At last, the secret of internal bliss is revealed: The discovery of anandamide, the body's natural form of the drug cannabis, casts new light on depressive illnesses, says Ruth McKernan

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The Independent Online
MARIJUANA, hash, grass, weed, pot, dope, gear and, in the East End of London, salmon and trout (cockney rhyming slang for snout) are all names for the same substance: cannabis. An international team of scientists has now added another word, anandamide, to the list. Anandamide is a chemical in the brain which, they believe, acts as the body's natural cannabis.

The term is derived from the Sanskrit ananda, meaning 'internal bliss'. The compound is the last piece in a puzzle that scientists have been trying to put together for decades. Why have millions of years of evolution apparently shaped the human brain in a way that enables us to get high? The answers may cast light on such conditions as depression and schizophrenia.

Dr Roger Pertwee, of Aberdeen University, secretary of the International Cannabis Research Society, explains that the plant contains psychotropic substances, known as cannabinoids, that change human perception. After taking cannabis, 'colour is brighter, music more vivid and time appears to pass more slowly. Mood is elevated but cognition is impaired - you may believe you're thinking great thoughts, but you're not'.

Cannabis was most popular during the 'make love not war' era of the Sixties, and it still conjures up an image of long-haired students with flared loons, ankle-length skirts and flowers in their hair, advocating free sex and an end to the Vietnam war.

It is not just a drug of abuse. Cannabis was used by Eastern civilisations thousands of years ago for social and religious rituals, and as a medicine. Nowadays a cannabinoid called Cesamet, manufactured by the American drug company Eli Lilly, is used to treat the nausea and vomiting that accompanies cancer chemotherapy.

For many years Dr Pertwee and his team have collaborated with a group led by Raphael Mechoulam at Hebrew University in Jerusalem. In 1964, Professor Mechoulam extracted and identified the most active ingredient in the cannabis plant, delta-9-tetrahydrocannabinol, or THC for short. But knowing the chemical structure did not provide many clues as to how cannabis produces its effects.

Many drugs, particularly those that occur in plants, work by mimicking a chemical that occurs naturally in the human body. In this case, THC was present in the plant, but none exists in the brain of abstinent individuals and neither do any compounds remotely like it. At first, scientists thought that because cannabinoids dissolved easily in fat, they might work in the same way as general anaesthetics, by seeping into the fatty membranes of brain cells and disrupting their normal functions. But after years of research, this theory had to be dismissed.

The first clue was that only tiny quantities of cannabinoids are needed to produce mind-distorting effects. If they worked by dissolving in membranes, much larger amounts would be required. THC, like many chemical structures, occurs in two forms that are mirror images of each other, rather like the left and right hands of a pair of gloves. The researchers found that one form was much more active than the other. But when both forms were dissolved in fat, there was no preference for either type. Therefore, the team concluded, psychotropic cannabinoids must interact with a special structure to which they bind in a specific way.

By tagging a cannabinoid with a radioactive tracer, the scientists traced the areas in the brain where THC was binding. The distribution was uneven. Some regions retained a lot of the chemical. These included the hippocampus, a structure deep within the brain, shaped like a sea-horse and important for learning and memory. Other areas, such as the brainstem at the back of the head, which is important for controlling respiration and heart function, had relatively few binding sites. The most fatty parts of the brain did not contain the most cannabinoid.

All this evidence pointed in one direction: there must be a specific target or 'receptor' for THC in some brain cells. But why should there be a receptor in the brain purely to react to a substance that is not found there? Could millions of years of evolution have produced a receptor just to get humans high? It seemed unlikely.

The next piece in the jigsaw was found, as many scientific advances are, by accident. An American team stumbled on the cannabinoid receptor while looking for something else. Tom Bonner and his colleagues at the National Institute of Mental Health in Maryland were interested in receptors that respond to a natural molecule called 'substance P', responsible for transmitting pain signals between nerves.

Dr Bonner's group found a receptor that did not respond to substance P - or any other natural brain chemical. For more than a year this 'orphan' receptor remained a mystery. But when the researchers looked at how it was distributed in the brain, they realised that it matched the pattern for cannabinoid binding sites. Further experiments confirmed that the receptor responded to THC.

The researchers, therefore, knew the structure of the receptor, but still did not know why the receptors were there. 'There must be something in the brain which acts on them, and so the search was on,' Dr Pertwee says. Now, the combined efforts of the Jerusalem and Aberdeen teams have come up with anandamide. It was not an easy task - 'like looking for a needle in a haystack', Dr Pertwee says. 'The brain is chock-a-block with active chemicals.' Professor Mechoulam's group purified minute amounts of fat-soluble chemicals obtained from pigs' brains. These were sent to Aberdeen, where Dr Pertwee had developed highly sensitive tests to find out whether any of them acted like cannabinoids. Among the candidate compounds was anandamide. 'There wasn't even enough to see in the bottom of the vial, but we hit on the right dose straight away - and it behaved just like a cannabinoid,' Dr Pertwee says.

When the chemists in Israel attempted to create the compound in the laboratory, they found to their great relief that it had the same properties as the minuscule amount of chemical they had extracted from pigs' brains. The last piece of the puzzle had fallen into place.

Anandamide is chemically quite different from THC and other cannabinoids. Its shape resembles a hairpin, and bears only a fleeting similarity to the cannabinoid structure. This is not uncommon: morphine, also extracted from a plant, the opium poppy, bears little resemblance to the chemical in the brain that it mimics.

As ever in science, more questions remain. 'We need to know where anandamide is, and if - as we suspect - it is a mediator of brain activity, what does it mediate?' Dr Pertwee says. Since cannabis affects so many functions, including memory, perception, mood and movement, he suggests that anandamide may play a role in mental disorders such as schizophrenia and

depression.

(Photographs omitted)

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