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Three years ago, Israeli archaeologists stumbled upon a 1600-year-old
tragedy: the remains of a narrow-hipped teenage girl with the skeleton of a
full-term fetus still cradled in her abdomen. With her were grey ashes
that contained traces of tetra – hydrocannabinol, the active ingredient of
marijuana. Could it be that the midwife had administered the plant in a
last-ditch effort to bring on labour or to ease her pain?

Today, in nearby Jerusalem, another chemical is in the news – this one
extracted not from ancient ashes but from fresh, pulverised pig brain. It is
anandamide, a newly christened chemical that might do naturally in our
heads what marijuana does when we choose to smoke it. Anan-damide’s
discovery, along with that of the molecule it binds to in the brain, has
marijuana researchers buzzing with the best high they have had in years. The
findings provide new hope for therapies that draw on the weed’s long list of
anecdotal medical uses: as a painkiller, appetite stimulant or nausea
suppres-sant, to name a few. They also throw open windows onto the
mysterious workings of our brains.

Research into marijuana, or Cannabis sativa, has long been marginalised by
official disapproval of the weed and its use. It is, after all, classed as a
drug with no medical merit, and its recreational use is widely frowned upon.
But this was not always so. For thousands of years, India revered the plant
for its effects on the mind. In China, where opium was the mind-bending drug
of choice, the cannabis plant was used for medicines and its tough fibres
for making clothes. The West also used marijuana: Queen Victoria’s doctor
administered it for Her Majesty’s menstrual cramps; George Washington and
Thomas Jefferson both grew the plant on their southern estates as a source
of fibre for ropes and sails. (History does not record whether either of
these presidents ever tried smoking their crop and, if so, whether they
inhaled or not.)

But as demand for hempen rope and cloth diminished, and the recreational use
of marijuana increased, anti-marijuana feeling grew, reaching a peak in the
1930s. ‘If the hideous monster Frankenstein came face to face with the
monster marijuana he would drop dead of fright,’ trumpeted Harry Anslinger,
commissioner of the Federal Bureau of Narcotics and a leading anti-cannabis
crusader of the times. In 1937, marijuana use was outlawed in the United
States. By 1971 even its medical use was banned in the US and Britain.

Marijuana may have been outlawed, but marijuana research has not, though it
is not most governments’ top funding priority. In 1964 Raphael Mechoulam,
an Israeli chemist, identified and synthesised the main mind-altering
substance in the plant, delta-9-tetrahydro-cannabinol, the most abundant of
about 60 related chemicals. ¿ìè¶ÌÊÓƵs speculated that THC did its deed by
sticking randomly to brain cells, interfering with their ability to
communicate by altering the electrical properties of their membranes, much
as alcohol does.

More recently came other exciting finds: in 1988, Allyn Howlett of St Louis
Uni-versity Medical School discovered a specific protein receptor for THC in
mouse nerve cells – a protein that only THC and its relatives dock onto. Two
years later, Tom Bonner’s group at the National Institute of Mental Health
pinpointed the DNA that encodes the same receptor in rats. It is now known
that humans have the receptor, too.

Finding a cannabinoid receptor implies that THC – unlike alcohol – has a
quite precise modus operandi that taps into a specific brain function.
Presumably the drug binds to nerves that have the receptor, and the nerves
respond in turn by altering their behaviour. The classic effects of
marijuana smoking are the consequences: changes in mood, memory, appetite,
movement and perception, including pain. Researchers think THC affects so
many mental processes because receptors are found in many brain regions,
especially in those that perform tasks known to be disturbed during THC
intoxication: in the banana-shaped hippocampus, crucial for proper memory;
in the crumpled cerebral cortex, home of higher thinking; and in the
primitive basal ganglion, controller of movement.

Once a specially tailored receptor was found, the next step was simple – in
theory, anyway. ‘The receptor had to be there for a purpose – presumably it
didn’t evolve so that people could smoke cannabis and get high,’ says Roger
Pertwee, a pharmacologist at Aberdeen University. Instead, there had to be a
natural chemical inside of us that fitted onto the receptor and sent some
biochemical signal cascading through the nerve cell to do who knows what.
But plucking that one chemical out of a brain stuffed with millions of
others was never going to be easy.

Blissful thinking

Several laboratories set to work on the problem and, fittingly, Mechoulam’s
was the first to come up with an answer, in the form of a greasy,
hairpin-shaped chemical. The researchers dubbed it anandamide, from
‘ananda’, the Sanskrit word for bliss. ‘The guy discovers the active
ingredient of marijuana back in the 1960s, and now, almost 30 years later to
the day, he discovers anandamide,’ says Paul Consroe, a neuropharmacologist
at the University of Arizona. ‘Isn’t that great?’

Mechoulam’s strategy was to chase after chemicals that, like THC, are
soluble in fat. By teasing these substances away from those that are water
soluble, his group extracted a substance from pig brain that did indeed bind
to the cannabinoid receptor. But did it act like THC? To find out they sent
their specimen to Pertwee who had devised a sensitive test for cannabinoids
that involved monitoring a substance’s ability to stop muscle-twitching in
mouse tissue, when dropped on certain nerves. ‘When it arrived, there was so
little of it in the phial I couldn’t even see it,’ Pertwee recalls. ‘We
didn’t know what it was – just that it was a greasy substance.’ But the
tests went well: anandamide depressed the twitch just like THC, and last
December the researchers published their results in Science.

The mouse result gave Mechoulam and his group the encouragement they needed
to extract more anandamide from pig brains and then analyse and synthesise
the chemical in the lab. They also wanted more evidence that anandamide
docked specifically onto the cannabinoid receptor and acted like THC, which
has a very different molecular structure. And so, with Zvi Vogel and
colleagues at the Weizmann Institute near Tel Aviv, they came up with a
plan. They would add the DNA encoding the cannabinoid receptor to hamster or
monkey cells growing in dishes. The cells equipped with this DNA would then
produce masses of receptor, which would sit in the cell membrane ready and
available for any chemical ‘key’ that should happen along. Vogel’s
researchers would add anandamide to the cells and watch what happened.

The results, published in July’s issue of the Journal of Neurochemistry,
were clear: anandamide acted as a key, and a precise one at that, sticking
only to the cells containing the receptor, and not to others. What’s more,
when anandamide stuck to the cells, it triggered biochemical changes similar
to those associated with THC and related chemicals. Not only did anandamide
fit the same lock as THC, but it appeared to open similar doors in the
brain.

More tests followed in a number of laboratories, and these researchers found
that in every way that has been tested so far, anandamide acts very much
like THC. But why would we want such a mind-altering substance in our
brains?

Studies on another class of drugs provide a useful parallel. Opiates such as
morphine and heroin act upon the body’s nervous system to cause euphoria and
block pain. In 1973, natural opioids, which behave in the same way as
opiates, but have a different structure, were pulled out of the body. It
appears that when the body is under serious assault, nerve cells spit out
these opioids, which promptly bind to other nerve cells to stop pain signals
dead in their tracks. At the same time, they fasten onto sites in the brain
to induce a feeling of wellbeing.

Anandamide, like the natural opioids, will probably have its own specific
set of jobs to perform in the brain and body. The effects of THC give a
rough guide to what these might be: involvement in mood, memory and pain
are obvious examples.

But what would the brain be like without anandamide? Researchers intend to
find out. Bonner is gearing up to produce a genetically engineered mouse
that has no cannabinoid receptors: no receptors, no anandamide function.
Others want to tinker with anandamide to make a version that binds to the
receptor but doesn’t trigger any change in the nerve’s behaviour. Added to a
mouse, it would stop the body’s real, internal anandamide from doing its
job. Researchers are also excited by anandamide’s possible role in mental
and neurological disease. There are also other questions to be asked. If
anandamide, like THC, hampers memory, could a drug with the opposite effects
– a ‘memory pill’ – be made? ‘It’s all speculation for now,’ says Steven
Childers, a pharmacologist at Bowman Gray School of Medicine, North
Carolina.

‘But we like to think about these things.’ It will take more time before
anandamide is firmly established as the bona fide partner to the cannabinoid
receptor. Meanwhile, Mechoulam’s lab has two other anandamide-like chemicals
waiting in the wings. And in the US, Howlett and Childers both have
chemicals of an entirely different kind that bind to the receptor: they are
water soluble, not fat soluble. The importance of each remains to be seen.

High hopes

Whatever anandamide turns out to be, it provides pharmacologists with a
fresh plan of attack in their hunt for drugs that act like the cannabinoids.
Such drugs could be valuable to help keep at bay the nausea of cancer
chemotherapy; to stimulate appetite in AIDS patients; to dampen tremors in
neurological disorders; to reduce eye pressure in patients with glaucoma;
and to dull pain in those for whom other painkillers do not work.

Cannabinoids can do at least some of these things, with one small drawback:
they also make the recipient high. The holy grail of cannabinoid
therapeutics has been to separate what causes the high from the source of
the desired effects, by chemical tinkering with THC or its relations –
shortening a side group on one part of the molecule, lengthening a carbon
chain in another – in the hope that the ‘undesirable’ effects will be lost
in the reshuffle. Despite the drug’s dubious reputation, several US
pharmaceuticals spent several years trying to make this work, but without
success. Nor did they reach another equally sought after goal: an antagonist
that will block the effects of THC and similar substances when taken.

Until marijuana researchers succeed in doing something along these lines, it
is unlikely that drugs companies will pay much attention. ‘There is a real
stigma with working with drugs of abuse,’ says Billy Martin, a
pharmacologist at the Medical College of Virginia. ‘If drugs companies had
three choices of classes of drugs to work on and one was a drug of abuse,
they’re just not going to work on the drug of abuse.’ This view is shared by
Larry Melvin, who worked on the Pfizer pharmaceuticals company’s now defunct
cannabinoid therapeutics programme. ‘What will ultimately legitimise the
field in a big way is if researchers can come up with a really good
therapeutic ability. Then you’ll see the companies turn around.’

But Gabriel Nahas, an anaesthetist from Columbia University in New York, who
has spoken out against marijuana use for many years, maintains that THC’s
effects on the brain are too general and too toxic for this route ever to
work. The discovery of anandamide and its receptor have not changed his
mind. ‘The brain is a computer,’ he says. ‘To put THC in the brain is akin
to putting a bug in the computer. I’m sticking to my guns about its harmful
effects – not only to man but to society.’

Only time will reveal the value of anandamide and its receptor to drug
therapy. But the importance of these discoveries to brain research is not in
doubt. ‘We’re no longer just dealing with the pharmacology of a recreational
drug,’ says Pertwee. ‘We’re dealing with the physiology of a newly
discovered system in the brain. And that’s an enormously bigger field.

* * *

Just what the doctor ordered?

Every month, Robert Randall receives a gift from the US government: a tin
box stuffed with 300 marijuana cigarettes. He gets them because he has
glaucoma, a condition which damages the retina. Marijuana helps to reduce
the pressure in his eyes.

Randall and eight others are participants in the Compassionate Investigative
New Drug programme, under which people with glaucoma, cancer, chronic pain,
multiple sclerosis and AIDS are given the drug for its supposed
effectiveness in relieving pain, suppressing nausea from AZT or
chemotherapy, and stimulating appetite.

If the programme seems like an anomaly, given mari-juana’s official status
as a drug with no medical use, it is no longer. Only those patients
originally on the programme now receive marijuana from the government.
Others must now buy it illegally off the street.

That is a hardship, says Randall, president of the Alliance for Cannabis
Therapeutics (ACT), which lobbies for the medical use of marijuana. ‘We get
calls from AIDS patients who say ‘I can either buy food that I can’t eat
because I’m so nauseous, or I can buy marijuana and get hungry because I
can’t afford to buy food’,’ he says.

In 1975, those steep street prices had driven Randall to grow cannabis
plants to treat his glaucoma. This led to his arrest, fol-lowed by an
acquittal and ultimately – after he filed a lawsuit to a legal supply from
the government. Later, a handful of patients with cancer or suffering
chronic pain won access, and in 1990 a man known as Steve L became the
first person with AIDS to get the drug, just ten days before he died. Later
that year, Kenny Jenks and his wife Barbra won the same right, after a
fierce fight following their arrest for possessing two cannabis plants.

Until 1991, anyone wanting to get on the programme had to fill in forms so
complex that the task took about 50 hours. Then the government reduced the
red tape, cutting the time to apply to about one hour – and found itself
inundated with applications for therapeutic marijuana. The US Public Health
Service responded by scrapping the programme.

Many doctors think that ending the programme was wrong, and that they should
be allowed to prescribe marijuana under some circumstances. In a 1991
survey, 48 per cent of the oncologists questioned said that they would
prescribe it to patients if they could, and 44 per cent said they had
advised at least one of their patients to use it illegally.

The remaining patients on the programme also regret being the last to get
marijuana legally. ‘We let doctors decide every day whether we’re allowed
to take morphine and all kinds of dangerous drugs’ said Jenks who died on
19 July. ‘The decision to take marijuana should be between the doctor and
the patient.