Brain Chemicals Mimic Marijuana
By Johnathan S. Choi

NEW YORK (Reuters) -- Two chemicals found in the brain seem to mimic some of the effects of marijuana and bind to the same brain receptor, according to two studies to be published Thursday. The research offers new clues on how the brain regulates memory and learning, and may lead to the development of new drugs.

The substances -- anandamide and sn-2 arachidonylglycerol (2-AG) -- bind to the same receptors in the brain as tetrahydrocannabinol (THC), the active compound in marijuana and hashish. Besides their psychoactive properties, THC has some therapeutic effects such as pain relief and appetite stimulation. THC also interferes with a process in the hippocampus of the brain called long-term potentiation (LTP), which is important to memory and learning.

``Normally, these brain cells would communicate with a certain level of efficacy or strength. However, under certain conditions -- these are the conditions under which we tend to remember things -- the strength of the communication will be increased,'' explains Daniele Piomelli of the Neurosciences Institute in San Diego, senior author on the report published in Science. ``This phenomenon is called potentiation of synaptic (nerve) transmission. Potentiation that is prolonged for many hours is therefore called long-term potentiation.''

The fact that the cannabinoid receptors are highly concentrated in the hippocampus is very important in understanding LTP and learning, says Piomelli. ``The hippocampus is a small region of the brain present in all mammals, including man, that participates in short-term memory formation and learning. The way people look at the hippocampus is as a 'relay station' where sensory inputs go to become either discarded, or become prolonged memories. In fact, patients who have lesions in the hippocampus, while they can retain old memories, cannot form new memories.'' By blocking LTP, drugs like THC interfere with this memory-relaying process.

The study found that 2-AG mimicked the effect of THC by blocking long-term potentiation. They believe this is the same mechanism by which smoking marijuana may cause short-term memory lapses. In contrast, there was no production of anandamide detected in the hippocampus. This suggests that 2-AG, but not anandamide, modulates the formation of short-term memories, producing a type of ``physiological forgetting.''

In a separate study published in the journal Nature, scientists report on the mechanism by which anandamide becomes biologically inactivated. Anandamide released from neural cells binds to the cannabinoid receptors present on the surface of neighboring cells. Once it is bound, a way to stop its actions is required. Otherwise, THC stimulation could continue indefinitely, and a perpetual 'high' could be maintained from just a few puffs of marijuana. The researchers discovered that anandamide was deactivated by being transported into the cell and broken down into nonfunctional fragments. Though anandamide was not found in the hippocampus, it is believed that THC is inactivated in a similar manner.

``This is of course a hypothesis, but we think that there is a division of labor between anandamide and 2-AG. 2-AG is produced in certain areas and subserves certain functions, whereas anandamide is produced in other areas and subserves other functions,'' explains Piomelli. ``In both cases, the compounds bind to the cannabinoid receptors, but they're not necessarily produced together or at the same time.... Now that's important, because it opens a number of perspectives from the standpoint of therapy. As I mentioned before, there are certain effects of THC which are favorable and interesting therapeutically, such as analgesia. There are others that are not considered favorable such as the psychotropic effects. If they could be split apart... they would be very useful, therapeutically. They might have some of the positive effects of anandamide and THC, without most of the negative effects.''

SOURCE: Science (1997;277:1094-1096); Nature (1997;388:773-777)