Effects of Galantamine on Cocaine Use in Chronic Cocaine Users

A growing body of evidence supports disruptions of the cholinergic system as a result of chronic cocaine use.¹ Medications enhancing cholinergic transmission, especially cholinesterase inhbitors, have shown some promise for the treatment of stimulant addiction in both preclinical and clinical studies.² Cholinesterase inhibitors work by preventing the breakdown of acetylcholine (ACh), which leads to increased stimulation of nicotinic and muscarinic type of cholinergic receptors.³ Cholinesterase inhibitors, including galantamine, donepezil and rivastigmine, are clinically used in the treatment of Alzheimer's dementia.

In this study, we evaluated the safety and feasibility of galantamine treatment in methadone maintained cocaine users, and its potential efficacy as a treatment of cocaine addiction. Galantamine, similar to other cholinesterase inhibitors, has shown efficacy in preclinical models of cocaine addiction.^4,5 As a unique feature, galantamine also directly stimulates the nicotinic receptors: it is an allosteric modulator of the α₇ and α₄β₂ subtypes.⁶ Galantamine has not been examined as a potential treatment for cocaine addiction. We hypothesized that galantamine would be associated with reduced cocaine use.

This was an 8-week double-blind, placebo-control clinical trial. We enrolled 14 cocaine dependent individuals who were maintained on methadone. Of the 14 individuals randomized to treatment (7 to galantamine, 7 to placebo), there were 5 (35.7%) female, 3 (21.4%) African American, 1 Native American, and 10 (71.4%) Caucasian. The mean age of the sample was 40.1 (SD 10.4). The subjects reported they used cocaine an average of 13.1 (SD 8.8) of the past 28 days, alcohol an average of 3.0 (SD 7.3) of the past 28 days, and marijuana an average of 2.4 (SD 7.4). At baseline, the subjects had an average mean daily methadone dose of 61.1 mg (SD 23.3).

This study was approved by the Yale Human Investigation Committee and all subjects signed informed consent forms prior to their entry into the study. This study was registered at the Clinicaltrials.gov (NCT00809835).

All subjects were offered standard methadone maintenance treatment at the clinic, which typically consisted of daily methadone, with weekly individual and group therapy sessions. In addition, all participants had access to a computer assisted version of cognitive behavioral therapy (CBT).⁷ We used galantamine extended release (ER) capsules or matched placebos administered once daily. Participants received their study medication once daily at the time they received their regular methadone dose. Those randomized to galantamine received galantamine ER, with an initial dose of 8 mg/day which was increased to a maximum dose of 16 mg/day after 4 weeks of treatment.

The main outcomes were self-report drug use, assessed with the Substance Abuse Calendar, and weekly urine drug screening. Given the small sample size and the exploratory nature of this study, the analysis focused on key outcome measures including the number of days in the treatment, number of positive urines, and self-report cocaine use. Treatment differences for these outcomes were evaluated using ANOVA. Baseline characteristics were compared with ANOVA and chi-square tests, when appropriate.

The average number of days in treatment was 47 days for the placebo and 41 days for the galantamine group (p>0.05). Those assigned to galantamine submitted fewer cocaine-positive urine specimens. The mean number of cocaine positive urine specimens was 3.4 out of 7.5 versus 7.6 out of 7.9 samples, for the galantamine and placebo groups, respectively, F (1,10)=2.5, p=0.15). Similarly, participants reported a lower percentage of days of cocaine use during the study, 19 out of 47 days vs. 8.3 out of 41 days for the placebo and galantamine groups, respectively [F (1,11) = 4.3, p=0.06]. Five subjects did not complete the protocol (2 in galantamine, 3 in placebo), due to self-reported gastrointestinal symptoms including nausea (2 in galantamine, 1 in placebo) and non-compliance with treatment (n=2). The most common adverse effect associated with galantamine treatment was fatigue (n=3). There were no serious adverse events reported in either condition.

These preliminary findings point to a possible efficacy of galantamine in reducing cocaine use. Galantamine has not previously been evaluated for the treatment of cocaine addiction in human studies. Donepezil, another cholinesterase inhibitor, was evaluated for cocaine addiction in a 10-week clinical trial.⁸ Donepezil, 10 mg/day, was well tolerated but did not change cocaine use behavior. The study used only one dose of donepezil and also had a small sample size (17 subjects assigned to donepezil) providing limited statistical power to test the efficacy of donepezil for cocaine addiction. However, those treated with donepezil did show significant reductions in craving and other indexes of severity of addiction to cocaine and other drugs.⁸ To date, only one published study has evaluated galantamine as a treatment for addiction. In a sample of 114 alcohol-dependent individuals, galantamine was associated with significant reductions in smoking compared with placebo, although alcohol use outcomes did not show any treatment effects.⁹

This pilot study had several limitations. First, the length of the trial was limited to 8 weeks. Second, the dose of galantamine was limited to 16 mg/day, smaller than the average clinical dose for galantamine, 16 to 24 mg/day. It is possible that longer treatment with higher doses of galantamine may be needed for larger positive effects on cocaine use. The sample size was also quite modest, with only 14 participants. In spite of these limitations, our findings support the promise of galantamine as a therapeutic agent for the treatment of cocaine dependence. Randomized clinical trials testing the efficacy of galantamine as a treatment of cocaine addiction are warranted.