Monoamine Antagonist Therapies for Methamphetamine Abuse Prazosin
Condition: Continuous Methamphetamine Abuse
Study type: Interventional
Phase: Phase 2

Summary: 
      This protocol will test the safety, effectiveness and the metabolism and action of prazosin
      as a potential therapy for methamphetamine abuse. This will be accomplished by performing a
      series of human laboratory studies. In each of these studies, the safety and effectiveness of
      the test medication (prazosin) in the treatment of methamphetamine effects will be
      determined. The study hypothesis is that prazosin will block the methamphetamine receptor
      function, reducing the reinforcing effects of central nervous system effects in humans.
    

Detailed description: 
      Methamphetamine (METH) use has increased in the US and worldwide in the past years. Although
      associated with profound medical, psychiatric, legal, and social problems, no effective
      medicines for METH abuse have been identified or approved for human use. It is vitally
      important to identify compounds that alter METH effects without increasing the risk of METH
      toxicity. While the brain chemical transmitter dopamine plays a major role in the pleasurable
      reinforcing and psychomotor stimulant effects of amphetamines, the transmitters
      norepinephrine and serotonin also contribute substantially to these effects. Recent evidence
      suggests that the functional links that exist between norepinephrine and serotonin systems
      may be profoundly important in METH effects and dependence. However, these neurotransmitter
      systems have not been tested as extensively as targets of pharmacologic interventions. Thus,
      the purpose of this study is to examine whether the alpha-1-b antagonist prazosin blocks the
      self-reported effects, cognitive performance and cardiovascular effects of METH in a
      dose-related manner. Subsequent protocols will test the effect of the serotonin antagonist,
      cyproheptadine, and the combined norepinephrine/serotonin antagonist, quetiapine. Healthy,
      non-treatment-seeking METH users will be recruited. They will undergo extensive prestudy
      medical and psychiatric screening. Twelve volunteers (ages 18-50 years; 50% female; 10%
      Minority) who sign the informed consent will be recruited to complete the study on prazosin.

      METH-abusing volunteers will undergo 6 sessions spaced 2-3 days apart. A single oral dose of
      prazosin (placebo, 1 mg, or 2 mg po) will be given in a randomized, double-blind design
      before METH or METH placebo administration in each session. METH will be given po in a dose
      (20 mg) that is well-tolerated by humans but that results in easily measurable effects by
      itself (Cruickshank and Dyer, 2009; Sevak et al, 2009; Parrot et al, 2011). Prior to and at
      several time points after prazosin/placebo,METH/placebo, or prazosin/METH administrations,
      self-report, cognitive performance and physiologic measures will be obtained.

      The studies we propose are significant as they have the potential to identify treatment
      medications and elucidate new mechanisms of action and desirable characteristics for future
      medications development. Understanding the effects of treatment drugs in the context of
      concomitant METH use is an essential component of identifying potential pharmacotherapies for
      METH dependence that 1) alters the self-reported/performance effects 2) alters the
      cardiovascular effects and 3) alters the concentration-effect (pharmacodynamic) relationships
      of METH in human METH users. Using this broad pharmacologic approach to these human
      laboratory studies will provide insight into the appropriate combination of positive
      treatment effects with minimal side effects for the ultimate development of a successful
      treatment for METH abuse. The results should be generalizable to METH abusers and to the
      development of new treatments for METH abuse that will benefit all members of society.
      Understanding pharmacologic interactions will lessen complications of drug abuse and provide
      more rapid introduction of effective new treatments into medical practice.
    

Intervention name(s): Prazosin
Intervention type(s): Drug
Intervention description(s): Prazosin or oral placebo given before methamphetamine or iv placebo to determine effects of prazosin on methamphetamine.
Other intervention name(s): Minipress
Intervention MeSH terms: Prazosin
Intervention model: Single Group Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Health Services Research
Keywords: substance abuse