NIDA on Drugs, Brain, and Behavior

How Science Has Revolutionized the Understanding of Drug Addiction.

Addiction to alcohol, nicotine, and other drugs costs Americans as much as half a trillion dollars a year, according to the National Institute on Drug Abuse. Since the 1930s, when the science of addiction got its start, scientists have consistently battled against a prevailing view of addicted individuals as morally flawed and lacking in willpower. In an effort to dispel myths and keep drug arguments on track, NIDA has released an updated 2010 version of its valuable publication, “The Science of Addiction.” The report is available as a PDF for download.

As a disease that affects both brain and behavior, addiction is indeed the “cunning, baffling and powerful” disease described by Bill W., the founder of AA. Dr. Nora Volkow, director of NIDA, said that despite the plethora of scientific advances being made in addiction medicine, “many people today do not understand why individuals become addicted to drugs or how drugs change the brain to foster compulsive drug abuse. This booklet aims to fill that knowledge gap by providing scientific information about the disease of drug addiction, including the many harmful consequences of drug abuse and the basic approaches that have been developed to prevent and treat the disease.”

Dr. Volkow exhorted Americans to “adopt science-based policies and programs that reduce drug abuse and addiction in their communities, and support scientific research that improves the Nation's well-being.”

Today, "thanks to science,” writes Volkow, “our views and our responses to drug abuse have changed dramatically. Groundbreaking discoveries about the brain have revolutionized our understanding of drug addiction, enabling us to respond effectively to the problem.”

Seeking a Patch or a Pill for Pot

Drug treatments for marijuana withdrawal.

Sometimes it’s easy to forget that marijuana is the most widely used illegal drug of all. We demonize it, yet we take it for granted. We punish citizens for its possession, but we call it a “soft” drug.

The idea of marijuana as an addictive drug--for some but by no means all users—still seems preposterous to a large number of recreational pot smokers. Yet these same people have far less trouble dealing with the existence of raging alcoholics surrounded by a majority of controlled, recreational drinkers or non-drinkers.

 For purposes of this post, we are going to stipulate that sufficient scientific evidence now exists to include marijuana in the category of addictive psychoactive drugs. Heavy, daily users of marijuana sometimes find themselves in an unexpected bind if they decide to quit cold. Perhaps as many as one or two in every ten heavy pot smokers will find themselves suffering from flu-like symptoms, loss of appetite, insomnia, vivid dreams, irritability, generalized anxiety, and other side effects that can be at least as unpleasant as quitting cold turkey after a long cigarette habit.

 Why didn’t we know this earlier? Perhaps for the same reasons that we didn’t know until the 1980s, as a general piece of knowledge, that cocaine was highly addictive. (Marijuana Anonymous didn’t start up until 1989). Doesn’t that sound absurd now, the state of our understanding of cocaine’s effects only 30 years ago? For people who suffer strong and repeatable withdrawal symptoms when they try to quit smoking weed, it is equally absurd to proclaim that what they are wrestling with does not resemble a genuine drug addiction (See the Addiction Inbox thread on marijuana withdrawal, which is now approaching 1,000 comments, and which constitutes a major database of self-reported data on marijuana withdrawal).

Having identified marijuana as classically addictive for a small slice of the user population, the focus has lately turned toward human laboratory studies, although most of the human studies thus far have been open-label trials rather than controlled double-blind studies. A group of researchers at Columbia University has been testing a variety of medications in search of a compound with demonstrated effects on marijuana abstinence and withdrawal. A study published online last year examines the effectiveness of a variety of medications on the course of marijuana craving and withdrawal in users classified as marijuana dependent. In other words, they are looking for the equivalent of a nicotine patch for marijuana.

In an article for CNS Drugs, Ryan Vandrey of Johns Hopkins University School of Medicine and Margaret Haney of the New York State Psychiatric Institute, surveyed such studies as presently exist on the subject of pharmacotherapy for cannabis dependence. There are presently no clinically validated treatments for marijuana withdrawal. And, unlike the hundreds of controlled, double blind trials of pharmaceuticals for addiction to alcohol, cigarettes, cocaine, and heroin, recent research on medications for marijuana dependence has been sparse and scattershot.

 Nonetheless, the marijuana withdrawal syndrome is now well established in the scientific literature, as well as anecdotally.  Among heavy dope smokers, the authors write, cold-turkey cessation from marijuana “produces cellular changes in the brain reward pathway (increased corticotrophin-releasing factor, decreased dopamine) that have been linked to the dysphoric effects associated with withdrawal from drugs such as alcohol, opiates, and cocaine, and are thought to contribute to relapse.”

What have they discovered so far?

One obvious starting point was dronabinol, a.k.a. Marinol, the government-approved synthetic THC often prescribed for nausea, vomiting, and appetite loss due to chemotherapy. Marinol is a direct approach to the nicotine patch strategy: A substance that stimulates cannabis receptors in a manner similar to, but by no means identical with, the high produced by natural marijuana. Perhaps a regular low dose of Marinol would keep the cannabis cravings at bay among problem users trying to quit. As it turns out, not really. Some studies showed that you could reduce a pot addict’s withdrawal symptoms somewhat in a home environment with Marinol, but the dose required to accomplish this was high enough to represent potential problems of its own.

Another obvious candidate for investigation was rimonabant, a.k.a. Accomplia—but for the opposite reason. Rimonabant, which started out life as an anti-obesity medication, blocks the cannabinoid receptor CB1, so in that sense it should function roughly like Antabuse for alcoholics. It is the “anti-weed,” but as it turned out, rimonabant’s effect on cannabis receptors didn’t do the trick, either. Rimonabant “reduced the effects of smoked cannabis in two studies,” Vandrey and Haney write, “but a reduction of subjective drug effects was not consistently observed.” Furthermore, rimonabant is under suspicion for causing “adverse psychiatric effects” and is not much in favor at present.

Next up, naltrexone—an opiod receptor antagonist, which blocks the effects of heroin and is used in alcohol and heroin detox and withdrawal. Naltrexone has been shown in some studies to “reduce the subjective effects of cannabinoids in humans,” the authors note. But no dice: “In cannabis users, pretreatment with high doses of naltrexone (50-200 mg) failed to attenuate, and in some cases enhanced, the subjective effects of dronabinol and smoked cannabis.” To make matters worse, “the effect of naltrexone can be overcome with higher doses of cannabis.”

Other possible anti-craving drugs for marijuana have not been as rigorously studied. An open-label investigation of buspirone, which works on serotonin and dopamine systems, caused a decline in self-reported cannabis use, and pot smokers showed marked decreases in craving and irritability—but, as these things often go, buspirone was not well-tolerated by the participants, with too many dropouts due to adverse side effects.

Lithium, a mood stabilizer commonly prescribed for bipolar disorder, has shown promise in several small studies. An open-label lithium trial by the National Drug and Alcohol Research Centre in New South Wales resulted in “significant reductions in symptoms of depression and anxiety and cannabis-related problems.” More studies are needed.

Fluoxetine, better known to the world as Prozac, has been anecdotally associated with reduced marijuana use in depressed alcohol-dependent patients, but has never been the subject of any large clinical studies with a population of users whose primary drug is marijuana.

And finally, there is a dark-horse candidate, a treatment drug sometimes employed to prevent relapse

 in cases of heroin addiction. Lofexidine is an alpha-2-adrenergic agonist that has been in use for years in the U.K. under the name BritLofex to treat the common symptoms of heroin withdrawal, such as cramps, chills, sweating, loss of appetite, and diarrhea. Similar but less intense withdrawal symptoms also afflict heavily addicted marijuana users. In a 2008 paper published in Psychopharmacology, “lofexidene was sedating, worsened abstinence-related anorexia, and did not robustly attenuate withdrawal, but improved sleep and decreased marijuana relapse.” Lofexidine combined with THC yielded even better results.

It appears that immediate research might be most profitably focused on lofexidine and lithium. And indeed, additional studies of the two drugs for cannabis dependency are planned by NIDA.  Also, the combination of dronabinol and lofexidine appears to be worth pursuing in future clinical investigations of anti-craving drugs for marijuana.

Vandrey, R., & Haney, M. (2009). Pharmacotherapy for Cannabis Dependence CNS Drugs, 23 (7), 543-553 DOI: 10.2165/00023210-200923070-00001

Graphics Credit: http://archives.drugabuse.gov

Spice, K2, Other “Fake Pot” Illegal as of March 1

DEA makes synthetic marijuana a Schedule 1 drug.

The U.S. Drug Enforcement Administration (DEA) exercised its emergency scheduling authority yesterday to outlaw the use of “fake pot” products.

Sixteen states have already passed a mishmash of legislation outlawing one or more of the drugs in question, which are typically sold as Spice, K2 or Red X.

The DEA had already announced its intention to put 5 new drugs--JWH-018, JWH-073, JWH-200, CP-47, 497, and cannabicyclohexanol--on the official list of scheduled substances. “These products consist of plant material that has been coated with research chemicals that claim to mimic THC, the active ingredient in marijuana, and are sold at a variety of retail outlets, in head shops, and over the Internet,” the DEA said in a prepared statement. “The temporary scheduling action will remain in effect for at least one year while the DEA and the United States Department of Health and Human Services (DHHS) further study whether these chemicals should be permanently controlled."

According to the DEA, “Emergency room physicians report that individuals that use these types of products experience serious side effects which include: convulsions, anxiety attacks, dangerously elevated heart rates, increased blood pressure, vomiting, and disorientation.”

The smokable herbal products were designated as Schedule 1 substances, the federal government’s most restrictive category, ostensibly reserved for drugs with “no accepted medical use for treatment in the United States and a lack of accepted safety for use of the drug under medical supervision.” Marijuana is also a Schedule 1 drug, along with heroin, Ecstasy, and LSD. The supposedly less dangerous Schedule 2 drugs, bizarrely, contain the most problematic drugs of all in terms of human health and addictive potential: methamphetamine, oxycontin, and cocaine. Schedule 3 is so confusing as to defy coherent description, while Schedule 4 is the valium category and Schedule 5 is the Robitusson category.

One problem with the whack-a-mole approach to drug enforcement is that developers of designer drugs can easily stay one jump ahead of the law. What many drug officials and agencies, including the International Narcotics Control Board, want to see is sweeping, generic bans on whole categories of chemicals, in order to win the game of leapfrog.

However, as reported by Maia Szalavitz at Time Healthland, broad-spectrum drug bans “could have the unintended effect of keeping potential cures for diseases like Alzheimer’s out of the pharmaceutical pipeline.” As Szalavitz notes, “getting a drug out of Schedule 1 is much harder than getting it into that legal category, as supporters of medical marijuana and MDMA have discovered.”

And if clinical researchers wish, say, to pursue JWH-133--a chemical compound closely related to the newly banned drugs—for its ability to reduce the inflammation associated with plaque buildup in the brains of people with Alzheimer’s, they are going to find that research almost impossible to do, as more and more chemicals escape the lab or emerge from the work of underground chemists and ultimately become illegal substances.

Notice of Intent to Temporarily Control Five Synthetic Cannabinoids

Graphics Credit: http://newsbythesecond.com/

Smoking and Adolescent Attention Deficit

Are young smokers risking cognitive impairment as adults?

 Call it “nicolescence.” It’s that time of life when certain 18-and-unders discover cigarettes. Most adult smokers begin their habit before the age of 19, and a majority of adolescents have tried cigarettes at least once. But for some of them—those who were “born to smoke,” in a sense—early exposure to nicotine may influence adolescent cognitive performance in ways that adult exposure to nicotine does not. Furthermore, early exposure may result in “cognitive impairments in later life.”

These provocative notions are raised by a group of researchers at VU University, Amsterdam, The Netherlands, in a paper for Nature Neuroscience. And while the specifics of glutamate activity they have documented are fascinating, the leaps back and forth between adolescent humans and adolescent lab mice are dizzying. Nonetheless, the bold claims made in the paper prompted the scientists “to reconsider our views on the etiology of attention deficits.”

That may be more than many addiction researchers are willing to countenance, but the study makes an intriguing case for long-term effects on attentional processing. The Dutch researchers exposed adolescent rats to nicotine, assessed visuospatial attention and other markers associated with synaptic activity in the prefrontal cortex, and found impaired measures of attention and signs of increased impulsivity in adulthood after five weeks of abstinence. Adult rats exposed to nicotine for the first time did not show similar long-term consequences.

The molecular underpinnings for this phenomenon appear to be reduced glutamate receptor protein levels in the prefrontal cortex. Glutamate is a neurotransmitter involved in attention, among other cortical tasks. Glutamate levels were “altered specifically by adolescent and not adult nicotine exposure” in the lab animals, the researchers found.

The glutamate receptor mGluR2 is the likely culprit.  The researchers report that “a lasting downregulation of mGluR2 on presynaptic terminals of glutamatergic synapses in the prefrontal cortex persists into adulthood causing disturbances in attention…. Restoring mGluR2 activity in vivo in the prefrontal cortex of adult rats exposed to nicotine during adolescence remediated the attention deficit.”

The study concludes: “Not only from a behavioral, but also from a molecular point of view, the adolescent brain is more susceptible to consequences of nicotinic receptor activation.” In other words, there is at least some evidence that the neurotoxic effects of nicotine are potentially more severe in the early developmental stage called adolescence.

The Dutch study is not the only one of its kind. In 2005, Biological Psychiatry published a report on cognition in which adolescent smokers “were found to have impairments in accuracy of working memory performance irrespective of recency of smoking. Performance decrements were more severe with earlier age of onset of smoking.”

And a 2007 study published in Neuropsychopharmocology, based on testing and fMRI scans of 181 male and female adolescent smokers, concluded that “in humans, prenatal and adolescent exposure to nicotine exerts gender-specific deleterious effects on auditory and visual attention…” Boys were more sensitive than girls to attention deficits involving auditory processing, while girls tended to show equal deficits in both auditory and visual attention tasks. 

Counotte, D., Goriounova, N., Li, K., Loos, M., van der Schors, R., Schetters, D., Schoffelmeer, A., Smit, A., Mansvelder, H., Pattij, T., & Spijker, S. (2011). Lasting synaptic changes underlie attention deficits caused by nicotine exposure during adolescence Nature Neuroscience DOI: 10.1038/nn.2770

Photo Credit: http://smoking-quit.info/

From NINA to NSNA: No Smokers Need Apply

 Smoke-free workplace or job discrimination?

It started with hospitals and medical businesses. As more and more states adopted strict policies about smoking, state courts began to bump up against a vexing question—the legal system is being called upon to adjudicate the legality of refusing to hire smokers.

The issue has split the anti-smoking world into two camps, and shines light on the fundamental question: Is it legal to discriminate against tobacco consumers, usually known as smokers, for the use of a lawful product? Will courts uphold cases where employees have been fired for “smelling of smoke”?

20% of Americans continue to smoke. As the New York Times puts it, a shift from “smoke-free” to “smoker-free” workplaces reflects the general feeling that “softer efforts—like banning smoking on company grounds, offering cessation programs and increasing health care premiums for smokers—have not been powerful-enough incentives to quit.”

Join Together reports that under new “tobacco-free” hiring policies, “applicants can be turned away for smoking, or if they are caught smoking after hire. Policies differ by company, but some require applicants to take urine tests for nicotine.”

The chief executive of St. Francis Medical center in Cape Girardeau, Missouri, which recently stopped hiring smokers, said that it was “unfair for employees who maintained healthy lifestyles to have to subsidize those who do not. Essentially that’s what happens.”

The American Lung Association, the American Cancer Society, and the World Health Organization (WHO) do not hire smokers. However, the American Legacy Group, an anti-smoking advocacy organization that does hire tobacco users, argues that “smokers are not the enemy.” In the words of Ellen Vargyas, the group’s chief counsel,  “the best thing we can do is help them quit, not condition employment on whether they quit.”

As Dr. Michael Siegel of  the Boston University School of Public Health told the New York Times: “Unemployment is also bad for health.”

The issue has broader implications, as yet imperfectly explored. Will it become legal to discriminate against alcohol and drug users in general? How about junk food? Should a company be forced to saddle itself with the likely health costs associated with a junk food junkie?

And so on. This one bears watching.

Love, Loss, and Addiction

Review of “This River” by James Brown.

James Brown, author of “The L.A. Diaries,” has offered up another candid and courageous memoir in his new book, “This River.” In a series of related vignettes, the book amplifies and extends the basic story of Brown’s life as chronicled in “L.A. Diaries,”--a harrowing tale of genetic fate and social failure; a dysfunctional family riven by alcoholism and drug addiction, culminating in the suicide of the author’s brother, followed by the suicide of his  sister.

Throughout his descents into hard drug use, his ups and downs along the alcoholic’s rehab trail, Brown remains a fierce observer of his own behavior, and, heartbreakingly, its effect on those around him: “Worrying, damaging, terrorizing those closest to us, intentionally or not, is what alcoholics, addicts, and the mentally ill do best.” As was true of “The L.A. Diaries,” Brown writes in a spare, direct, unflinching style—a bracing antidote to the Stuart Smalleys of the world.  His observations on A.A., anti-craving medications, and antipsychotic drugs are those of a man unwilling to let prior prejudices and built-in excuses deter him from a search for the true nuts and bolts of his condition.

Reaching that point of understanding, and comprehending the need for action—none of it typically comes fast, cheap, or easy. Brown, who teaches in the MFA program at Cal State San Bernardino, masterfully captures the internal monologues of the addictive mind:

"Getting hooked is for weaklings, the idiots who can’t control themselves, those losers who end up broke and penniless, wandering the streets at night like zombies, like the walking dead…. For the budding addict, the supply is never enough, but your only regret, at least to date, is that you didn’t come across this miracle potion sooner."

The internal dialog eventually becomes an existential struggle: “True or not, I resist the idea that mental illness and alcoholism are somehow inborn. Accepting that premise means embracing the notion of fate, and I don’t. I prefer to believe that I’m in full control.”

As who among us does not. And although none of us are truly in full control—we are all a conflicting welter of “I”s, of shifting identities and roles—it is through the dissociations characteristic of addictive illness that the Jekyll and Hyde nature of these changes, which are somehow “in the blood,” sometimes manifest themselves most graphically.

Does the author prevail? He does, for now, and that is how we must leave it:

Things are changing deep inside you and have been for some time: hormones, genes, brain chemistry, all of it adapts to the alcohol and drugs you continually dump into your body. The cells habituate. The cells literally mutate to accommodate your cravings and now they crave too. Now your addiction has more to do with physiology than psychology. Now it’s the body that robs the mind of its power to choose, and it’s not long before you’ll wish you never came across that miracle potion, those powders and pills.

With suberb jacket reviews from the likes of Tim O’Brien, Robert Olmstead, and Duff Brenna, “This River” is a short read that will lodge itself firmly in your memory.  I read it in one sitting, and I bet you do, too.

Photo Credit: http://radaris.com/p/James/Rivers/

What’s the Best Valentine’s Day Present of All?

Answer: a healthy heart.

Valentine’s Day is all about hearts, so it’s not surprising that February was picked as American Heart Month almost 50 years ago.

The Office on Smoking and Health at the U.S. Centers for Disease Control (CDC) wants you to know that, if you smoke, “the cells that line your body's blood vessels react to the poisons in tobacco smoke almost immediately. Your heart rate and blood pressure go up. Your blood vessels grow narrower. Chemical changes caused by smoking also make blood more likely to clot."

Furthermore: “Plaque clogs and narrows your arteries. This can trigger chest pain, weakness, heart attack, or stroke. Plaque can rupture and cause clots that block arteries. Completely blocked arteries can cause sudden death. Smoking is not the only cause of these problems, but it makes them much worse.”

Worse like this---------------------------------------------->

The 2010 Surgeon General's Report, "How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease," documents the crucial importance to heart health of being smoke-free.

Okay, don’t quit for yourself. Because face it, you don’t want to. But how about quitting for someone else? As the CDC reminds us, “because secondhand smoke also affects others and can increase their risk for heart attack and death, quitting smoking can help protect your loved ones.”

And here are some CDC resources for supporting a stop-smoking program:

For support to quit, call 1-800-QUIT-NOW (1-800-784-8669; TTY 1-800-332-8615). This service provides free support and advice from experienced counselors, a personalized quit plan, self-help materials, the latest information about cessation medications, and more. 

Online cessation services and resources are also available online at www.smokefree.gov. This Web site provides free, accurate, evidence-based information and professional assistance to help support the immediate and long-term needs of people trying to quit smoking.

Photo Credit: http://inventorspot.com/