In the past few years, as addiction researchers have been mapping out the chemical alterations in the brain caused by alcohol, nicotine, methamphetamine, and other drugs, America’s most popular illegal drug has remained largely a scientific mystery. It is a drug that millions of Americans have been using regularly for years, and, from a clinical perspective, it remains the least studied illicit drug of all.

The most popular, and the least studied — not a prescription for rational decision making from a public health point of view. A variety of influences combined to force marijuana research off the table years ago, but the birth of “receptorology,” as molecular scientist Candace Pert once called it, and a more relaxed grip on federal funding has refueled the research.

Why did cannabis research lag behind that of other drugs of abuse? For decades, the prevailing belief among users and clinical researchers alike was that marijuana did not produce dependency and therefore could not produce major withdrawal symptoms. Nonetheless, heavy marijuana users were claiming that tolerance does build. And when they withdraw from use, many report strong cravings. Marijuana withdrawal, which typically affects only heavy smokers, has not been well characterized by the research community.

Back in the fall of 1988, pharmacology professor Allyn Howlett and her colleagues at St. Louis University Medical School came up with strong evidence for the specific brain receptor to which the THC molecules were binding. However, the nature of the organic chemical itself — the compound in the brain that was meant to bind to those reported sites — remained unidentified until 1992. That year, William A. Devane, one of the researchers at Hebrew University in Jerusalem, along with Rafael Mechoulam and others, identified the body’s own form of THC in pulverized pig brains. The substance that stuck to the THC receptors was known as arachidonyl ethanolamide. Devane christened the substance “anandamide,” after the Sanskrit ananda, or bliss. It was left for animal physiologist Gary Weesner of the U.S. Department of Agriculture (USDA) to ask the burning question: “How do pigs use their anandamide?” In a study of the possibility of using anandamide as a safe sedative for animals, Dr. Weesner discovered that pigs treated with anandamide tended to show lower body temperature, slower respiration, and less movement — all indicators of a calmer porcine state of mind.

THC and its organic cousin make an impressive triple play in the brain: They effect movement through receptors in the basal ganglia, they alter sensory perception through receptors in the cerebral cortex, and they impact memory by means of receptors in the hippocampus. However, there has been little evidence in animal models for tolerance and withdrawal, the classic determinants of addiction. To the early researchers, it did not look like cannabis should be addictive. And for at least four decades, million of Americans have used marijuana without clear evidence of a withdrawal syndrome.

Nevertheless, some people appear to exhibit a classic pattern of dependency. By the year 2000, more than 100,000 Americans a year were seeking treatment for marijuana dependency, by some estimates. Marijuana Anonymous, an organization modeled on the principles of Alcoholics Anonymous, had become a robust recovery organization. What was going on?

Some of the mystery of marijuana’s effects was resolved after researchers demonstrated that marijuana definitely increased dopamine activity in the limbic area of the brain, as do all other addictive drugs. Tanda, Pontieri, and Di Chiara demonstrated that dopamine levels in the nucleus accumbens doubled when rats received an infusion of THC. It appears that marijuana also raises dopamine and serotonin levels through the intermediary activation of opiate and GABA receptors.

In 2004, a study group at the University of Vermont undertook a critical review of all major relevant studies of marijuana withdrawal. The meta-review appeared to bear out the theory that there are heavy marijuana users who suffer a verifiable and often vivid set of withdrawal symptoms when they try to quit. The most common clinically significant symptoms of abrupt withdrawal in heavy pot smokers, according to the research group, were

anxiety, decreased appetite/weight loss, irritability, restlessness, sleep problems, and strange dreams. These symptoms were associated with abstinence in at least 70% of the studies in which they were measured. Other clinically important symptoms such as anger/aggression, physical discomfort (usually stomach related) depressed mood, increased craving for marijuana, and increased sweating and shakiness occurred less consistently.

These are not trivial issues. As one long-time heavy cannabis user put it: “It’s not suicidal ideation but it’s the feeling that life will just never ‘be right’… when you suffer from symptoms that you’ve been told don’t exist, you are left looking for the wrong cause. So, if you’re told that marijuana withdrawal does not increase anxiety, anger, or ‘hopelessness,’ you want to look for a cause of those things… I went through withdrawal periods where I was inappropriately angry at the wrong thing, thinking that specific people were upsetting me when they were not.”

In the final post of this series, we will hear from more heavy marijuana users, in their own words. Personal observations and selected case histories of frequent marijuana users were gathered from anonymous, unedited comments posted on a blog site maintained by the author.

References

Hanson D. “Marijuana Withdrawal: A Survey of Symptoms.” In The Praeger International Collection on Addictions. Ed. by Angela Browne-Miller. Westport, Connecticut: Praeger, 2009. Vol. 2 pp.111-124.

Budney, A. (2004). Review of the Validity and Significance of Cannabis Withdrawal Syndrome American Journal of Psychiatry, 161 (11), 1967-1977 DOI: 10.1176/appi.ajp.161.11.1967

Kouri, E., & Pope, H. (2000). Abstinence symptoms during withdrawal from chronic marijuana use. Experimental and Clinical Psychopharmacology, 8 (4), 483-492 DOI: 10.1037/1064-1297.8.4.483

Rodriguez de Fonseca, F. (1997). Activation of Corticotropin-Releasing Factor in the Limbic System During Cannabinoid Withdrawal Science, 276 (5321), 2050-2054 DOI: 10.1126/science.276.5321.2050

Tanda, G. (1997). Cannabinoid and Heroin Activation of Mesolimbic Dopamine Transmission by a Common µ1 Opioid Receptor Mechanism Science, 276 (5321), 2048-2050 DOI: 10.1126/science.276.5321.2048