A nice historical overview of cannabanoid research
The brain's own marijuana
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The Brain's Own Marijuana
Research into natural chemicals
that mimic marijuana's effects in the brain could help to explain--and
suggest treatments for--pain, anxiety, eating disorders, phobias and
other conditions By Roger A. Nicoll and Bradley N. Alger
Marijuana
is a drug with a mixed history. Mention it to one person, and it will
conjure images of potheads lost in a spaced-out stupor. To another, it
may represent relaxation, a slowing down of modern madness. To yet
another, marijuana means hope for cancer patients suffering from the
debilitating nausea of chemotherapy, or it is the promise of relief
from chronic pain. The drug is all these things and more, for its
history is a long one, spanning millennia and continents. It is also
something everyone is familiar with, whether they know it or not.
Everyone grows a form of the drug, regardless of their political
leanings or recreational proclivities. That is because the brain makes
its own marijuana, natural compounds called endocannabinoids (after the
plant's formal name, Cannabis sativa).
The study of
endocannabinoids in recent years has led to exciting discoveries. By
examining these substances, researchers have exposed an entirely new
signaling system in the brain: a way that nerve cells communicate that
no one anticipated even 15 years ago. Fully understanding this
signaling system could have far-reaching implications. The details
appear to hold a key to devising treatments for anxiety, pain, nausea,
obesity, brain injury and many other medical problems. Ultimately such
treatments could be tailored precisely so that they would not initiate
the unwanted side effects produced by marijuana itself.
A Checkered Past Marijuana
and its various alter egos, such as bhang and hashish, are among the
most widely used psychoactive drugs in the world. How the plant has
been used varies by culture. The ancient Chinese knew of marijuana's
pain-relieving and mind-altering effects, yet it was not widely
employed for its psychoactive properties; instead it was cultivated as
hemp for the manufacture of rope and fabric. Likewise, the ancient
Greeks and Romans used hemp to make rope and sails. In some other
places, however, marijuana's intoxicating properties became important.
In India, for example, the plant was incorporated into religious
rituals. During the Middle Ages, its use was common in Arab lands; in
15th-century Iraq it was used to treat epilepsy; in Egypt it was
primarily consumed as an inebriant. After Napoleon's occupation of
Egypt, Europeans began using the drug as an intoxicant. During the
slave trade, it was transported from Africa to Mexico, the Caribbean
and South America.
Marijuana
gained a following in the U.S. only relatively recently. During the
second half of the 19th century and the beginning of the 20th, cannabis
was freely available without a prescription for a wide range of
ailments, including migraine and ulcers. Immigrants from Mexico
introduced it as a recreational drug to New Orleans and other large
cities, where it became popular among jazz musicians. By the 1930s it
had fallen into disrepute, and an intense lobbying campaign demonized
"reefer madness." In 1937 the U.S. Congress, against the advice of the
American Medical Association, passed the Marijuana Tax Act, effectively
banning use of the drug by making it expensive and difficult to obtain.
Ever since, marijuana has remained one of the most controversial drugs
in American society. Despite efforts to change its status, it remains
federally classified as a Schedule 1 drug, along with heroin and LSD,
considered dangerous and without utility.
Millions of people
smoke or ingest marijuana for its intoxicating effects, which are
subjective and often described as resembling an alcoholic "high." It is
estimated that approximately 30 percent of the U.S. population older
than 12 have tried marijuana, but only about 5 percent are current
users. Large doses cause hallucinations in some individuals but simply
trigger sleep in others. The weed impairs short-term memory and
cognition and adversely affects motor coordination, although these
setbacks seem to be reversible once the drug has been purged from the
body. Smoking marijuana also poses health risks that resemble those of
smoking tobacco.
On
the other hand, the drug has clear medicinal benefits. Marijuana
alleviates pain and anxiety. It can prevent the death of injured
neurons. It suppresses vomiting and enhances appetite--useful features
for patients suffering the severe weight loss that can result from
chemotherapy.
Finding the Responsible Agent Figuring
out how the drug exerts these myriad effects has taken a long time. In
1964, after nearly a century of work by many individuals, Raphael
Mechoulam of the Hebrew University in Jerusalem identified
delta-9-tetrahydrocannabinol (THC) as the compound that accounts for
virtually all the pharmacological activity of marijuana. The next step
was to identify the receptor or receptors to which THC was binding.
Receptors
are small proteins embedded in the membranes of all cells, including
neurons, and when specific molecules bind to them--fitting like one
puzzle piece into another--changes in the cell occur. Some receptors
have water-filled pores or channels that permit chemical ions to pass
into or out of the cell. These kinds of receptors work by changing the
relative voltage inside and outside the cell. Other receptors are not
channels but are coupled to specialized proteins called G-proteins.
These G-protein-coupled receptors represent a large family that set in
motion a variety of biochemical signaling cascades within cells, often
resulting in changes in ion channels.
In 1988 Allyn C. Howlett
and her colleagues at St. Louis University attached a radioactive tag
to a chemical derivative of THC and watched where the compound went in
rats' brains. They discovered that it attached itself to what came to
be called the cannabinoid receptor, also known as CB1. Based on this
finding and on work by Miles Herkenham of the National Institutes of
Health, Lisa Matsuda, also at the NIH, cloned the CB1 receptor. The
importance of CB1 in the action of THC was proved when two researchers
working independently--Catherine Ledent of the Free University of
Brussels and Andreas Zimmer of the Laboratory of Molecular Neurobiology
at the University of Bonn--bred mice that lacked this receptor. Both
investigators found that THC had virtually no effect when administered
to such a mouse: the compound had nowhere to bind and hence could not
trigger any activity. (Another cannabinoid receptor, CB2, was later
discovered; it operates only outside the brain and spinal cord and is
involved with the immune system.)
As researchers continued to
study CB1, they learned that it was one of the most abundant G-protein
coupled receptors in the brain. It has its highest densities in the
cerebral cortex, hippocampus, hypothalamus, cerebellum, basal ganglia,
brain stem, spinal cord and amygdala. This distribution explains
marijuana's diverse effects. Its psychoactive power comes from its
action in the cerebral cortex. Memory impairment is rooted in the
hippocampus, a structure essential for memory formation. The drug
causes motor dysfunction by acting on movement control centers of the
brain. In the brain stem and spinal cord, it brings about the reduction
of pain; the brain stem also controls the vomiting reflex. The
hypothalamus is involved in appetite, the amygdala in emotional
responses. Marijuana clearly does so much because it acts everywhere.
Over
time, details about CB1's neuronal location emerged as well. Elegant
studies by Tam?s F. Freund of the Institute of Experimental Medicine at
the Hungarian Academy of Sciences in Budapest and Kenneth P. Mackie of
the University of Washington revealed that the cannabinoid receptor
occurred only on certain neurons and in very specific positions on
those neurons. It was densely packed on neurons that released GABA
(gamma-aminobutyric acid), which is the brain's main inhibitory
neurotransmitter (it tells recipient neurons to stop firing). CB1 also
sat near the synapse, the contact point between two neurons. This
placement suggested that the cannabinoid receptor was somehow involved
with signal transmission across GABA-using synapses. But why would the
brain's signaling system include a receptor for something produced by a
plant?
The Lesson of Opium The same question had
arisen in the 1970s about morphine, a compound isolated from the poppy
and found to bind to so-called opiate receptors in the brain.
Scientists finally discovered that people make their own opioids--the
enkephalins and endorphins. Morphine simply hijacks the receptors for
the brain's opioids.
It seemed likely that something similar
was happening with THC and the cannabinoid receptor. In 1992, 28 years
after he identified THC, Mechoulam discovered a small fatty acid
produced in the brain that binds to CB1 and that mimics all the
activities of marijuana. He named it anandamide, after the Sanskrit
word ananda, "bliss." Subsequently, Daniele Piomelli and Nephi Stella
of the University of California at Irvine discovered that another
lipid, 2-arachidonoyl glycerol (2-AG), is even more abundant in certain
brain regions than anandamide is. Together the two compounds are
considered the major endogenous cannabinoids, or endocannabinoids.
(Recently investigators have identified what look like other endogenous
cannabinoids, but their roles are uncertain.) The two cannabinoid
receptors clearly evolved along with endocannabinoids as part of
natural cellular communication systems. Marijuana happens to resemble
the endocannabinoids enough to activate cannabinoid receptors.
Conventional
neurotransmitters are water-soluble and are stored in high
concentrations in little packets, or vesicles, as they wait to be
released by a neuron. When a neuron fires, sending an electrical signal
down its axon to its tips (presynaptic terminals), neurotransmitters
released from vesicles cross a tiny intercellular space (the synaptic
cleft) to receptors on the surface of a recipient, or postsynaptic,
neuron. In contrast, endocannabinoids are fats and are not stored but
rather are rapidly synthesized from components of the cell membrane.
They are then released from places all over the cells when levels of
calcium rise inside the neuron or when certain G-protein-coupled
receptors are activated.
As unconventional neurotransmitters,
canna-bin-oids presented a mystery, and for several years no one could
figure out what role they played in the brain. Then, in the early
1990s, the answer emerged in a somewhat roundabout fashion. Scientists
(including one of us, Alger, and his colleague at the University of
Maryland School of Medicine, Thomas A. Pitler) found something unusual
when studying pyramidal neurons, the principal cells of the
hippocampus. After calcium concentrations inside the cells rose for a
short time, incoming inhibitory signals in the form of GABA arriving
from other neurons declined.
At the same time, Alain Marty, now
at the Laboratory of Brain Physiology at the Ren? Descartes University
in Paris, and his colleagues saw the same action in nerve cells from
the cerebellum. These were unexpected observations, because they
suggested that receiving cells were somehow affecting transmitting
cells and, as far as anyone knew, signals in mature brains flowed
across synapses in one way only: from the presynaptic cell to the
postsynaptic one.
A New Signaling System it seemed
possible that a new kind of neuronal communication had been discovered,
and so researchers set out to understand this phenomenon. They dubbed
the new activity DSI, for depolarization-induced suppression of
inhibition. For DSI to have occurred, some unknown messenger must have
traveled from the postsynaptic cell to the presynaptic GABA-releasing
one and somehow shut off the neurotransmitter's release.
Such
backward, or "retrograde," signaling was known to occur only during the
development of the nervous system. If it were also involved in
interactions among adult neurons, that would be an intriguing
finding--a sign that perhaps other processes in the brain involved
retrograde transmission as well. Retrograde signaling might facilitate
types of neuronal information processing that were difficult or
impossible to accomplish with conventional synaptic transmission.
Therefore, it was important to learn the properties of the retrograde
signal. Yet its identity remained elusive. Over the years, countless
molecules were proposed. None of them worked as predicted.
Then,
in 2001, one of us (Nicoll) and his colleague at the University of
California at San Francisco, Rachel I. Wilson--and at the same time,
but independently, a group led by Masanobu Kano of Kanazawa University
in Japan--reported that an endocannabinoid, probably 2-AG, perfectly
fit the criteria for the unknown messenger. Both groups found that a
drug blocking cannabinoid receptors on presynaptic cells prevents DSI
and, conversely, that drugs activating CB1 mimic DSI. They soon showed,
as did others, that mice lacking cannabinoid receptors are incapable of
generating DSI. The fact that the receptors are located on the
presynaptic terminals of GABA neurons now made perfect sense. The
receptors were poised to detect and respond to endocannabinoids
released from the membranes of nearby postsynaptic cells.
Over
time, DSI proved to be an important aspect of brain activity.
Temporarily dampening inhibition enhances a form of learning called
long-term potentiation--the process by which information is stored
through the strengthening of synapses. Such storage and information
transfer often involves small groups of neurons rather than large
neuronal populations, and endocannabinoids are well suited to acting on
these small assemblages. As fat-soluble molecules, they do not diffuse
over great distances in the watery extracellular environment of the
brain. Avid uptake and degradation mechanisms help to ensure that they
act in a confined space for a limited period. Thus, DSI, which is a
short-lived local effect, enables individual neurons to disconnect
briefly from their neighbors and encode information.
A host of
other findings filled in additional gaps in understanding about the
cellular function of endocannabinoids. Researchers showed that when
these neurotransmitters lock onto CB1 they can in some cases block
presynaptic cells from releasing excitatory neurotransmitters. As Wade
G. Regehr of Harvard University and Anatol C. Kreitzer, now at Stanford
University, found in the cerebellum, endocannabinoids located on
excitatory nerve terminals aid in the regulation of the massive numbers
of synapses involved in coordinated motor control and sensory
integration. This involvement explains, in part, the slight motor
dysfunction and altered sensory perceptions often associated with
smoking marijuana.
Recent discoveries have also begun to
precisely link the neuronal effects of endocannabinoids to their
behavioral and physiological effects. Scientists investigating the
basis of anxiety commonly begin by training rodents to associate a
particular signal with something that frightens them. They often
administer a brief mild shock to the feet at the same time that they
generate a sound. After a while the animal will freeze in anticipation
of the shock if it hears the sound. If the sound is repeatedly played
without the shock, however, the animal stops being afraid when it hears
the sound--that is, it unlearns the fear conditioning, a process called
extinction. In 2003 Giovanni Marsicano of the Max Planck Institute of
Psychiatry in Munich and his co-workers showed that mice lacking normal
CB1 readily learn to fear the shock-related sound, but in contrast to
animals with intact CB1, they fail to lose their fear of the sound when
it stops being coupled with the shock.
The results indicate that
endocannabinoids are important in extinguishing the bad feelings and
pain triggered by reminders of past experiences. The discoveries raise
the possibility that abnormally low numbers of cannabinoid receptors or
the faulty release of endogenous cannabinoids are involved in
post-traumatic stress syndrome, phobias and certain forms of chronic
pain. This suggestion fits with the fact that some people smoke
marijuana to decrease their anxiety. It is also conceivable, though far
from proved, that chemical mimics of these natural substances could
allow us to put the past behind us when signals that we have learned to
associate with certain dangers no longer have meaning in the real
world.
Devising New Therapies The repertoire of the
brain's own marijuana has not been fully revealed, but the insights
about endocannabinoids have begun helping researchers design therapies
to harness the medicinal properties of the plant. Several synthetic THC
analogues are already commercially available, such as nabilone and
dronabinol. They combat the nausea brought on by chemotherapy;
dronabinol also stimulates appetite in AIDS patients. Other
cannabinoids relieve pain in myriad illnesses and disorders. In
addition, a CB1 antagonist--a compound that blocks the receptor and
renders it impotent--has worked in some clinical trials to treat
obesity. But though promising, these drugs all have multiple effects
because they are not specific to the region that needs to be targeted.
Instead they go everywhere, causing such adverse reactions as
dizziness, sleepiness, problems of concentration and thinking
abnormalities.
One way around these problems is to enhance the
role of the body's own endocannabinoids. If this strategy is
successful, endocannabinoids could be called forth only under the
circumstances and in the locations in which they are needed, thus
avoiding the risks associated with widespread and indiscriminant
activation of cannabinoid receptors. To do this, Piomelli and his
colleagues are developing drugs that prevent the endocannabinoid
anandamide from being degraded after it is released from cells. Because
it is no longer broken down quickly, its anxiety-relieving effects last
longer.
Anandamide seems to be the most abundant endocannabinoid
in some brain regions, whereas 2-AG dominates in others. A better
understanding of the chemical pathways that produce each
endocannabinoid could lead to drugs that would affect only one or the
other. In addition, we know that endocannabinoids are not produced when
neurons fire just once but only when they fire five or even 10 times in
a row. Drugs could be developed that would alter the firing rate and
hence endocannabinoid release. A precedent for this idea is the class
of anticonvulsant agents that suppress the neuronal hyperactivity
underlying epileptic seizures but do not affect normal activity.
Finally,
indirect approaches could target processes that themselves regulate
endocannabinoids. Dopamine is well known as the neurotransmitter lost
in Parkinson's disease, but it is also a key player in the brain's
reward systems. Many pleasurable or addictive drugs, including nicotine
and morphine, produce their effects in part by causing dopamine to be
released in several brain centers. It turns out that dopamine can cause
the release of endocannabinoids, and various research teams have found
that two other neurotransmitters, glutamate and acetylcholine, also
initiate endocannabinoid synthesis and release. Indeed,
endocannabinoids may be a source of effects previously attributed
solely to these neurotransmitters. Rather than targeting the
endocannabinoid system directly, drugs could be designed to affect the
conventional neurotransmitters. Regional differences in
neurotransmitter systems could be exploited to ensure that
endocannabinoids would be released only where they were needed and in
appropriate amounts.
In a remarkable way, the effects of
marijuana have led to the still unfolding story of the
endocannabinoids. The receptor CB1 seems to be present in all
vertebrate species, suggesting that systems employing the brain's own
marijuana have been in existence for about 500 million years. During
that time, endocannabinoids have been adapted to serve numerous, often
subtle, functions. We have learned that they do not affect the
development of fear, but the forgetting of fear; they do not alter the
ability to eat, but the desirability of the food, and so on. Their
presence in parts of the brain associated with complex motor behavior,
cognition, learning and memory implies that much remains to be
discovered about the uses to which evolution has put these interesting
messengers.
ROGER A. NICOLL and BRADLEY E. ALGER first worked
together in the late 1970s, when they both were forming what has become
an enduring interest in synaptic transmission. At that time, Nicoll had
just moved to the University of California, San Francisco, where he is
now professor of pharmacology; Alger, currently professor of physiology
and psychiatry at the University of Maryland School of Medicine, was
his first postdoctoral fellow. Nicoll is a member of the National
Academy of Sciences and recent winner of the Heinrich Wieland Award.
MORE TO EXPLORE: Marijuana and Medicine. Edited by J. E. Joy, S. J. Watson, Jr., and J. A. Benson, Jr. Institute of Medicine, 1999. Endocannabinoid Signaling in the Brain. R. I. Wilson and R. A. Nicoll in Science, Vol. 296, pages 678-682; April 26, 2002. Retrograde
Signaling in the Regulation of Synaptic Transmission: Focus on
Endocannabinoids. B. E. Alger in Progress in Neurobiology, Vol. 68, No.
4, pages 247-286; November 2002.
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