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COPYRIGHT 2006 SCIENTIFIC AMERICAN, INC.
COPYRIGHT 2006 SCIENTIFIC AMERICAN, INC.

The brain produces its own "marijuana" to protect neurons, and researchers hope to exploit it to ease anxiety, obesity and addiction COPYRIGHT 2006 SCIENTIFIC AMERICAN, INC.

hemically speaking, we are all potheads. ling appetite, and in the cerebellum, which gov- Raphael Mechoulam of Hebrew Uni- erns muscle coordination. They are also preva- versity in Jerusalem discovered that lent in the hippocampus, important to memory astounding fact in 1992, and now the formation, as well as in the amygdala, involved Creasons why are fi nally emerging. Nu-in emotion and anxiety. And they are found in merous experiments with genetically the neocortex, the site of such cognitive functions altered mice and rats have shown that as speech and integration of the senses. Given the when natural brain compounds, called endocannabinoids' roles, it is easy to understand endocannabinoids, are missing or their re- the classic signs of a pot smoker who is high: ceptors are blocked, the animals are more sus- calm demeanor, poor motor coordination, al- ceptible to pain, cannot control their appetites, tered sensory perceptions and an eventual attack have trouble handling anxiety and are less able of the munchies.
to cope with stress.
What surprised investigators, when it became By fully understanding and then harnessing clear that the endocannabinoids were communi- the endocannabinoid mechanisms, researchers cating between neurons, was that the direction are eager to devise new ways to reduce pain, calm of communication occurred in reverse. When a anxiety, fi ght obesity, stop nicotine addiction typical neuron fi res, it releases neurotransmitters and even treat traumatic shock and Parkinson's that are stored near the tip of its axon. The sig- disease—without the unwanted side effects of naling chemicals cross a small gap, or synapse, smoking marijuana. and dock with receptors on the dendrite of the next neuron, causing it to fi re, and so on down Signals in Reverse the chain. The endocannabinoids, however, are To be precise, endocannabinoids do not mim- rapidly synthesized in the recipient neuron's cell ic the effects of marijuana. It is the drug, derived membrane. They cross the gap in reverse, dock- from the hemp plant, that approximates the brain's ing at the axon [see box on page 64]. Neurosci- endocannabinoid chemistry. A decade of study entists had thought this retrograde signaling oc- has shown that a specifi c receptor on certain neu- curred only during fetal development of the ner- rons—the cannabinoid receptor 1, or CB1—binds vous system.
to delta-9-tetrahydrocannabinol (THC), the ac- Using mice and rats in labs, researchers slow- tive ingredient in cannabis, the dried leaf of mari- ly fi gured out the reason for the retrograde com- juana. The same receptor binds to a class of fatty munication. "A neuron that has just received a The human brain's cannabinoid system seems to fulfi ll multiple functions.
acids produced by neurons—the endocannabi- message can send one right back that says, ‘Stop noids. Mechoulam named the one he discovered transmitting!'" explains Andreas Zimmer, a anandamide—after ananda, the Sanskrit word for neurobiologist at the University of Bonn in Ger- "bliss." Subsequently, Daniele Piomelli and Nephi many who helped defi ne the backward mecha- Stella of the University of California, Irvine, found nism. "The endocannabinoids are an inhibitory a second compound, called 2-AG, with similar feedback loop. The second neuron reports back characteristics. THC happens to resemble these to the sender: ‘Message received. Cease fi ring. I substances closely enough that the CB1 receptors e ) (pisb latch onto it, unleashing similar or magnifi ed ef- . (nc ann fects on the toker's brain.
CB1 receptors are not everywhere in the According to Ibn Al Badri, an Arab chronicler, eh is (c brain—they exist in concentrated pockets in people knew about the inhibitory effects of hash- es C many varied locations. The distribution suggests ish, also derived from hemp, at the court of the that the human cannabinoid system fulfi lls mul- caliphs in 15th-century Baghdad. For one thing, tiple functions [see box on opposite page]. For hashish reportedly stopped the epileptic seizures in example, numerous receptors exist in the hypo- the son of a high offi cial. Such attacks arise when thalamus, which plays a central role in control- neurons fi re in rampant unison across the brain— 62 SCIENTIFIC AMERICAN MIND August /September 2006 COPYRIGHT 2006 SCIENTIFIC AMERICAN, INC.
Crucial Roles Endocannabinoid receptors are concentrated in many classic behaviors associated with smoking marijuana and brain regions, making them crucial to various func- the potential payoff of drugs that mimic endocannabinoid tions. Their distribution also explains some of the effects for patients with severe pain or other problems.
Controls appetite, hormone levels and Site of higher cognitive the integration of sensory information Involved in motor Crucial to memory and the learning of facts anxiety, fear and emotion Brain Stem and Spinal Cord Seat of motor control Central to the vomiting reflex and the sensation of pain meaning no inhibition signal stops them. Today at the University of Texas at San Antonio, has some epileptics can somewhat manage their at- confirmed this theory working with Parkinson's tacks by smoking cannabis regularly. And yet for patients. In Parkinson's disease, neurons in cer- others, seizures worsen after this self-therapy.
tain brain regions that produce the neurotrans-mitter dopamine die off. As a result, victims de- velop severe motor problems. A certain toxin Still, experts now for the most part agree that that kills dopamine-producing neurons causes the main function of the endocannabinoids is to similar symptoms. So Giuffrida injected the tox- protect neurons from excessive activity. The in into lab mice a few minutes after giving them brain "has created a kind of emergency brake for a synthetic cannabinoid. The cannabinoid pre- use when needed," says Beat Lutz, a physiologi- vented the toxin's destructive effects. "The brains cal chemist at the University of Mainz in Germany of the mice that had been treated with the mari- who has also helped elucidate endocannabinoid juanalike substance could scarcely be distin- mechanisms. If a neuronal storm threatens, the guished from those of normal mice," Giuffrida endocannabinoids are released to block it. Ac- says. He hopes that his work will ultimately lead cording to Lutz, this protective mechanism plays to compounds that stop the destruction of dopa- an important role well beyond epilepsy. "It ap- pears to be quite general," the researcher ex- plains. "If the brain has a problem, it produces ULRICH KRAFT, a freelance science writer in Berlin, wrote the cover story Andrea Giuffrida, a pharmacology professor on burnout in the June/July issue of Scientific American Mind. w w w. sciammind.com SCIENTIFIC AMERICAN MIND 63 COPYRIGHT 2006 SCIENTIFIC AMERICAN, INC.
Retrograde Communication A t a typical synapse, the knob at the end of a neuron postsynaptic cell's membrane, then exit and dock at the secretes neurotransmitters such as glutamate knob's CB1 receptors. When docking occurs, that tells (green). These neurotransmitters diffuse across the presynaptic cell to stop releasing glutamate. The the gap to receptors on a neighboring neuron. The endo- endocannabinoids, acting as neuromodulators, may cannabinoids work in reverse. They are produced in the protect neurons from overarousal.
Signal direction for Signal direction for mine-producing neurons, helping to fight Parkin- ger a threat, gradually extinguishing the fear. son's in its early stages.
Rodents with missing or blocked CB1 receptors, Zimmer concurs that the endocannabinoids' however, do not lose their fear. The endocan- primary purpose is to help protect the mental nabinoids, it seems, are crucial to diminishing organism from stress. He says, "They protect bad feelings, and a faulty system might be a prime nerve cells not just from overarousal, but also, for contributor to post-traumatic stress syndrome or example, from the harmful effects of stress hor- mones such as cortisol." Lutz adds that cannabi- t ise noids also "put the body into recovery mode"; muscles slacken, pulse and blood pressure go That a whole lot of things happen when you down, and mental activity is lessened flood your brain with THC is old news for e G marijuana smokers, but the effects have sudden- Experts are starting to explain various psy- ly piqued the interest of the pharmaceutical chological effects as well. They have trained ro- dents to fear certain stimuli, then retrained them The pharmaceutical company Sanofi-Aven- to subsequently learn that the stimuli are no lon- tis, based in Paris, has developed a new drug 64 SCIENTIFIC AMERICAN MIND August /September 2006 COPYRIGHT 2006 SCIENTIFIC AMERICAN, INC.
called Acomplia, which is already in trials. Its Second, possible side effects related to sus- active ingredient, rimonabant, blocks CB1 recep- tained alteration of the CB1 receptors are un- tors and is thus supposed to help overweight known and cannot be ruled out. "We have al- people shed pounds. "Cannabinoids arouse one's most no idea what will happen if we inhibit the appetite, apparently through the reward system," endogenous cannabinoid system over the long Zimmer explains. Because rimonabant binds to term," Zimmer says of the brain's natural reward the sites normally used by endocannabinoids, it mechanisms. His perspective comes from his lat- may be able to stop cravings for food. The prin- est experiments with genetically altered mice. ciple seems to work, according to results of a When they were young, the mice did markedly company study of 3,000 U.S. and Canadian vol- better than their unaltered peers in various learn- unteers, which Sanofi-Aventis released in Febru- ing tests. But at the age of three to five months— ary. Participants who took the CB1 blocker each the prime of life—the mice without CB1 recep- day lost more weight than a control group given tors were learning almost as poorly as normal a placebo. In addition, markers in standard blood mice at 18 months old, which is elderly. Studies No one anticipated what has proved to be an entirely new communication system in the brain.
tests that indicate a high risk of stroke or heart of the pothead mice revealed they had suffered attack were lower.
damage to the hippocampus, the central switch- How much of the advantage comes from af- board for storing memories. The mice that pos- fecting signals among neurons is not clear, how- sessed no receptors for their endogenous canna- ever, in Lutz's opinion. He ascribes the positive binoids lost significantly more neurons in the metabolic effects at least partially to the drug's ef- hippocampus than the regular mice did.
fect on peripheral organs, which harbor CB1 recep- This premature cell death, Zimmer believes, tors, too. "In the obese, the endocannabinoid sys- could be caused by the loss of the neuroprotective tem is overactive in the liver," he says. "Rimonabant effects of the endocannabinoids. "We must move seems to restore it to equilibrium." very carefully to make sure that deliberate medi- Of course, eating is not the only activity that cal inhibition of the CB1 receptors does not lead triggers the brain's reward system. Many addic- to such damage," he says, adding that appropri- tive substances do so as well; nicotine prompts ate long-term trials must be held before drugs are the secretion of more dopamine, providing users released for clinical use in human patients. The with satisfied, euphoric feelings. Blocking the en- pharmaceutical industry may have a different docannabinoid receptors could negate the in- point of view, however; companies such as Sano- creased secretion of dopamine, reducing the fi-Aventis hope to bring products to the market pleasant feelings that make smokers reach for an- other cigarette.
Drug sales aside, the unraveling of the endo- cannabinoid system is exciting neuroscientists. Long-Term Concerns No one anticipated what has proved to be an en- Despite some possible benefits, experts are tirely new communication system in the brain. still wary about tinkering with our natural mar- Further research will outline the complete mech- ijuana network. "The brain is a sensitive system anisms and could provide novel treatments for a based on inhibitory and excitatory influences, wide range of psychiatric conditions and brain and the endocannabinoids keep this system in balance," Lutz notes.
One fundamental complication is that, like (Further Reading) marijuana itself, man-made versions of endocan-nabinoids do not simply travel only to desired ◆ Endocannabinoid Signaling in the Brain. R. I. Wilson and R. A. Nicoll in sites. They spread throughout the brain when Science, Vol. 296, pages 678–682; April 26, 2002.
taken, causing multiple effects, including dizzi- ◆ Early Age-Related Cognitive Impairment in Mice Lacking Cannabinoid CB1 Receptors. A. Bilkei-Gorzo et al. in Proceedings of the National ness, drowsiness, and concentration and think- Academy of Sciences USA, Vol. 102, No. 43, pages 15670–15675; ing problems.
October 25, 2005. w w w. sciammind.com SCIENTIFIC AMERICAN MIND 65 COPYRIGHT 2006 SCIENTIFIC AMERICAN, INC.

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