Monday, February 17, 2014
Acamprosate For Alcohol: Why the Research Might Be Wrong
“Occasionally,” reads the opening sentence of a commentary published online last month in Neuropsychopharmacology, “a paper comes along that fundamentally challenges what we thought we knew about a drug mechanism.” The drug in question is acamprosate, and the mechanism of action under scrutiny is the drug’s ability to promote abstinence in alcoholics. The author of the unusual commentary is Markus Heilig, Chief of the Laboratory of Clinical and Translational Studies at the National Institute on Alcohol Abuse and Alcoholism (NIAAA).
Acamprosate, in use worldwide and currently the most widely prescribed medication for alcohol dependence in the U.S., may work by an entirely different mechanism than scientists have believed on the basis of hundreds of studies over decades. Rainer Spanagel of the Institute of Psychopharmacology at the University of Heidelberg, Germany, led a large research group in revisiting research that he and others had performed on acamprosate ten years earlier. In their article for Neuropsychopharmacology, Spanagel and coworkers concluded that a sodium salt version of acamprosate was totally ineffective in animal models of alcohol-preferring rats.
“Surprisingly,” they write, “calcium salts produce acamprosate-like effects in three animal models…. We conclude that N-acetylhomotaurinate is a biologically inactive molecule and that the effects of acamprosate described in more than 450 published original investigations and clinical trials and 1.5 million treated patients can possibly be attributed to calcium.”
At present, the Food and Drug Administration (FDA] has approved three drugs for alcoholism— Antabuse, naltrexone, plus acamprosate in 2004. In addition, there is considerable clinical evidence behind the use of four other drugs—topiramate, baclofen, ondansetron, and varenicline. Acamprosate as marketed is the calcium salt of N-acetyl-homotaurinate, a close relative of the amino acid taurine. It has also been found effective in European studies.
What did scientists think acamprosate was doing? Various lines of research had linked acamprosate to glutamate transmission. Changes in glutamate transmission have been directly implicated in active alcoholism. A decade ago, the Spanagel group had decided that acamprosate normalized overactive glutamate systems, and hypothesized that acamprosate was modulating GABA transmission. So it became known as a “functional glutamate antagonist.” But specific mechanisms have remained elusive ever since.
Now, as Heilig comments, “the reason it has been difficult to pin down the molecular site of acamprosate action may simply be because it does not exist. Instead, the authors propose that the activity attributed to acamprosate has all along reflected actions of the Ca++ it carries.” As the researcher paper explains it: “N-acetylhomotaurinate by itself is not an active psychotropic molecule…. We have to conclude that the proposed glutamate receptor interactions of acamprosate cannot sufficiently explain the anti-relapse action of this drug.” Further work shows that acamprosate doesn’t interact with glutamate binding sites at all. In other words, calcium appears to be the major active ingredient in acamprosate. Animal studies using calcium chloride or calcium gluconate reduced alcohol intake in animals at rates similar to those seen in acamprosate, the researchers claim.
Subsequently, the researchers revisited the earlier clinical studies, subjected them to secondary analysis, and concluded that “in acamprosate-treated patients positive outcomes are strongly correlated with plasma Ca++ levels. No such correlation exists in placebo-treated patients.” In addition, calcium salts delivered via different carrier drugs replicated the suppression of drinking in the earlier animal findings.
Where there cues pointing toward calcium? The researchers conclude that “calcium sensitivity of the synapse is important for alcohol tolerance development, calcium given intraventricularly significantly enhances alcohol intoxication in a dose-dependent manner,” and “activity of calcium-dependent ion channels modulate alcohol drinking.”
Interestingly, in the late 50s and early 60s, there was a brief period of interest in calcium therapy for the treatment of alcoholism. In 1964, the Journal of Psychology ran an article titled “Intensive Calcium Therapy as an Initial Approach to the Psychotherapeutic Relationship in the Rehabilitation of the Compulsive Drinker.” Now it appears possible that a daily dose of acamprosate is effective for some abstinent alcoholics because it raises calcium plasma levels. Calcium supplements may be in for a round of intensive clinical testing if these findings hold up.
The authors now call for “ambitious randomized controlled clinical trials,” to directly compare “other means of the Ca++ delivery as an approach to treat alcohol addiction. Data in support of a therapeutic role of calcium would open fascinating clinical possibilities.” Indeed it would.
Spanagel R., Vengeliene V., Jandeleit B., Fischer W.N., Grindstaff K., Zhang X., Gallop M.A., Krstew E.V., Lawrence A.J. & Kiefer F. (2013). Acamprosate Produces Its Anti-Relapse Effects Via Calcium, Neuropsychopharmacology, 39 (4) 783-791. DOI: 10.1038/npp.2013.264