Objective: The possibility that acetaldehyde is responsible for some of the central nervous system effects of ethanol has been a popular hypothesis for many years. This review examines the evidence of a role for acetaldehyde in the actions of ethanol in the brain.
Method: The literature review was confined primarily to effects of acetaldehyde in the central nervous system in the realization that a great deal of information is also available on the actions of acetaldehyde in the periphery. The emphasis is on more recent findings, with only occasional references to older work.
Results: There are studies implicating acetaldehyde in nearly every central nervous system effect of ethanol that has been studied. With a few exceptions, the evidence for most of these effects is conflicting. For many years the dogma was that the brain did not metabolize ethanol. Any effects of acetaldehyde were therefore held to be due to acetaldehyde diffusing in from the blood. Recently, however, it has been established that ethanol is metabolized to acetaldehyde (primarily by catalase) and then to acetate (by aldehyde dehydrogenase) in the brain. These findings remove the problem that acetaldehyde does not penetrate the brain very well but leave questions as to what it does there. Almost invariably, the concentrations of acetaldehyde in the brain, under normal conditions of ethanol intoxication, are in the low micromolar range. Inhibition of aldehyde dehydrogenase will lead to increases of both peripheral and central acetaldehyde and usually to increases in the effects of ethanol or to behaviorally aversive effects. Stimulation of catalase should lead to increased levels of acetaldehyde in the brain, but this has not been directly demonstrated. Inhibition of catalase should lead to decreased acetaldehyde concentrations in vivo, but, again, this has not been directly demonstrated. Various effects of the direct application of acetaldehyde to the brain have been noted, but in most studies the concentration of acetaldehyde resulting from such manipulations has not been determined, and it is probably higher than that occurring during ethanol intoxication. These experiments tell us what acetaldehyde is capable of doing, not what it does after administration of ethanol. Still, this is a first step.
Conclusions: Acetaldehyde is a product of ethanol metabolism in the brain. It clearly has central nervous system effects in its own right. The jury is still out as to whether it has effects under normal conditions of ethanol intoxication. This will remain the case until direct measurement of acetaldehyde concentrations in the brain is routinely accomplished under conditions in which behavioral effects of ethanol are also measured.