Up until the late 1980s, marijuana research remained a rather esoteric field involving a small number of scientists in the United States and abroad. Their efforts were circumscribed by the politicized agenda of the National Institute of Drug Abuse, which subsidized studies designed to prove the deleterious effects of cannabis, while blocking inquiry into marijuana’s potential benefits. But rather than discrediting cannabis, NIDA inadvertently helped to facilitate a series of major discoveries about the inner workings of the human brain. These breakthroughs spawned a revolution in medical science and a profound understanding of health and healing. “By using a plant that has been around for thousands of years, we discovered a new physiological system of immense importance,” says Raphael Mechoulam, the dean of the transnational cannabinoid research community. “We wouldn’t have been able to get there if we had not looked at the plant.”
Since the identification and synthesis of THC by Mechoulam’s team in Israel in 1965, scientists had learned a great deal about the pharmacology, biochemistry, and clinical effects of cannabis. Everybody seemed to have an opinion about marijuana, but no one really knew how it worked. Smoking pot got you stoned, but what it actually did inside the brain on a molecular level to alter consciousness was still unknown. No one could yet explain how cannabis worked as an appetite stimulant, how it dampened nausea, quelled seizures, and relieved pain. No one understood how smoked marijuana could stop an asthma attack in seconds, not minutes. No one knew why it lifted one’s mood. Although there was considerable evidence that cannabis could ameliorate a wide range of disease symptoms, it took scientists a long time to figure out how marijuana produced its myriad effects.
When American researchers at Johns Hopkins University identified receptor sites in the brain capable of binding with opiates in 1973, some scientists expected that the discovery of receptor sites for marijuana would soon follow. But these were difficult to pin down. Fifteen years would elapse before a government-funded study at the St. Louis University School of Medicine determined that the mammalian brain has receptor sites—specialized protein molecules embedded in cell membranes—that respond pharmacologically to compounds in marijuana resin. Every cell membrane has lots of receptors for many types of messenger molecules, which influence the activity of the cell.
Initially identified by Professor Allyn Howlett and her graduate student William Devane, cannabinoid receptors turned out to be far more abundant in the brain than any other G-protein-coupled receptors.1 Tagged radioactively, a potent THC analog synthesized by Pfizer (“CP55,940”) enabled researchers to begin mapping the locations of cannabinoid receptors in the brain. These receptors were found to be concentrated in regions responsible for mental and physiological processes that are affected by marijuana—the hippocampus (memory), cerebral cortex (higher cognition), cerebellum (motor coordination), basal ganglia (movement), hypothalamus (appetite), the amygdala (emotions), and elsewhere. There are few cannabinoid receptors in the brain stem, the region that controls breathing and heartbeat—which is why no one has ever suffered a fatal overdose of marijuana.
On July 18, 1990, at a meeting of the National Academy of Science’s Institute of Medicine, Lisa Matsuda announced that she and her colleagues at the National Institute of Mental Health (NIMH) had achieved a major breakthrough—they pinpointed the exact DNA sequence that encodes a THC-sensitive receptor in the rat’s brain. People have the same receptor, which consists of 472 amino acids strung together in a crumpled chain that squiggles back and forth across the cell membrane seven times. Cannabinoid receptors function as subtle sensing devices, tiny vibrating scanners perpetually primed to pick up biochemical cues that flow through fluids surrounding each cell. Matsuda also disclosed that she had successfully cloned the marijuana receptor.
The cloning of the cannabis receptor was crucial. It opened the door for scientists to sculpt molecules—new drugs—that “fit” these receptors somewhat like keys in a slot. Some keys (“agonists”) turned the receptor on; others (“antagonists”) turned it off.2 In addition to synthesizing cannabinoid receptor agonists and antagonists, scientists experimented with genetically engineered “knockout” mice that lacked this receptor. When administered to knockout mice, the THC had nowhere to bind and hence could not trigger any activity. This was further proof that THC works by activating cannabinoid receptors in the brain and central nervous system. Finally, after fifty centuries of medicinal usage, the scientific basis of cannabis therapeutics was coming into focus.
Researchers soon identified a second type of cannabinoid receptor, dubbed “CB-2,” which is prevalent throughout the peripheral nervous system and the immune system. CB-2 receptors are also present in the gut, spleen, liver, heart, kidneys, bones, blood vessels, lymph cells, endocrine glands, and reproductive organs. THC stimulates the CB-2 receptor, but this does not result in the psychoactive high that pot is famous for (because CB-2 receptors are not concentrated in the brain); THC binding to CB-1, the central nervous system receptor, causes the high. The CB-1 receptor mediates psychoactivity. CB-2 regulates immune response. Marijuana is such a versatile substance because it acts everywhere, not just in the brain.
Just as the study of opium resulted in the discovery of endorphins, the brain’s own morphinelike substance, so, too, marijuana research would lead to the discovery of a natural, internal THC-like compound, our “inner cannabis,” so to speak. In 1992, Raphael Mechoulam, in collaboration with NIMH research fellow William Devane and Dr. Lumír Hanuš, found a novel neurotransmitter, a naturally occurring endogenous (meaning “made internally”) cannabinoid. This “endocannabinoid” attaches to the same mammalian brain cell receptors as THC. Mechoulam decided to call it “anandamide,” deriving from the Sanskrit word for bliss. In 1995, his group discovered a second major endocannabinoid molecule—“2-AG” [2-arachidonoylglycerol]—which binds to both CB-1 and CB-2 receptors.3
By tracing the metabolic pathways of THC, scientists had stumbled upon a hitherto unknown molecular signaling system that plays a crucial role in regulating a broad range of biological processes. This molecular signaling system modulates how we experience pain, stress, hunger, sleep, our circadian rhythms, our blood pressure, body temperature, bone density, fertility, intestinal fortitude, mood, metabolism, memory retention, and more.
Scientists call it “the endocannabinoid system”—so named after the plant that led to its discovery. The name suggests that the plant came first, but in fact, as Dr. John McPartland explained, this ancient internal signal system started evolving more than 500 million years ago (long before cannabis appeared), when the most complex lifeform was sponges. Endocannabinoids and their receptors are present in fish, reptiles, earthworms, leeches, amphibians, birds, and mammals—every animal except insects. Its long evolutionary history indicates that the endocannabinoid system must serve a very important and basic purpose in animal physiology.
Drug-company investigators paid close attention to cutting-edge developments in cannabinoid research, which few people outside the scientific community were privy to.4 Endocannabinoids and their receptors emerged as a hot topic among scientists who shared their findings in highly technical peer-reviewed journals and at annual conclaves hosted by the International Cannabinoid Research Society (ICRS). Advances in the burgeoning field of cannabinoid studies would pave the way for new treatment strategies for various pathological conditions—cancer, diabetes, neuropathic pain, arthritis, osteoporosis, obesity, Alzheimer’s, multiple sclerosis, and several odd diseases of unknown etiology that seemed to have as their common denominator an inflammatory or autoimmune dysfunction.
The discovery of the endocannabinoid system has breathtaking implications for nearly every area of medicine, including reproductive biology. Dr. Mauro Maccarrone at the University of Teramo, Italy, describes the endocannabinoid system as the “guardian angel” or “gatekeeper” of mammalian reproduction. Endocannabinoid signaling figures decisively throughout the reproductive process—from spermatogenesis to fertilization, ovuductal transport of the zygote, embryo implantation, and fetal development. Cannabinoid receptors proliferate in the placenta and facilitate neurochemical “cross-talk” between the embryo and the mother. A misfiring of the endocannabinoid system could result in serious problems, including ectopic pregnancy and miscarriage. Appropriate levels of endocannabinoids in maternal milk are critically important for the initiation of suckling in newborns. Infant colic has been attributed to a dearth of endocannabinoids.
Israeli scientist Ester Fride observed that knockout mice missing CB receptors resemble babies who suffer from “failure to thrive” syndrome. (Mice lacking CB receptors don’t suckle and they die prematurely.) This is one of many enigmatic conditions that may arise because of a dysfunctional endocannabinoid system. Individuals have different congenital endocannabinoid levels and sensitivities. University of Washington neurologist Ethan Russo postulates that “clinical endocannabinoid deficiency” underlies migraines, fibromyalgia, irritable bowel disease, and a cluster of other degenerative conditions, which may respond favorably to cannabinoid therapies.5
For Big Pharma, cannabinoid research became a tale of knockout mice and men. Using genetically engineered rodents that lacked CB receptors, researchers were able to prove that cannabinoid compounds can alter disease progression and attenuate experimentally induced symptoms. An “animal model” of osteoporosis, for example, was created in normal mice and in knockout mice without cannabinoid receptors. When a synthetic cannabinoid drug was given to both groups of osteoporotic mice, bone damage was mitigated in the normal mice but had no effect on rodents sans CB receptors—which means that cannabinoid receptors are instrumental in regulating bone density.6
Other experiments would establish that CB receptor signaling modulates pain and analgesia, inflammation, appetite, gastrointestinal motility, neuroprotection and neurodegeneration, along with the ebb and flow of immune cells, hormones, and other mood-altering neurotransmitters such as serotonin, dopamine, and glutamate. When tickled by THC or its endogenous cousins, cannabinoid receptors trigger a cascade of biochemical changes on a cellular level that put the brakes on excessive physiological activity.
The human immune system, an amazing physiological wonder, kicks on like a furnace when a fever is required to fry a virus or bacterial invader. And when the job is done, endocannabinoid signaling turns down the flame, cools the fever, and restores homeostasis. (Cannabinoids—endo, herbal, and synthetic—are anti-inflammatory; they literally cool the body.) But if the feed- back loop misfires, if the pilot light burns too high, if the immune system overreacts to chronic stress or mistakes one’s body for a foreign object, then the stage is set for an autoimmune disease or an inflammatory disorder to develop.
Endocannabinoids are the only neurotransmitters known to engage in “retrograde signaling,” a unique form of intracellular communication that inhibits immune response, reduces inflammation, relaxes musculature, lowers blood pressure, dilates bronchial passages, increases cerebral blood flow (a rush of thoughts!), and normalizes overstimulated nerves.7 Retrograde signaling serves as an inhibitory feedback mechanism that tells other neurotransmitters to cool it when they are firing too fast.8
Prior to the discovery of the endocannabinoid system, retrograde signaling was known to occur only during the embryonic development of the brain and nervous system. Endocannabinoids choreograph “a broad array of developmental processes in the embryonic brain,” explains Dr. John McPartland, including neural stem cell proliferation and differentiation, a process guided by extracellular cues conveyed via CB receptors. Scientists would learn that cannabinoid receptor signaling also regulates adult neurogenesis (brain cell growth) and stem cell migration.
High endocannabinoid levels in the brain are triggered by strokes and other pathological events—attesting to the neuroprotective function of the endocannabinoid signaling. A major function of the endocannabinoid system—and therefore a significant effect of the cannabinoids in marijuana—is neuroprotective in nature: protecting brain cells from too much excitation. The endocannabinoid system, according to Mechoulam, is part of the body’s “general protective network, working in conjunction with the immune system and various other physiological systems.” His discoveries posed a direct challenge to scientific orthodoxy by revealing that the brain has a natural repair kit, an in-built mechanism of protection and regeneration, which can mend damaged nerves and brain cells.
Ironically, the U.S. government’s unending search for marijuana’s harmful properties yielded astonishing scientific insights that validated the herb’s therapeutic utility. By stimulating CB-1 and CB-2 receptor signaling, marijuana functions as a substitute “retrograde messenger” that mimics the way our bodies try to maintain balance. Cannabis is a unique herbal medicine that taps into how our bodies work naturally. Thanks to this plant, scientists have been able to decipher the primordial language that nerve and brain cells use to communicate. From womb to tomb, across countless generations, the endocannabinoid system guides and protects.
But a big disconnect existed between the world of science and the general public. Aside from certain segments of the scientific community, few people knew about the endocannabinoid system. Doctors, journalists, public officials—hardly anyone was clued in to the latest scientific research that went a long way toward explaining why marijuana is such a versatile remedy and why it is, by far, the most-sought-after illicit substance on the planet.
1 Cannabinoid receptors recognize and respond to three kinds of agonists (turn-on keys): endogenous fatty acid cannabinoids found in all mammals; phytocannabinoids concentrated in the oily resin on the buds and leaves of the marijuana plant; and potent, synthetic cannabinoids concocted in university and drug company laboratories.
2 Cannabinoid receptors belong to the superfamily of G-protein-coupled receptors, which includes opioid receptors. When these receptors sense certain molecules outside the cell, a biochemical response is triggered via specific “signal transduction pathways.” G-protein- coupled receptors are involved in many disease processes and are reportedly the target of approximately 40 percent of all modern pharmaceuticals.
3 Anandamide and 2-AG impact the organism in ways that are “predominantly local and specific,” says Mechoulam. “Their actions are ubiquitous. They are involved in most physiological systems that have been investigated” (“Conversation with Raphael Mechoulam,” Addiction 102: 887–93; see also “The New Science of Cannabinoid-Based Medicine: An Interview with Dr. Raphael Mechoulam,” in David Jay Brown, ed., Mavericks of Medicine.
4 In a lengthy 2006 review, “The Endocannabinoid System as an Emerging Target of Pharmacology,” scientists with the National Institutes of Health reported that cannabinoid com- pounds held “therapeutic promise” for disparate pathological conditions “ranging from mood and anxiety disorders, movement disorders such as Parkinson’s and Huntington’s disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, and osteoporosis,” as well as other diseases that are seemingly beyond the reach of orthodox medicine (Pal Pacher, Sándor Bátkai, and George Kunos, “The Endocannabinoid System as an Emerging Target of Pharmacotherapy,” Pharmacology Review 58: 389–462).
5 Recent research has established that clinical depression is an endocannabinoid-deficiency disease. Matthew Hill, a scientist at the University of British Columbia, analyzed the “serum endocannabinoid content” in depressed women and found that it was “significantly reduced” compared with controls. Hill observed that this reduction “negatively correlated to episode duration,” meaning “the longer the depressive episode the lower the 2-AG content.”
6 A German research team would later demonstrate that CB-2 receptor activation restrains the formation of bone reabsorbing cells, known as osteoclasts, by down-regulating osteoclast precursors, thus tipping the balance in favor of osteoblasts, cells that facilitate bone formation
7 The human brain has about 100 billion neurons that communicate through neurotransmitters (endogenous messenger molecules) that operate in the space between cells, the “synaptic cleft.” The synaptic cleft is where two nerve tendrils converge without actually touching; it’s in the space between nerve endings that messages are chemically communicated (transmit- ted) from one cell to the next. Whereas every other neurotransmitter (serotonin, dopamine, GABA, etc.) enables nerve impulses to jump across the synaptic cleft, endocannabinoid compounds travel backwards and interact with CB receptors strategically situated on “presynaptic” nerve axons. CB receptor retrograde signaling facilitates a process known as “presynaptic inhibition,” which interrupts and slows down the release of other neurotransmitters.
8 This is the basis of marijuana’s biphasic effect: The body synthesizes endocannabinoids that act as a “slow down” mechanism when nerve cells are stimulated by excitory neurotransmitters such as norepinephrine and glutamate; and cannabinoid receptors also transmit chemical signals that “slow down” the release of sedative neurotransmitters such as GABA (which binds to the same receptor as Valium and alcohol). By slowing down or inhibiting GABA activity, the endocannabinoid system speeds things up.