If the Genes Fit....

U.K psychiatrists agree addiction is "genetically determined."

Although the verdict is very little in doubt these days, the heritability of addictions was reaffirmed by the U.K.'s Royal College of Psychiatrists in London on July 4th.

In a presentation at the group's annual meeting, held at Imperial College, Professor Wim van den Brink of the University of Amsterdam's Academic Medical Center pinned the blame for addiction squarely on the absence of a sufficient number of dopamine receptors in the brain. "Addicts find it difficult to receive pleasure," he said. "They are not likely to enjoy most of the ordinary things most of us enjoy... they are looking for more stimulus."

Professor van den Brink also made clear the importance of environmental interactions for gene expression: "You might start off smoking or taking cocaine, and that first introduction is very much determined by your environment. But to stick with it and become dependent on it is genetically determined."

The self-defeating nature of addiction is graphically illustrated by the overall decrease in the number of pleasure receptors for dopamine and serotonin over time, as drug use escalates. Moreover, addicts show a striking deficiency in the ability to engage in long-term thinking. This behavioral link, the Royal College maintained, is the reason addicts fail to realistically differentiate between short-term pleasure and long-term negative effects.

This inability of drug addicts to engage in effective long-term thinking is well summarized in the old Reverend Gary Davis song: "Cocaine's for horses and it's not for men/Doctor said it kill you, but he didn’t say when."

Photo Credit: National Institute on Drug Abuse

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Meth to the West, Cocaine to the East, Pot in the Middle

The geography of drug use.

To paraphrase an old tune by Gerry Rafferty, we got meth to the left of us, cocaine to the right, and here we are, stuck in the middle with pot.

The National Drug Threat Survey of 2007, a product of the National Drug Intelligence Center (NDIC) at the Department of Justice, illustrates the stark nature of regional variation when it comes to illegal drugs of choice in the United States. The map at the right represents the responses of state and local law enforcement agencies to the question: "What drug poses the greatest threat to your area?" Blue indicates cocaine, red indicates methamphetamine, and green stands for marijuana. (Click map for larger image.)

According to the Oregonian in Portland, reporting on similar numbers from the U.S. Substance Abuse and Mental Health Services Administration: "The politics of methamphetamine have been shaped by geography. Lawmakers from the East, Midwest and South focused on cocaine--the most heavily abused drug by far in their home states. By contrast, more than 90 percent of people treated for meth abuse live west of the Mississippi River."

The NDIC's stated mission is "to provide strategic drug-related intelligence, document and computer exploitation support, and training assistance to the drug control, public health, law enforcement, and intelligence communities of the United States...." NDIC obtains its data through direct surveys of federal, state and local law enforcement and intelligence agencies, as well as information from court documents, news sources, and public health agencies.

The NDIC has produced a National Drug Threat Survey annually since 2000, and began deriving state-level estimates in 2003. Federal, state and local government agencies use the statistical estimates as guidelines for promulgating drug legislation and enforcement strategies.

Graphics Credit: National Drug Intelligence Center

Epigenetics and Addiction

Turning off the genes for substance abuse.

If psychiatric disorders, including depression and addiction, are rooted in nature, but modified by nurture, some better way of viewing the interaction between genes and the environment is desperately needed.

Enter "epigenetics," defined as the study of how gene expression can be modified without making direct changes to the DNA. Writing in Science News, Tina Hesman Saey explains that "epigenetic mechanisms alter how cells use genes but don't change the DNA code in the genes themselves.... The ultimate effect is to finely tune to what degree a gene is turned on or off. Often the fine tuning is long-lasting, setting the level of a gene's activity for the lifetime of the cell."

A common form of epigenetic modification involves adding molecules to the DNA structure. Adding molecules from a methyl group or an acetyl group can change the manner in which genes interact with a cell's transcribing system. Cells can "mark" specific genes by attaching a methyl group consisting of three hydrogen atoms and one carbon atom to cytosine in the DNA base, effectively turning genes on or off without making major alterations to genetic structure. (Gene mutations or insertions, on the other hand, are capable of fundamentally altering the DNA protein structure.)

Scientists have learned that epigenetic changes can be caused by environmental impacts, but the details are not well understood. We have not yet reached the point of being able to link a specific experience of stress or infection or chemical exposure to specific epigenetic alterations.

What does any of this have to do with drug addiction or depression? One of the environmental impacts researchers have linked to epigenetic changes is drug addiction. The DNA double helix is packaged in proteins collectively called chromatin. One set of proteins, the histones, is a frequent site of epigenetic modification. In a study published in Neuron, Eric Nestler and co-workers in the Southwestern Medical Center at the University of Texas found that alterations in chromatin packaging were tied up with the dopamine release caused by cocaine addiction. The researchers concluded that chronic cocaine use was influenced by "chromatin remodeling." Specifically, modulating histone activity "alters locomotor and rewarding responses to cocaine."

How does this work? As Saey writes in Science News: "Another gene, known as delta-FosB, also switches on when a wave of dopamine washes over the nucleus accumbens.... Delta-FosB teams up with other transcription factors and recruits enzymes that acetylate histones and remodel control regions of some genes..... Such findings suggest that medicines that interrupt or reverse epigenetic changes caused by drugs of abuse could one day prevent or cure addiction."


Image Credit: Science in School

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Annals of Addiction: Malcolm McDowell

From The Harder They Fall

"My father was an alcoholic, so I never really drank much. I kept away from it, but I didn't realize that cocaine was really the same thing. Alcohol eventually started getting a little out of control, but in the form of 'fine wine.' That was my excuse....

"So I didn't consider wine a problem, but cocaine was a problem, and that got out of hand quite fast. It had a very bad effect on my marriage. The lies and deceit and everything that goes with addiction. I went from snorting it occasionally to now smoking it, doing freebase. Doing as much as I could. Finish a batch at four in the morning. Driving around the San Fernando Valley looking for some more of it. Driving while completely stoned, of course. How I was never in an accident, I just don't know....

"The using ended because I went down to the Betty Ford Center.... I didn't thank God at the time time, however. I felt I'd lost a great friend or mistress, that I'd lost the one thing that I could totally trust--all that bullshit! It wasn't until I started to work on myself at Betty Ford, which is a wonderful place as is any place that gets you sober....And, of course, it's hard work, recovery. Less and less hard as the years have gone by, but you know, the way we live our lives is all recovery in one sense or another. We go through a shattering experience like that, and everything we do in life from then on is in a way influenced by what we've been through."

Excerpted from:
The Harder They Fall, by Gary Stromberg and Jane Merrill. Center City, MN: Hazelden.

Photo Credit: MTV News

The Chemistry of Cocaine Addiction

Crack, free-base, and powder

The cocaine high is a marvel of biochemical efficiency. Cocaine works primarily by blocking the reuptake of dopamine molecules in the synaptic gap between nerve cells. Dopamine remains stalled in the gap, stimulating the receptors, resulting in higher dopamine concentrations and greater sensitivity to dopamine in general.

Since dopamine is involved in moods and activities such as pleasure, alertness and movement, the primary results of using cocaine--euphoria, a sense of well being, physical alertness, and increased energy—are easily understood. Even a layperson can tell when lab rats have been on a cocaine binge. The rapid movements, sniffing, and sudden rearing at minor stimuli are not that much different in principle from the outward signs of cocaine intoxication among higher primates.

Chemically, cocaine and amphetamine are very different compounds. Psychoactively, however, they are very much alike. Of all the addictive drugs, cocaine and speed have the most direct and most devastatingly euphoric effect on the dopamine systems of the brain. Writing in the November 2004 issue of Synapse, Jonathan D. Brodie and colleagues at the New York University School of Medicine reported that “A rapid elevation in nucleus accumbens dopamine characterizes the neurochemical response to cocaine, methamphetamine, and other drugs of abuse."

In the late 1990s, scientists at Johns Hopkins and NIDA had shown that opiate receptors play a role in cocaine addiction as well. PET scans demonstrated that cocaine addicts showed increased binding activity at mu opiate receptors sites in the brain during active cocaine addiction. Take away the cocaine, and the brain must cope with too many empty dopamine and endorphin receptors.

Cocaine and amphetamine produce rapid classical conditioning in addicts, demonstrated by the intense cravings touched off by such stimuli as the sight of a building where the user used to buy or sell. Environmental impacts of this nature can produce marked blood flow increases to key limbic structures in abstinent addicts.

When the crack "epidemic" first became news, it was clear that the old specialty of free-basing was now within reach of existing cocaine users. No paraphernalia needed except for a small pipe; no more butane and mixing; no muss, no fuss. Like basing, smoking crack was a drug dealer’s dream. The “rush” from smoking crack was more potent, but even more transient, than the short-lived high from nasal ingestion

Both the cocaine high and the amphetamine high are easily augmented with cigarettes or heroin. These combinations result in “nucleus accumbens dopamine overflow,” a state of neurochemical super saturation similar to the results obtained with the notorious “speedball”—heroin plus cocaine.

It has been clear for more than a decade that most cocaine treatment programs are failures. In the case of the newly arrived crack cocaine, relapse rates after formal treatment sometimes approach one hundred per cent. Clearly, a piece of the puzzle has been missing. If receptors were the sites that controlled how drugs affected the mind, and if genes controlled how receptors were grown, then one implication of all the receptor theories was that sensitivity to addictive drugs could conceivably have a genetic basis. It was a large step in the right direction, because there were already good reasons for seeing alcoholism and other addictions as inherited dysfunctions in brain chemistry.

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

Photo Credit: Legal Drug Alternatives

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Fewer People Testing Positive For Meth and Cocaine

Quest Diagnostics releases 2007 figures.

Quest Diagnostics, the nation’s leading provider of employee drug testing services, reported a 22 percent drop in the number of U.S. workers and job applicants testing positive for methamphetamine last year. The percentage of positive tests for cocaine fell 19 percent in the same period—the largest single-year decline since 1997, the company reported.

Overall, drug test positives were at an all-time low (see chart). The company said 3.8 percent of employees had tested positive for drug use in 2007, compared to a high of 13.6 in 1988.

Quest Diagnostics based its conclusions on a summary of results from more than 8 million workplace drug tests the company conducted in 2007. The data include pre-employment, random, and for-cause testing. The primary test population included federally mandated testing of “safety-sensitive” workers such as pilots, truck drivers, and employees at nuclear power plants
It is not immediately clear what conclusions can be drawn from the Quest Drug Testing Index. Do the results indicate a falloff of stimulant use, or are they a reflection of scarcities of supply?

The DEA was quick to jump in and claim the latter: “The fact that America’s workers are using cocaine and methamphetamine at some of the lowest levels in years is further evidence of the tremendous success that law enforcement is having at impacting the nation’s illicit drug supply,” Drug Enforcement Administration (DEA) Acting Administrator Michele Leonhard said in a press release.

In the same press release, Dr. Barry Sample of Quest Diagnostics, citing figures that show a 5 percent increase in the use of all forms of amphetamines last year, said: “Although some may conclude that there is a reduced availability for methamphetamine, the fact that our data show an increase in amphetamines suggests that some workers might be replacing one stimulant drug for another in the larger drug class of amphetamines.”

It is also unclear whether or not the lower numbers reflect greater employee awareness of drug testing, and greater knowledge of methods for finessing the testing system, such as a crash course of abstinence when testing is considered likely.

Moreover, drug testing remains a controversial practice. Critics maintain that the costs of drug testing far exceed the benefits of identifying a very small percentage of workers with testing procedures that are not always and inevitably reliable.

In a review of a report on drug testing by the National Academy of Sciences in 1999, the American Civil Liberties Union (ACLU) concluded: “There is as yet no conclusive evidence from properly controlled studies that employment drug testing programs widely discourage drug use or encourage rehabilitation.” According to the ACLU, the federal government spends more than $77,000 dollars for each positive drug test, when overall costs of the federal government’s drug testing program are taken into consideration.

Graphics Credit: Market Wire

FDA Puts Coke/Meth Treatment on Fast Track

Sabril may block cravings for stimulants.

The U.S. Food and Drug Administration (FDA) has given Fast Track designation to vigabatrin, an anticonvulsant marketed as Sabril, for evaluation as an anti-craving drug for cocaine and methamphetamine addiction. If approved, it would be the first medication ever approved for the treatment of addiction to stimulants.

The Fast Track designation at the FDA is intended to speed up the evaluation of drug treatments aimed at life-threatening disorders for which no current treatments exist. A 2006 study by the Substance Abuse and Mental Health Services Administration estimated that there were more than one million cocaine and methamphetamine addicts in the U.S.

First synthesized as a drug treatment for epilepsy in 1974, Sabril increases brain levels of the neurotransmitter GABA, an inhibitory compound also implicated in alcoholism. According to a press release from Ovation Pharmaceuticals, a marketer of the drug, “Sabril may block the euphoria associated with cocaine administration in humans and may suppress craving by increasing brain levels of gamma-aminobutyric acid (GABA).” Catalyst Pharmaceutical Partners has also announced plans to proceed with Sabril testing.

Ovation is collaborating with the NIDA on Phase II studies to evaluate the safety of Sabril, with Phase III trials scheduled for the end of this year. FDA has never approved the drug for use in the U.S., citing concerns over retinal damage in patients overseas.

Earlier animal testing and two limited early-stage studies on human addicts in 2003-2004 have convinced the company that Sabril diminishes cravings for stimulants. It may also blunt the euphoric effect of meth and cocaine. "This is unheard of in addiction treatment," Stephen Dewey of the Brookhaven National Laboratory, a member of an earlier vigabatrin study team, told New Scientist in 2003. "There are no medicines that are effective at blocking cocaine craving in addicts."

Writing in the November 2004 issue of Synapse, Jonathan D. Brodie and colleagues at the New York University School of Medicine reported that “A rapid elevation in nucleus accumbens dopamine characterizes the neurochemical response to cocaine, methamphetamine, and other drugs of abuse. CITE Previously, we demonstrated that this response and associated behaviors are attenuated or even blocked by Vigabatrin, an antiepileptic drug and an irreversible inhibitor of GABA-transaminase."

However, the New Scientist also reported that many doctors who work with cocaine addicts were skeptical. "Cocaine is a recreational drug. The vast majority of people who take cocaine or crack want to continue doing so," said Allan Parry, a drug counselor in Liverpool, UK. "So in that sense this work is only likely to be relevant to a tiny minority of people. People often give up cocaine because their lifestyle changes or they just grow up."

Ovation said it was “pleased that the FDA has recognized the significant need for effective treatment options to address stimulant addiction, which is a major public health problem.”

Since there are no FDA-approved medications for cocaine or methamphetamine addiction, current treatment strategy centers on cognitive and behavioral approaches.

Cocaine is Cocaine: New Sentencing Guidelines

U.S. Supreme Court relaxes jail time for crack crimes.

In a little-noted ruling last month, the U.S. Supreme Court bowed to reality and restored a measure of sanity to cocaine sentencing guidelines. The Court ruled, on a 7-2 vote in the case of Kimbrough v. U.S., that federal judges had the discretion to reduce prison terms for crack-cocaine offenses.

The move was an effort by the Supreme Court to bring crack cocaine sentences more in line with sentencing guidelines for powdered cocaine. Many drug experts expressed relief, noting that the changes were long overdue. “There’s no scientific justification to support the current laws,” said National Institute of Drug Abuse (NIDA) director Dr. Nora Volkow.

Writing for the majority, Judge Ruth Bader Ginsburg noted that the two substances in question “have the same physiological and psychotropic effects.” A number of federal judges have long advocated the change, the importance of which was demonstrated when the U.S. Sentencing Commission announced that as many as 20,000 federal inmates serving time for crack possession may be due for sentence reductions, based on the new ruling.

A 1986 law, the Anti-Drug Abuse Act, reset mandatory minimum sentences for cocaine, allowing for as much as a 100-to-1 disparity between prison time for crack and prison time for powdered cocaine. As an article in the International Herald Tribune noted, the law allowed a prison term of “five years for trafficking in 5 grams of crack, or less than the amount in two packets of sugar. It would take 100 times as much cocaine [in powder form] to get the same sentence.”

Several bills with a similar aim have been introduced in Congress, including legislation jointly sponsored by Senators Edward Kennedy and Orrin Hatch, which would revise the crack-powder sentencing ratio to 20-1.

This Alice-in-Wonderland situation was triggered by the cocaine-related death of college basketball star Len Bias in 1986. The widely publicized death set off a cocaine panic in America that quickly reached the White House and Congress. In addition, doctors and the press were busy wildly overestimating the number of handicapped “crack babies” being born. Craig Reinarman, author of the book, “Crack in America,” told the Associated Press: “You had politicians manipulating fear, and instead of being seen as a more direct mode of ingestion of a very old drug, [crack] became a demonic new substance.”

Moreover, civil rights advocates have long claimed that the sentencing structure is racist: Blacks prefer crack and Whites prefer powder, if arrest records are any indication. (Crack is produced by dissolving powdered cocaine and baking soda in water, then boiling away the water.)

According to Graham Boyd of the American Civil Liberties Union (ACLU) drug law reform project, “This may be the first sentencing decision since the mid-1980s that actually talks about justice, that seems to have some blood in it.”

“There is a sense of a turning point,” Jack B. Weinstein, a federal district court judge in New York, told Newsweek. “The cost [of the current drug war] is tremendous, to the community and to taxpayers.”

Justices Clarence Thomas and Samuel Alito dissented in the case.

Vote of No Confidence For Prometa

Addiction drug loses major funding.

It is composed of three common and inexpensive drugs used for other purposes. It has never been subjected to clinical double blind testing. It costs thousands of dollars for the full treatment package, and the company that markets it says it cures about 80 percent of the drug addicts who use it.

If that description sounds familiar—if it seems to give off a faint whiff of blue-green algae and multi-level marketing—such concerns have not stunted the promotion and acceptance of the anti-addiction drug Prometa. But MSNBC reported last week that Prometa, the drug “cocktail” designed to combat addiction to cocaine and methamphetamine, was dealt a severe blow when accountants in Pierce County, Washington froze the funding for an $800,000 pilot program, citing irregularities in testing.

The treatment involves intravenous infusions of Flumazinil, a reversal agent for benzodiazepines like Valium and Klonopin. The second drug, hydroxyzine, is an antihistamine, and the third, sold as Neurontin, as an anti-seizure medication frequently used “off prescription” as a treatment for a number of ailments, including alcoholism and hearing loss.

The treatment does not require approval by the Food and Drug Administration (FDA) because all three ingredients are already in common use in clinics and hospitals. The Prometa Regimen marketed by Hythium involves formulating the protocol and contracting with doctors to deliver the medications.

To date, there is no published clinical data to support treatment for addiction with these three drugs in proprietary combination.

Marketed heavily by anecdote and personal testimonials, the Prometa marketing campaign included ads in 2006 featuring the late comedian Chris Farley, who died of a drug overdose.

Hythiam, the company that markets Prometa, has touted the treatment with claims of success rates as high as 98 per cent, but Pierce County Councilman Shawn Bunney found the results of the county audit “alarming,” according to MSNBC. “It’s clear to me that we are much more involved in a marketing scheme…”

Hythiam Executive Vice President Richard Anderson disagreed. “The people who are using it,” he said, “the doctors, patients, administrators, and drug court judges—are seeing an impact with it, so I think the treatment will carry it at the end of the day.”

The dispute centers on the manner in which dropouts were counted in surveys done by Hythiam’s non-profit arm, the Pierce County Alliance. The Alliance had been responsible for administering the Prometa program in Pierce County drug courts. According to county auditors, dropouts and no-shows (patients who fail to show up for drug testing) were not included in the Alliance’s final report on 35 patients over a 14-month period. In Pierce and neighboring counties of Washington, drug courts record no-shows as equivalent to positive drug tests. This was not how the alliance scored it, although alliance spokespeople have insisted that county officials have misunderstood the mechanics of the study.

An investigation by the Tacoma News Tribune threw more cold water on the Prometa numbers. “According to the multiple public statements by the alliance,” wrote Sean Robinson, 86 percent of the Prometa clients ‘remained drug-free’ at the end of the 14-month program. According to county auditors, the number was 50 percent.”

Furthermore, the alliance “defined success in the Prometa program as 60 or more days of clean drug tests…. In Pierce County, drug-court clients must show 90 days of clean drug tests… In Snohomish and Thurston counties, drug-court clients must show six months.”

Investors in Hythiam, which is publicly traded, were counting on the Pierce program after similar programs in Fulton County, Georgia, and in Idaho failed to get off the ground. Things only got worse when the Tacoma News Tribune revealed that several county officials who had gotten behind the program also owned Hythiam stock.

Small rural communities that have felt the impact of meth sales and production in their communities are looking for help, and represent a significant market for an anti-addiction medication. However, in the case of Prometa, “The marketing is way ahead of the science,” claimed Lori Karan of the Drug Dependence Research Laboratory at the University of California-San Francisco.

Double-blind studies of Prometa are underway at the University of California-Los Angeles and at the University of South Carolina.