Last month Ovation Pharmaceuticals was granted FDA Fast Track designation for its anti-seizure medication vigabatrin (Sabril®) a potential treatment for methamphetamine and cocaine addiction. (http://www.medicalnewstoday.com/articles/94989, php Medical News Today, accessed 2/5/08). The “Fast Track” designation, mandated by the FDA Modernization Act of 1997, is reserved for products with the potential to treat a serious or life-threatening condition for which there are no available treatments and also have the potential to address an unmet medical need. Vigabatrin is a GABA-transaminase (GABA-T) inhibitor, which blocks the brain enzyme responsible for metabolizing the amino acid neurotransmitter gamma-aminobutyric acid (GABA). This mechanism causes a two- to three-fold increase in GABA brain levels. Animal and human research indicates that drug craving is associated with increased dopamine activity in the nucleus accumbens septi of the brain. Environmental cues or triggers associated with drug use dramatically increase the levels of dopamine in the nucleus accumbens. It is believed that GABA modulates or reduces the dopamine levels in that area of the brain and abolishes the cue-induced increase. (MR Gerasimov, et al., 2001, GABAergic blockade of cocaine-associated cue-induced increases in nucleus accumbens dopamine. European Journal of Pharmacology, 414(2-3): 205-209)
GABAergic medications increase the level or effectiveness of GABA in the brain and have attracted interest in recent years as potential anti-craving treatments for substance use disorders. Campral® (acamprosate), a medication proposed to act either directly at GABA receptors or to decrease glutamate activity was approved to treat alcohol craving in 2004. Neurontin® (gabapentin), Gabitril® (tiagabine), Lamictal® (lamotrigine), Topamax® (topiramate) and Lyrica® (pregabalin) have all been anecdotally mentioned as possible treatments for cravings in a variety of substance use disorders (i.e. alcohol, stimulants, opioids, sedative-hypnotics). Though these medications were developed and approved to treat epileptic seizures, pain, sleep disorders, anxiety or mood disorders, their ability to increase the action of GABA is causing great interest in their potential to treat drug cravings associated with chemical dependency.
Use of addictive substances disrupts the brain’s natural balance of GABA and glutamate. Lower GABA levels are conducive to increased dopamine and glutamate activity, this results in greater drug reinforcement when an addictive substance is taken or increased drug hunger when an addict is abstinent. Medications that increase GABA or decrease glutamate lower drug reinforcement and craving. Vigabatrin does this by blocking the enzymatic destruction of GABA. Gabapentin used in the Prometa treatment protocol may enhance synthesis of GABA in the brain. Pregabalin is thought to work by the same mechanism as gabapentin. Tigabine is a GABA reuptake inhibitor that causes an increase of GABA in the synaptic gap. Lamotrigine and topiramate seem to enhance GABA activity at its receptor sites by blocking sodium ion and facilitating chlorine ion influx.
The benzodiazepine class of sedative-hypnotics (i.e. diazepam, alprazolam, clonazepam, lorazepam, chlordiazepozide) causes significant chemical dependence and a life-threatening withdrawal syndrome. All benzodiazepines work by attaching to post-synaptic receptors adjacent to GABA receptors. Their action at these receptors enhances GABA’s inhibitory effects resulting in an overall decrease in neuron activity and sedation. Though vigabatrin, gabapentin, topiramate and the newer medications also increase GABA activity, physical dependence accompanied by severe withdrawal symptoms has not been documented with their use. This makes the potential of GABAergic medications for the treatment of substance use disorders a promising new development in the “Recovery” community.
Darryl S. Inaba, PharmD. CADC III
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