Monoamine Antagonist Therapies for Methamphetamine Abuse Prazosin

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.

Inclusion criteria

• Must be between the ages of 18-50 years (inclusive).
• Must be a current methamphetamine user, with self-reported amount of IV use being greater than the total administered in the study.
• Must have recent use confirmed by a urine toxicology screen positive for amphetamines.
• Must not be seeking treatment for methamphetamine abuse/dependence.

Exclusion criteria

• Ill health (major cardiovascular, renal, endocrine, hepatic disorder, to be determined by history provided by the prospective subject or laboratory evaluation as outlined below).
• Current diagnosis of other drug or alcohol physical dependence (other than nicotine or caffeine).
• History of major organic psychiatric disorder (psychosis, schizophrenia, bipolar, mania) or significant psychiatric symptoms at the time of evaluation for study participation, including suicidal ideation.
• Pregnancy, plans to become pregnant, or fertile women without adequate means of contraception.
• Present or recent use of over-the-counter or prescription psychoactive drug or drug that would have major interaction with drugs to be tested.
• Liver function tests greater than three times normal, blood urea nitrogen and creatinine outside of normal range, or thyroid function tests outside of normal range.
• EKG abnormalities including but not limited to: bradycardia (<60 bpm); prolonged corrected QT interval interval (>450 msec); Wolff-Parkinson-White syndrome; wide complex tachycardia; 2nd degree, Mobitz type II heart block; 3rd degree heart block; left or right bundle branch block.
• Medical contraindication to or prior serious adverse effects from METH or stimulants (i.e., seizures, cardiac arrest) or medical contraindication to test agents (see risks section). Significant physical or psychiatric illness which might impair the ability to safely complete the study or that might be complicated by the study drugs, including prior seizures (after age 8) or other active neurological disease or clinically significant abnormalities on physical examination or screening laboratory values.
• Current enrollment in a methamphetamine, alcohol, or other drug treatment program or current legal problems relating to METH, alcohol, or other drug use, including awaiting trial or supervision by a parole or probation officer.
• Left ventricular ejection fraction < 40% as determined in the screening echocardiogram.
• Body Mass Index >35 or <18.
• Currently trying to quit METH use.
• History of serious adverse event or hypersensitivity to methamphetamine or other study drugs
• Currently taking any medication (including highly active antiretroviral therapy for HIV) other than over-the-counter nonsteroidal anti-inflammatory medications, topical medications, inhaled asthma therapy, and over-the-counter nonsedating antihistamines.
• Any other condition the PI or staff feels will put the subject at risk for entering the study.