮质边缘多巴胺(DA)的释放有助于急性药物使用的奖赏效应，通过GABA能神经元受到紧张性抑制控制，通过谷氨酸能神经元受到兴奋控制，因此TPM同时存在的GABA能兴奋和谷氨酸能拮抗被认为在一定程度上通过减轻渴求来减少药物使用。事实上，TPM减少了酒精、尼古丁和可卡因的使用。尽管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通路来发挥增强作用，因此也可能受到TPM的影响。我们建议将未接受治疗的年轻人(n=132；年龄15-18岁)随机分为滥用大麻或依赖TPM(200 mg/天)或安慰剂6周。青少年将使用手持电子日记在6周内监测他们的大麻使用、渴望、吸烟的急性主观影响和戒断症状。此外，参与者将完成对与大麻有关的线索的反应性的实验室评估。这一全面而有效的分析将提供关于TPM对青少年大麻使用的影响的迫切需要的数据，同时增加关于TPM对大麻使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托吡酯这种药物是否减少了滥用或依赖大麻的青少年的大麻使用。它还将有助于回答这样一个问题，“托吡酯如何减少大麻的使用？”了解托吡酯可如何减少青少年的大麻使用，将有助于采取更有针对性的药物治疗方法，并有助于确定可能有望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.