Aspirin or amiloride for cerebral perfusion defects in cocaine dependence Thomas R. Kosten a, *, P. Christopher Gottschalk a , Karen Tucker a , Christine S. Rinder b , Holly M. Dey c , Henry M. Rinder d a Department of Psychiatry, 151D, Yale University School of Medicine, VA Connecticut Healthcare System, 950 Campbell Avenue Bldg., Room 41, West Haven, CT 06516, USA b Department of Anesthesiology and Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520-8035, USA c Department of Nuclear Medicine and Radiology, Yale University School of Medicine, VA Connecticut Healthcare System, West Haven, CT 06516, USA d Department of Laboratory and Internal Medicine, Yale University School of Medicine, New Haven, CT 06520-8035, USA Received 23 January 2003; received in revised form 28 March 2003; accepted 4 April 2003 Abstract Cocaine dependent (CD) patients have regional cerebral blood flow (rCBF) deficits that may be related to occlusion of blood vessels by vasoconstriction and abnormal platelet aggregation. This study determined whether aspirin, which reverses platelet aggregation, or amiloride, a vasodilator, significantly reversed this rCBF hypoperfusion. This 1-month randomized trial compared clusters of voxels with significant hypoperfusion in recently abstinent CD patients after aspirin (325 mg daily), amiloride (10 mg daily) or placebo treatment. Forty-nine primary CD patients and 18 non-drug abusing controls were compared using single photon emission computed tomography (SPECT) neuroimaging with 99m Tc-hexamethyl-propyleneamine-oxime and statistical parametric mapping (SPM). Platelet aggregation to adenosine diphosphate (ADP) was examined after treatment to determine whether rCBF improvement was related to decreased platelet aggregation. Following treatment, areas of hypoperfusion were improved with amiloride, unchanged with aspirin, and worsened with placebo in comparison to baseline levels. Platelet aggregation after ADP showed no significant change during the month, but reduced rCBF significantly improved after 1-month treatment with amiloride compared with placebo and cocaine abstinence alone. # 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Aspirin; Cocaine; Imaging; Clinical trial; Amiloride; Treatment; Pharmacotherapy 1. Introduction Over the last 10 years, several groups of investigators have found that chronic cocaine use is associated with persistent multiple focal decreases in regional cerebral blood flow (rCBF) as measured by positron emission tomography (PET) with oxygen-15 labeled water and single photon emission computed tomography (SPECT) (Weber et al., 1993; Tumeh et al., 1990; Mena et al., 1990; Volkow et al., 1988; Holman et al., 1991, 1992, 1993; Kosten et al., 1998). The pathophysiology of these flow deficits is unknown, but it is possible that two different mechanisms may contribute. First, vasocon- striction may be sustained after acute cocaine use due to cocaine’s major metabolites including benzoylecgonine (BE). BE has a much longer half-life than cocaine and may bind to brain proteins well beyond when it is detectable in serum (Madden et al., 1995; Saady et al., 1995). Second, platelet function in cocaine dependent (CD) patients is abnormal. Some studies demonstrated that platelets in cocaine abusers were pathological because they were primed to adhere to undamaged as well as damaged blood vessel walls (Rinder et al., 1991, 1993, 1994; Kugelmass et al., 1993). This pathologic adhesion leads to platelet-rich thrombus formation in blood vessels that are otherwise normal. The formation of these thrombi may obstruct rCBF leading to areas of * Corresponding author. Tel.:  /1-203-932-5711x7438; fax:  /1-203- 937-4915. E-mail address: thomas.kosten@yale.edu (T.R. Kosten). Drug and Alcohol Dependence 71 (2003) 187 /194 www.elsevier.com/locate/drugalcdep 03765-8716/03/$ - see front matter # 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/S0376-8716(03)00132-7