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Marijuana: The High and the Low

A New Leaf: The End of Cannabis Prohibition

by Alyson Martin and Nushin Rashidian
New Press, 264 pp., $17.95 (paper)
groopman_1-022014.jpg
Jeff Chiu/AP Images
Medical marijuana patient Kevin Brown at the Apothecarium, a medical cannabis dispensary in San Francisco, December 2011

In the summer of 2006, a young scientist from Israel joined my laboratory. He came to learn how viruses attack cells, a major focus of my research program. And I looked forward to drawing on his expertise in an emerging area of science that intrigued me: the biological effects of cannabinoids, the active chemical compounds in the marijuana plant. The Israeli researcher had trained at Jerusalem’s Hebrew University with Professor Raphael Mechoulam, a chemist credited with the discovery in 1964 of delta-9-tetrahydrocannabinol (THC), the primary psychoactive compound in marijuana. Mechoulam later characterized cannabidiol (CBD), a related substance plentiful in the plant, as distinct from THC in that it had no discernible effects on mood, perception, wakefulness, or appetite.1

The work of the young scientist proved productive. In short order, he tested the effects of several cannabinoids on a herpes virus that promotes the development of Kaposi’s sarcoma, a disfiguring and sometimes fatal tumor among people with impaired immunity, like those with AIDS. It turned out that CBD, the plentiful, nonpsychoactive compound, could switch off the malignant effects of the virus.2 Scientists in my department also found that cannabinoids could alter how white blood cells migrated in response to physiological stimuli, a key aspect of immune defense; other research teams found that THC inhibited the growth and spread of lung cancer and CBD of breast cancer in laboratory models.3 Clearly, chemicals in the plant could have diverse and potent effects on normal and malignant cells.

But what I found most fascinating was that we have a natural or “endogenous” cannabinoid system. In 1988, researchers identified a specific docking site, or receptor, on the surface of cells in the brain that bound THC. This first receptor was termed cannabinoid receptor 1, or CB1.4 Five years later, a second receptor for cannabinoids, CB2, was found.5 This latter docking protein was less plentiful in the central nervous system but richly present on white blood cells. Again, it was Raphael Mechoulam who discovered the first endogenous cannabinoid, a fatty acid in the brain, which he termed “anandamide.” (The name is derived from the Sanskrit word ananda, which means “bliss.”) When anandamide attached to CB1 it triggered a cascade of biochemical changes within our neurons.6

Other endogenous cannabinoids were later identified. This makes evolutionary sense, since the CB1 and CB2 receptors would not be present on our cells if we did not normally make molecules to dock on them. The physiological ramifications of endogenous cannabinoids appeared quite broad; their most impressive effects were related to perception of and response to pain.

Cannabis is one of the oldest psychotropic drugs in continuous use. Archaeologists have discovered it in digs in Asia that date to the Neolithic period, around 4000 BCE. The most common species of the plant is Cannabis sativa, found in both tropical and temperate climates. Marijuana is a Mexican term that first referred to cheap tobacco and now denotes the dried leaves and flowers of the hemp plant. Hashish is Arabic for Indian hemp and refers to its viscous resin. An emperor of China, Shen Nung, also the discoverer of tea and ephedrine, is held to be among the first to report on therapeutic uses of cannabis in a medicinal compendium that dates to 2737 BCE. In 1839, William O’Shaughnessy, a British doctor working in India, published a paper on cannabis as an analgesic and appetite stimulant that also tempered nausea, relaxed muscles, and might ameliorate epileptic seizures. His observations led to widespread medical use of cannabis in the United Kingdom; it was prescribed to Queen Victoria for relief of menstrual discomfort.7

The cannabis plant contains some 460 compounds, including more than 60 cannabinoids. THC, the key psychoactive substance in marijuana, has increased from about 1–5 percent to as much as 10–15 percent in cultivated plants since the 1960s. When herbal cannabis is smoked, some 20 to 50 percent of the THC is absorbed via the lungs. When herbal cannabis is eaten, less THC reaches the brain because it is metabolized as it passes from the gut through the liver. THC accumulates in fatty tissues, from which it is slowly released, and acts primarily on CB1 receptors in the brain’s mesolimbic dopamine system, which is believed to contribute to the positive reinforcing and rewarding effects of the drug.8

While smoking or eating cannabis typically results in the user’s feeling “high,” with a relaxed, euphoric sense as anxiety and alertness decrease, some first-time users, as well as individuals who have psychological problems, can experience dysphoria, fear, and panic. Typically, when high on marijuana, there is an increased sense of sociability, although among those who have a dysphoric reaction, there can be sharp social withdrawal. Perception of time is altered, generally with perceived time faster than clock time; spatial perception also may change, and colors may seem brighter and music more resonant. High doses of cannabis can result in hallucinations, which may account for its religious use in some cultures. Yet unlike opioids, there are no reported cases of death due to a THC overdose, probably because cannabinoids do not inhibit our respiratory drive, which would result in asphyxiation. Among regular users, abstinence from marijuana can cause an uncomfortable or distressing withdrawal syndrome.

In 2008 the World Health Organization published a Mental Health Survey of 54,068 persons age sixteen and older in seventeen nations. On the basis of this survey, cannabis was found to have been used at least once by some 160 million people between the ages of fifteen and sixty-five; reported use was lowest in the People’s Republic of China, 0.3 percent, and highest in the United States, 42.4 percent, with New Zealand close behind.9

Despite such widespread use, cannabis is illegal in most countries. Harry J. Anslinger, a prominent prohibitionist, successfully lobbied Congress to pass the Marihuana Tax Act in 1937, making access to the plant costly. Anslinger was the head of the Federal Bureau of Narcotics and presented cannabis use to the public as an unalloyed danger, resulting in “reefer madness.” The American Medical Association opposed the Marihuana Tax Act, fearing that it would limit medicinal study and potential prescription of the plant. Long a part of the United States Pharmacopeia, a compendium that set standards for medicines and foods, cannabis was removed in 1942.

In 1970, Congress enacted the Controlled Substances Act, classifying marijuana along with heroin as a Schedule I drug. Drugs in this category have a proven potential for abuse and no medical value. (Opium, the source of morphine, and amphetamines are Schedule II drugs, classified as less dangerous despite their potent addictive properties.) Soon thereafter, President Nixon launched the “war on drugs,” and in 1986, President Reagan signed the Anti-Drug Abuse Act, which mandated prison sentences without parole for offenders convicted of possession and sale of all illegal drugs, including marijuana.

The study of cannabinoids, both those derived from plant sources as well as the endocannabinoids that exist naturally within our body, is now an extensive enterprise that spans the globe and links numerous scientists in both academic centers and pharmaceutical companies.

Mitch Earleywine, a prominent researcher on drugs and addiction at SUNY Albany, observed how results from current studies on marijuana are akin to Rorschach blots. “People purportedly see these ambiguous pictures in a way that reveals more about them than the ink.” Many who make public policy or are associated with interest groups, he contends, may respond to marijuana research according to the views of these groups: their interpretations say more about their own biases than about the actual data. For example, prohibitionists contend that THC often appears in the blood of people involved in auto accidents; yet they omit the fact that most of these people also had been drinking alcohol. Antiprohibitionists cite research that showed no sign of memory problems in chronic marijuana smokers; but they do not mention that the cognitive tests were so easy that even an impaired person could perform them.

Two recent reviews avoid such biases and critically examine data from more than a hundred randomized placebo-controlled clinical trials involving some 6,100 patients with a variety of medical conditions.10 Marijuana appears useful in treating anorexia, nausea and vomiting, glaucoma, irritable bowel disease, muscle spasticity, multiple sclerosis, symptoms of amyotropic lateral sclerosis (Lou Gehrig’s disease), epilepsy, and Tourette’s syndrome. (Recent clinical trials confirm many of the claims of Emperor Shen Nung and Dr. O’Shaughnessy.) Despite findings from experiments in my laboratory and others, its anticancer effects in patients are more uncertain and neither THC nor CBD is a proven antineoplastic agent, i.e., effective in treating abnormal growth of tissue.

Judy Foreman, an accomplished medical journalist, devotes a chapter to marijuana in her recent book A Nation in Pain: Healing Our Biggest Health Problem.11 She judiciously reviews the data on the risks and benefits of marijuana as a therapy for medical conditions marked by pain, highlighting where it appears ameliorative, where it falls short, and where there is lack of clarity about its value. Foreman writes:

To put it bluntly, marijuana works. Not dazzlingly, but about as well as opioids. That is, it can reduce chronic pain by more than 30 percent. And with fewer serious side effects. To be sure, some researchers think it’s too soon to declare marijuana and synthetic cannabinoids a first-line treatment for pain, arguing that other drugs should be tried first. But that may be too cautious a view.

Ultimately, marijuana may be used in conjunction with opioids like morphine to allow for lower doses and fewer of the side effects of the opioid family of analgesics. While chronic pain seems amenable to amelioration by marijuana, its impact on reducing acute pain, such as after surgery, is minimal.

How do cannabinoids reduce pain? Some of the benefit appears to result from cognitive dissociation: you realize that pain is present, but don’t respond to it emotionally. If you are able to detach yourself from pain in that way, there is less suffering.

Every therapy, whether a drug or a procedure, involves a tradeoff of benefits versus risks. Perhaps the most controversial and important concern around cannabinoids is whether they increase the risk of psychoses like schizophrenia. This question is most germane for adolescents and young adults. A number of studies reviewed the health records of young people in Sweden, New Zealand, and Holland who reported cannabis use, as compared to the records of those who did not. A combined or metaanalysis of results from nearly three dozen such studies linked cannabis use to later development of schizophrenia and other psychosis.12

The limitation of such observational studies is that they may suggest an association but in no way prove a causal link. Indeed, the medical literature is littered with observational studies that were taken as meaningful but later overturned when randomized placebo-controlled trials were conducted. Here the Women’s Health Initiative comes to mind. This was a randomized study, using placebos as controls, that reversed some four decades of thinking about the alleged benefits of hormonal replacement therapy among postmenopausal women in preventing dementia and heart disease. No one is likely to conduct a randomized controlled trial of thousands of teenagers, assigning one group to smoke or ingest cannabis and the other group to receive placebos. The issue of marijuana as a cofactor in the development of schizophrenia and other psychosis will therefore remain unresolved.

  1. 1

    Mohamed Ben Amar, “Cannabinoids in Medicine: A Review of Their Therapeutic Potential,” Journal of Ethno-pharmacology, Vol. 105 (2006); Arno Hazekamp and Franjo Grotenhermen, “Review on Clinical Studies with Cannabis and Cannabinoids 2005–2009,” Cannabinoids, Vol. 5 (2010). 

  2. 2

    Y. Maor, J. Yu, P.M. Kuzontkoski, B.J. Dezube, X. Zhang, and J.E. Groopman, “Cannabidiol Inhibits Growth and Induces Programmed Cell Death in Kaposi Sarcoma–Associated Herpesvirus-Infected Endothelium,” Genes & Cancer, Vol. 3, No. 7–8 (2012); X. Zhang, J.F. Wang, G. Kunos, and J.E. Groopman, “Cannabinoid Modulation of Kaposi’s Sarcoma–Associated Herpesvirus Infection and Transformation,” Cancer Research, Vol. 67, No. 15 (August 1, 2007). 

  3. 3

    S. Ghosh, A. Preet, J.E. Groopman, and R.K. Gaju, “Cannabinoid Receptor CB 2 Modulates the CXCL 12/ CXCR 4-Mediated Chemotaxis of T Lymphocytes,” Molecular Immunology, Vol. 43 (2006); A. Preet, R.K. Ganju, and J.E. Groopman, “∆ 9 -Tetrahydrocannabinol Inhibits Epithelial Growth Factor–Induced Lung Cancer Cell Migration in Vitro as Well as Its Growth and Metastasis in Vivo,” Oncogene, Vol. 27 (2008); X. Zhang, Y. Maor, J.F. Wang, G. Kunos, and J.E. Groopman, “Endocannabinoid-like N-arachidonoyl Serine Is a Novel Pro-angiogenic Mediator,” British Journal of Pharmacology, Vol. 160 (2010); A. Preet, Z. Qamri, M. Nasser, A. Prasad, K. Shilo, X. Zou, J.E. Groopman, and R. Ganju, “Cannabinoid Receptors, CB 1 and CB 2, as Novel Targets for Inhibition of Non-Small Cell Lung Cancer Growth and Metastasis,” Cancer Prevention Research, Vol. 4 (2011); A. Shrivastava, P.M. Kuzontkoski, J.E. Groopman, and A. Prasad, “Cannabidiol Induces Programmed Cell Death in Breast Cancer Cells by Coordinating the Cross-Talk Between Apoptosis and Autophagy,” Molecular Cancer Therapeutics, Vol. 10 (2011). 

  4. 4

    W.A. Devane, F.A. Dysarz III, M.R. Johnson, L.S. Melvin, and A.C. Howlett, “Determination and Characterization of a Cannabinoid Receptor in Rat Brain,” Molecular Pharmacology, Vol. 34 (November 1, 1988). 

  5. 5

    S. Munro, K.L. Thomas, and M. Abu-Shaar, “Molecular Characterization of a Peripheral Receptor for Cannabinoids,” Nature, Vol. 365 (1993). 

  6. 6

    W.A. Devane, L. Hanus, A. Breuer, R.G. Pertwee, L.A. Stevenson, and G. Griffin, “Isolation and Structure of a Brain Constituent That Binds to the Cannabinoid Receptor,” Science, Vol. 258 (December 18, 1992). 

  7. 7

    D. Baker, G. Pryce, G. Giovannoni, and A.J. Thompson, “The Therapeutic Potential of Cannabis,” Lancet Neurology, Vol. 2 (May 2003). 

  8. 8

    Mitch Earleywine, Understanding Marijuana: A New Look at the Scientific Evidence (Oxford University Press, 2002). 

  9. 9

    L. Degenhardt, W.T. Chiu, N. Sampson, et al., “Toward a Global View of Alcohol, Tobacco, Cannabis, and Cocaine Use: Findings from the WHO World Mental Health Surveys,” PLoS Medicine, Vol. 5 (July 2008). 

  10. 10

    See Amar, “Cannabinoids in Medicine: A Review of Their Therapeutic Potential,” and Hazekamp and Grotenhermen, “Review on Clinical Studies with Cannabis and Cannabinoids 2005–2009.” 

  11. 11

    Oxford University Press, 2014 

  12. 12

    M. Large, S. Sharma, M.T. Compton, T. Slade, O. Nielssen, “Cannabis Use and Earlier Onset of Psychosis,” Archives of General Psychiatry, Vol. 68, No. 6 (2011). 

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