Is Marijuana Addictive?

The argument continues.

For more, see Marijuana Withdrawal.
See also Marijuana Withdrawal Revisited

Marijuana may not be a life-threatening drug, but is it an addictive one?

There is little evidence in animal models for tolerance and withdrawal, the classic determinants of addiction. For at least four decades, million of Americans have used marijuana without clear evidence of a withdrawal syndrome. Most recreational marijuana users find that too much pot in one day makes them lethargic and uncomfortable. Self-proclaimed marijuana addicts, on the other hand, report that pot energizes them, calms them down when they are nervous, or otherwise allows them to function normally. They feel lethargic and uncomfortable without it. Heavy marijuana users claim that tolerance does build. And when they withdraw from use, they report strong cravings.

Marijuana is the odd drug out. To the early researchers, it did not look like it should be addictive. Nevertheless, for some people, it is. Recently, a group of Italian researchers succeeded in demonstrating that THC releases dopamine along the reward pathway, like all other drugs of abuse. Some of the mystery of cannabis had been resolved by the end of the 1990s, after researchers had demonstrated that marijuana definitely increased dopamine activity in the ventral tegmental area. Some of the effects of pot are produced the old-fashioned way after all--through alterations along the limbic reward pathway.

By the year 2000, more than 100,000 Americans a year were seeking treatment for marijuana dependency, by some estimates.

A report prepared for Australia’s National Task Force on Cannabis put the matter straightforwardly:

There is good experimental evidence that chronic heavy cannabis users can develop tolerance to its subjective and cardiovascular effects, and there is suggestive evidence that some users may experience a withdrawal syndrome on the abrupt cessation of cannabis use. There is clinical and epidemiological evidence that some heavy cannabis users experience problems in controlling their cannabis use, and continue to use the drug despite experiencing adverse personal consequences of use. There is limited evidence in favour of a cannabis dependence syndrome analogous to the alcohol dependence syndrome. If the estimates of the community prevalence of drug dependence provided by the Epidemiologic Catchment Area Study are correct, then cannabis dependence is the most common form of dependence on illicit drugs.

While everyone was busy arguing over whether marijuana produced a classic withdrawal profile, a minority of users, commonly estimated at 10 per cent, found themselves unable to control their use of pot. Addiction to marijuana had been submerged in the welter of polyaddictions common to active addicts. The withdrawal rigors of, say, alcohol or heroin would drown out the subtler, more psychological manifestations of marijuana withdrawal.

What has emerged is a profile of marijuana withdrawal, where none existed before. The syndrome is marked by irritability, restlessness, generalized anxiety, hostility, depression, difficulty sleeping, excessive sweating, loose stools, loss of appetite, and a general “blah” feeling. Many patients complain of feeling like they have a low-grade flu, and they describe a psychological state of existential uncertainty—“inner unrest,” as one researcher calls it.

The most common marijuana withdrawal symptom is low-grade anxiety. Anxiety of this sort has a firm biochemical substrate, produced by withdrawal, craving, and detoxification from almost all drugs of abuse. It is not the kind of anxiety that can be deflected by forcibly thinking “happy thoughts,” or staying busy all the time. A peptide known as corticotrophin-releasing factor (CRF) is linked to this kind of anxiety.

Neurologists at the Scripps Research Institute in La Jolla, California, noting that anxiety is the universal keynote symptom of drug and alcohol withdrawal, started looking at the release of CRF in the amygdala. After documenting elevated CRF levels in rat brains during alcohol, heroin, and cocaine withdrawal, the researchers injected synthetic THC into 50 rats once a day for two weeks. (For better or worse, this is how many of the animal models simulate heavy, long-term pot use in humans). Then they gave the rats a THC agonist that bound to the THC receptors without activating them. The result: The rats exhibited withdrawal symptoms such as compulsive grooming and teeth chattering—the kinds of stress behaviors rats engage in when they are kicking the habit. In the end, when the scientists measured CRF levels in the amygdalas of the animals, they found three times as much CRF, compared to animal control groups.

While subtler and more drawn out, the process of kicking marijuana can now be demonstrated as a neurochemical fact. It appears that marijuana increases dopamine and serotonin levels through the intermediary activation of opiate and GABA receptors. Drugs like naloxone, which block heroin, might have a role to play in marijuana detoxification.

In the end, what surprised many observers was simply that the idea of treatment for marijuana dependence seemed to appeal to such a large number of people. The Addiction Research Foundation in Toronto has reported that even brief interventions, in the form of support group sessions, can be useful for addicted pot smokers.

--Excerpted from The Chemical Carousel: What Science Tells Us About Beating Addiction © Dirk Hanson 2008, 2009.

addiction drugsmedical marijuana

Speed Causing Strokes?

During the cocaine boom of the 1980s, addiction researchers learned that cocaine was sometimes capable of setting off serious seizures in users. Now, a related effect has been tentatively identified in two methamphetamine abusers-- strokes caused by microscropic tears in major arteries of the neck.

Although the study, published in the journal Neurology by researchers at the University of Texas Southwestern Medical Center, documented only the two cases, both young subjects-- women aged 29 and 36--were free of other risk factors. Stroke neurologists took note. Neurologist Steven Cramer at the University of California, Irvine, quoted at scientificamerican.com, said: “If I ever see any young person with a stroke--that is, anyone under 65--I’ll be sure now to do a toxicology screen.”

Stimulants like speed and cocaine markedly increase blood pressure while constricting blood vessels. According to Wengui Yu, one of the authors of the study, such work may help doctors “to better diagnose, treat, and prevent stroke in young adults.”

Sources:

--Choi, Charles Q. “Strokes in Young People Could be Due to Meth.” scientificamerican.com. December 26, 2006.

--McIntosh A., Hungs M., Kostanian V., Yu W. “Carotid artery dissection and middle cerebral artery stroke following methamphetamine use.” Neurology. 2006 Dec 26;67(12):2259-60.

Neurobiology of Addiction

Book Review




By George F. Koob and Michel Le Moal.
Academic Press
(Elsevier), London, 2006.

Over the past twenty-five years, the neurobiology of addiction has become established as an important arena of scientific study. In particular, the molecular adaptations the brain makes in response to addictive drugs has placed addiction squarely in the forefront of modern brain science.

Dr. George F. Koob, a respected American alcoholism researcher of long standing, has put together an academic treatise beyond the expertise and the pocketbooks of most laypersons, but the book is of crucial importance in the burgeoning
field of addiction science.

In Neurobiology of Addiction, Koob and co-worker Michel Le Moal review the neural and molecular mechanisms responsible for the effects of individual addictive drugs in five categories--psychostimulants, opium, alcohol, nicotine,and cannabis.

Particularly well documented is the “anti-reward” system, by which the abuse of addictive drugs leads to a net decrease in dopamine and serotonin in the nucleus accumbens,the brain structure associated with withdrawal and craving. Thus, the
pursuit of artificial pleasure becomes, through the process of addiction, a state of chronic depletion of the brain neurotransmitters associated with states of joy, happiness and well-being.

The authors also do a good job of putting forth their theory of “allostasis,” defined as a “state of chronic deviation of the regulatory system from its normal (homeostatic) operating level.” The addicted brain is constantly attempting to normalize through counteradaptions at the neural level, as well as by switching on the body’s stress responses. Craving and anxiety are among the behavioral results.

[For more on George Koob,
The Chemical Carousel: What Science Tells Us About Beating Addiction © Dirk Hanson 2008, 2009.

Sources:

--Koob, George, and Le Moal, Michel. “Drug Abuse: Hedonic Homeostatic
Dysregulation.” Science. October 3, 1997. 278: 55.

--Everitt, Barry J. “From the Dark Side to the Bright Side of Drug Addiction.”
Science 314 p. 59, 6 October 2006.

Pot For Alzheimer's?

An enzyme responsible for the malformed proteins characteristic of Alzheimer’s disease may be better suppressed by marijuana than by any other known treatment for the brain disorder, scientists say.

Research published in the Journal of Neuroscience and Molecular Pharmaceutics showed that rats injected with the amyloid protein that forms Alzheimer’s plaques showed characteristic activation of immune cells and resulting inflammation and memory impairment, but animals receiving an additional infusion of cannabinoids show greatly reduced inflammation in the brain.

Recently, researchers at the Scripps Institute in La Jolla, California, showed that THC reduced Alzheimer’s-style clumping of proteins significantly better than donepezil and tacrine, two common treatment medications for Alzheimer’s.

Inflammation of the Alzheimer’s kind leads to memory loss. Old lab rats get progressively worse at learning to solve mazes, but an injection of cannabinoids improves their learning rate markedly. “They gave them a relatiely low dose, even for a rat,” Ken Mackie of the University of Washington told NewScientist News Service. Mackie added that this made the results “more promising.”

The key to the puzzle is the neurotransmitter acetylcholine, which is suppressed by Alzheimer’s treatment drugs--and by THC, but at vastly lower concentrations. In a paradoxical turn of events, the drug most noted for it’s effects on short-term memory may one day be given to the elderly as a medication for combatting age-related memory impairment.

Sources:

--Choi, Charles Q., “Marijuana’s Key Ingredient Might Fight Alzheimer’s.” Health SciTech. 5 October 2006. http://www.LiveScience.com.

--”Marijuana may block Alzheimer’s.” BBC News. February 22, 2005. http://news.bb.co.uk/go/pr/fr/-/2/hi/health/4286435.stm

--Khamsi, Roxanne. “Hope for cannabis-based drug for Alzheimer’s.” NewScientist.com News Service. 18 October 2006. http://www.newscientist.com.

medical marijuana

Coffee and Your Heart

Recent research shows that coffee drinkers come in two flavors: “fast” metabolizers and “slow” metabolizers. People with a particular gene variant are more vulnerable to it’s effects. The gene in question controls the production of a key enzyme, known as CYP1A2, responsible for metabolizing coffee in the liver. People who inherit the slow version face a greater risk of non-fatal heart attacks at high levels of caffeine intake.

“The association between coffee and myocardial infarction [heart attack] was found only among individuals with the slow CYP1A2 allele [gene variant], which impairs caffeine metabolismm, suggesting that caffeine plays a role in the association,” the authors wrote in the Journal of the American Medical Association (JAMA).

The University of Toronto’s Ahmed El-Sohemy, a co-author of the published study, told the Associated Press that metabolic differences might help to explain why previous studies of caffeine’s cardiovascular effects have proven to be contradictory and inconclusive.*

Unfortunately, at present only an expensive lab test will reveal which variant a given coffee drinker has inherited.

Sources:

--Cornelis, Marilyn, C., et al. “Coffee, CYP1A2 Genotype, and Risk of Myocardial Infarction.” Journal of the American Medical Association. 295 10: 1135 March 8, 2006.

--”Coffee May Spell Heart Trouble for Some.” Associated Press. March 7, 2006.
--------------------

*Drugs are broken down into their constituent waste products by specific sets of enzymes. A subset of the human population, variously estimated at 3% to 7%, are categorized as “poor metabolizers.” For them, a drug’s recommended dosage is often far too high.

The culprit is a genetic variant that codes for a liver enzyme called cytochrome P450 isoenzyme 2D6, known in shorthand as CYP2D6. Poor metabolizers produce less of this crucial enzyme, which means that drugs are broken down and excreted at a much slower pace. In these people, the recommended dose results in higher drug concentrations. This obviously can make a crucial difference in how a person reacts to the drugs.

About one out of 20 people has a mutation in the 2D6 gene that causes a lack of the enzyme, according to UC-San Francisco biochemist Ira Herskowitz. “Those people are really getting a whopping dose.” In addition, if a person with normal CYP2D6 levels is taking several drugs that are broken down by CYP2D6, then the enzyme’s ability to degrade one drug can greatly inhibit its ability to degrade the others. This increases the possibility of adverse drug interactions, particularly among the elderly, who may already be suffering from liver disease or impaired renal function. Drugs of abuse severely complicate these enzymatic issues, since addicts and alcoholics are not known for volunteering information about their condition to medical or hospital personnel. Poor metabolizers often have little or no reaction to codeine-based medications. Screening tests for CYP2D6 variations are becoming cheaper and more widely available.

Enzyme interactions can work the other way, too. St. John’s Wort, for example, is suspected of activating another drug breakdown enzyme, CPY3A, thereby accelerating, rather than retarding, the destruction of other drugs. The herb can alter the metabolization of Phenobarbital, tamoxifen, oral contraceptives, and antiviral medications. Drugs must be combined with caution, and people need to monitor dosages, because of the tremendous degree of metabolic variation that exists.

“Start low and go slow” is still the best advice.

--The Chemical Carousel: What Science Tells Us About Beating Addiction © Dirk Hanson 2008, 2009.

Vaccinating Against Vices

Developing a pill or a vaccine for a specific drug addiction has long been one of the tantalizing potential rewards of addiction research. Now a company in Florida has garnered national attention, a spate of clinical trails, and a positive response from the National Institute on Drug Abuse (NIDA) with a compound called NicVAX, aimed at nicotine addiction. In addition, Celtic Pharma in Bermuda is working on a similar product for cocaine addiction.

The idea of vaccinating for addictions is not new. If you want the body to recognize a heroin molecule as a foe rather than a friend, one strategy is to attach heroin molecules to a foreign body--commonly a protein which the body ordinarily rejects--in order to switch on the body’s immune responses against the invader. The idea of a vaccine for cocaine, for example, is that the body’s immune system will crank out antibodies to the cocaine vaccination, preventing the user from getting high. A strong advantage to this approach, say NIDA researchers, is that the vaccinated compound does not enter the brain and therefore is free of neurological side effects.

Preliminary research at the University of Minnesota showed that a dose of vaccine plus booster shots markedly reduce the amount of nicotine that reaches the brain. Animal studies have shown the same effect. NicVAX, from Nabi Biopharmaceuticals, consists of nicotine molecules attached to a protein found in a species of infectious bacteria. When smokers light up, antibodies attack the protein-laden nicotine molecules, which, further encumbered by these antibodies, can no longer fit through the blood-brain barrier and allow the user to enjoy his smoke.

That, at least, is the idea. It is a difficult and expensive proposition, the closest thing to a miracle drug for addiction, but it does not specifically attack drug craving in addicted users. The idea of vaccination is that, once a drug user cannot get high on his or her drug of choice, the user will lose interest in the drug.

This assertion is somewhat speculative, in that users of the classic negative reinforcer, Antabuse, have found ways to circumvent its effects--primarily by not taking it. There remain a wealth of questions related to the effects of long-lasting antibodies. And it is sometimes possible to “swamp” the vaccine by ingesting four or five times as much cocaine or nicotine as usual.

Drugs that substantially reduce the addict’s craving may yet prove to be a more fruitful avenue of investigation. While several anti-craving medications have been approved for use by the Food and Drug Administraton (FDA), no vaccines have made it onto the approved least yet.

For more on pharmaceutical approaches to fighting drug addiction, see my website at http://www.dirkhanson.org

Brain Injury Stops Smokers Cold

In a research development that the director of the National Institute on Drug Abuse (NIDA) calls nothing short of “ming-boggling,” stroke victims lost all desire for cigarettes after suffering damage to a tiny structure in the forebrain. The stroke victims who smoked were seemingly freed from nicotine addiction by damage to the insula, a part of the brain that has not previously been a primary target of addiction research.

Along with the nucleus accumbens, the amygdala, and other structures in the limbic system, certain regions of the cerebral cortex are also implicated in active addiction. Now, said NIDA’s Dr. Nora Volkow, “Everybody’s going to be looking at the insula.”

Researchers at the University of Iowa and the University of Southern California collaborated on the brain injury study, published in the January 26 issue of Science. Neuroscientist Antoine Bechara of USC had learned of a stroke patient known only as N.

A heavy smoker from the age of 14, N. quit cold after a stroke at age 28, telling doctors: “My body forgot the urge to smoke.” A striking percentage of smokers with similar damage to the insula had apparently quit smoking after the injury just as effortlessly as had Patient N.

The role of the insula in brain activity is not well understood, but neurologists believe that the structure may help integrate subcortical inputs into coherent emotions and conscious urges.

No one is suggesting brain surgery for nicotine addiction, but researchers hope to discover ways of interfering with the operation of the insula, perhaps by means of a targeted drug. However, it is not yet clear what other functions the insula may perform, and whether the damage that seemingly eliminates the cigarette urge might also eliminate more positive urges and emotions as well.

Sources:

--Naqvi. N.H., et. al. “Damage to the insula disrupts addiction to cigarette smoking.” Science 315 531-534. Jan 26, 2007.

--Brownlee, Christen. “Addiction Subtraction: Brain damage curbs cigarette urge.” Science News 171 51. Jan 27, 2007.

--Carey, Benedict. “In Clue to Addiction, Brain Injury Halts Smoking.” New York Times. January 26, 2007.