Category: Cocaine

Cigarettes and alcohol serve as gateway drugs, which people use before progressing to the use of marijuana and then to cocaine and other illicit substances; this progression is called the "gateway sequence" of drug use. An article in Science Translational Medicine by study author Denise Kandel, PhD, of the Mailman School of Public Health; and Amir Levine, MD; Eric Kandel, MD; and colleagues at Columbia University Medical Center provides the first molecular explanation for the gateway sequence. They show that nicotine causes specific changes in the brain that make it more vulnerable to cocaine addiction — a discovery made by using a novel mouse model.

Alternate orders of exposure to nicotine and cocaine were examined. The authors found that pretreatment with nicotine greatly alters the response to cocaine in terms of addiction-related behavior and synaptic plasticity (changes in synaptic strength) in the striatum, a brain region critical for addiction-related rewards. On a molecular level, nicotine also primes the response to cocaine by inhibiting the activity of an enzyme―histone deacetylase―in the striatum. This inhibition enhances cocaine's ability to activate a gene called FosB gene, which promotes addiction.

The relationship between nicotine and cocaine was found to be unidirectional: nicotine dramatically enhances the response to cocaine, but there is no effect of cocaine on the response to nicotine. Nicotine's ability to inhibit histone deacetylase thus provides a molecular mechanism for the gateway sequence of drug use.

Nicotine enhances the effects of cocaine only when it is administered for several days prior to cocaine treatment and is given concurrently with cocaine. These findings stimulated a new analysis of human epidemiological data, which shows that the majority of cocaine users start using cocaine only after they have begun to smoke and while they are still active smokers. People who begin using cocaine after they've started smoking have an increased risk of cocaine dependency, compared with people who use cocaine first and then take up smoking.

"These studies raise interesting questions that can now be further explored further in animal models," said Dr. Kandel, a professor of Sociomedical Sciences at the Mailman School. "Do alcohol and marijuana — the two other gateway drugs — prime the brain by the same mechanism as nicotine? Is there a single mechanism for all gateway sequences, or does each sequence utilize a distinct mechanism?"

The results also emphasize the need for developing effective public health prevention programs encompassing all nicotine products, especially those targeted toward young people. Effective interventions not only would prevent smoking and its negative health consequences but could also decrease the risk of progression to chronic use of illicit drugs.

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Journal Reference:

1. A. Levine, Y. Huang, B. Drisaldi, E. A. Griffin, D. D. Pollak, S. Xu, D. Yin, C. Schaffran, D. B. Kandel, E. R. Kandel. Molecular Mechanism for a Gateway Drug: Epigenetic Changes Initiated by Nicotine Prime Gene Expression by Cocaine. Science Translational Medicine, 2011; 3 (107): 107ra109 DOI: 10.1126/scitranslmed.3003062

 A landmark study in mice identifies a biological mechanism that could help explain how tobacco products could act as gateway drugs, increasing a person's future likelihood of abusing cocaine and perhaps other drugs as well, according to the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health. The study is the first to show that nicotine might prime the brain to enhance the behavioral effects of cocaine.

The gateway drug model is based upon epidemiological evidence that most illicit drug users report use of tobacco products or alcohol prior to illicit drug use. This model has generated significant controversy over the years, mostly relating to whether prior drug exposure (to nicotine, alcohol or marijuana) is causally related to later drug use. Before now, studies have not been able to show a biological mechanism by which nicotine exposure could increase vulnerability to illicit drug use.

In the current study, by researchers at Columbia University, New York City, and published in Science Translational Medicine, mice exposed to nicotine in their drinking water for at least seven days showed an increased response to cocaine. This priming effect depended on a previously unrecognized effect of nicotine on gene expression, in which nicotine changes the structure of the tightly packaged DNA molecule, reprograms the expression pattern of specific genes, in particular the FosB gene that has been related to addiction, and ultimately alters the behavioral response to cocaine.

To examine whether the results from this study paralleled findings in humans, the researchers reexamined statistics from the 2003 National Epidemiological Study of Alcohol Related Consequences to explore the relationship between onset of nicotine use and degree of cocaine dependence. They found that the rate of cocaine dependence was higher among cocaine users who smoked prior to starting cocaine compared to those who tried cocaine prior to smoking.

These findings in mice suggest that if nicotine has similar effects in humans, effective smoking prevention efforts would not only prevent the negative health consequences associated with smoking but could also decrease the risk of progression and addiction to cocaine and possibly other illicit drug use. In the meantime, this mouse model provides a new mechanism to study the gateway theory from a biological perspective.

"Now that we have a mouse model of the actions of nicotine as a gateway drug this will allow us to explore the molecular mechanisms by which alcohol and marijuana might act as gateway drugs," said Eric Kandel, M.D., of Columbia University Medical Center and a senior author of the study. "In particular, we would be interested in knowing if there is a single, common mechanism for all gateway drugs or if each drug utilizes a distinct mechanism."

For more information on nicotine and cocaine, go to www.drugabuse.gov/drugpages/nicotine.html and www.drugabuse.gov/drugpages/cocaine.html.

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Journal References:

1. Amir Levine, Yanyou Huang, Bettina Drisaldi, Edmund A. Griffin, Jr., Daniela D. Pollak, Shiqin Xu, Deqi Yin, Christine Schaffran, Denise B. Kandel, Eric R. Kandel. Molecular Mechanism for a Gateway Drug: Epigenetic Changes Initiated by Nicotine Prime Gene Expression by Cocaine. Science Translational Medicine, 2011; 3 (107): 107ra109 DOI: 10.1126/scitranslmed.3003062
2. Nora D. Volkow. Epigenetics of Nicotine: Another Nail in the Coughing. Science Translational Medicine, 2011; 3 (107): 107ps43 DOI: 10.1126/scitranslmed.3003278

Parents of young caffeine consumers take heed: that high-calorie energy drink or soda might present more than just obesity risk. In fact, according to a double-blind, placebo-controlled study that examined responses to stimulants, an individual's subjective response to caffeine may predict how he or she will respond to other stimulant drugs, possibly reflecting differences in risk for abuse of other more serious drugs of abuse, such as amphetamine and cocaine.

The new findings are reported in the November issue of the journal Drug and Alcohol Dependence by Stacey Sigmon, Ph.D., associate professor of psychiatry at the University of Vermont College of Medicine, a drug abuse researcher whose previous studies have looked at caffeine withdrawal and interactions between psychomotor stimulants and cigarette smoking.

"People differ dramatically in how they respond to drugs," says Sigmon. "For example, a single dose of a drug can produce completely opposite effects in two people, with one absolutely loving and the other hating the drug's effects. It is important to improve our understanding of these differences, as they may reflect key individual differences in vulnerability or resilience for drug abuse," adds Sigmon, who, with colleagues from Johns Hopkins University, examined how individual differences in response to caffeine might predict a person's subsequent response to d-amphetamine, a classic psychomotor stimulant with similar effects to other commonly-abused stimulants like cocaine.

Sigmon and coauthor Roland Griffiths, Ph.D., professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine, first employed a choice procedure to identify participants as caffeine "Choosers" and "Nonchoosers" for the study. Choosers were those who chose caffeine over placebo in the majority (>/= 7) of 10 choice session and Nonchoosers chose placebo over caffeine in the majority of choice sessions. There were no significant differences regarding pre-study caffeine intake or other characteristics between the two groups. During the second phase of the study, all participants received various doses of d-amphetamine and rated how much they liked or disliked each dose. The researchers found that caffeine Choosers reported significantly more positive subjective effects and fewer negative/unpleasant effects of d-amphetamine compared to Nonchoosers, particularly at the highest doses. On the other hand, caffeine Nonchoosers reporter fewer positive effects and more unpleasant effects of d-amphetamine compared to Choosers.

According to Sigmon and Griffiths, the study is the first to demonstrate that caffeine reinforcement prospectively predicts the positive subjective effects of another drug.

"While these data do not mean that every coffee lover is at risk for proceeding to cocaine abuse," says Sigmon, "this study does show that individuals vary markedly in their subjective and behavioral response to psychomotor stimulants, and those for whom a modest caffeine dose serves as a reinforcer are the same folks who subsequently report more positive subjective effects of d-amphetamine. Future research will be important to examine whether caffeine reinforcement predicts vulnerability to reinforcement and abuse of classic psychomotor stimulants such as amphetamine and cocaine."

A total of 22 participants completed the study, which took place over a 10- to 14-week timeframe and was supported by funding from the National Institute on Drug Abuse.

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Journal Reference:

1. Stacey C. Sigmon, Roland R. Griffiths. Caffeine choice prospectively predicts positive subjective effects of caffeine and d-amphetamine. Drug and Alcohol Dependence, 2011; DOI: 10.1016/j.drugalcdep.2011.04.018

When a research team asked cocaine addicts to choose, hypothetically, between money now or cocaine of greater value later, "preference was almost exclusively for the money now," said Warren K., Bickel, professor in the Virginia Tech Carilion Research Institute, director of the Advanced Recovery Research Center, and professor of psychology in the College of Science at Virginia Tech. This result is significantly different from previous studies where a subject chooses between some money now or more money later.

Hollywood portrays cocaine addicts as people who will do anything to get their drug and cocaine as the most strongly valued commodity in an addict's life. But research led by Bickel suggests a revision of that view– cocaine is strongly valued only when it is immediately available. "When it is available later, it is not worth very much," he said.

The finding is good news for developing drug treatment programs based on incentives for delaying drug use, he said.

Research has demonstrated that addicts — whether, smokers, drinkers, gamblers, or overeaters — do tend to prefer the near-term reward. Such findings have provided insights into understanding addiction and the challenges for treatments that promise long-range benefits.

But most of the past research has been done with a single commodity — such as money. "In real life, important choices for those with addiction depend on making decisions across commodities, such as cigarettes now or money later," said Bickel. His research team examined how the type of commodity and timing of a reward impacted decision making by cocaine addicts. They asked addicts to decide between cocaine now vs. more cocaine later; money now vs. more money later; cocaine now vs. money later; and money now vs. cocaine later.

Participants were 47 cocaine addicts, by criteria of the American Psychiatric Association, who were seeking treatment. They averaged in their early 40s, with 12 years of education, and a median income of $7,000. Each was asked to estimate the number of grams of cocaine worth $1,000 and the experiments were based on that value. The initial amount offered for the immediate choice has half of the full value; the delayed amount was always the full value. If the choice was money now versus cocaine later, the immediate reward was $500 and the future reward was $1,000 worth of cocaine.

When the participant chose one of the options, the immediate value was adjusted in the next trial up or down by half. If the participant chose the immediate reward, its value dropped by half for the next question. If he chose the future reward, its value increased by 50 percent, but delivery was further in the future. Participants made a choice between immediate and delayed rewards for each of seven delay periods — one day, one week, one month, six months, one year, five years, and 25 years.

Findings for money now versus money later and cocaine now versus cocaine later replicated previous studies with single commodities. The mixed commodity conditions are novel to this study. In the money now-cocaine later choices, "participants soon became indifferent to future cocaine amounts, preferring immediate money even when the value of the future cocaine was significantly greater. That is, cocaine is discounted more steeply than money," said Bickel.

However, when the immediate reward was the drug and the future reward was money, the decline was less steep. "It took longer for the future money to lose favor compared to a lesser value of cocaine," said Bickel. Discounting rates for cocaine now versus money later were not much different than the single commodity results.

Reflecting on the implications for drug treatment programs, Bickel pointed out, "We showed that a delayed drug is discounted more than when the drug is immediately available, no matter what the other option is. In other words, drug users are less likely to use drugs when the choice to use is presented only as a future outcome rather than an immediately available one. For treatment programs for which abstinence is reinforced immediately and drug consumption is available only after a delay, the incentive to abstain may outweigh future drug consumption." 

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Journal Reference:

1. Warren K. Bickel, Reid D. Landes, Darren R. Christensen, Lisa Jackson, Bryan A. Jones, Zeb Kurth-Nelson, A. David Redish. Single- and cross-commodity discounting among cocaine addicts: the commodity and its temporal location determine discounting rate. Psychopharmacology, 2011; DOI: 10.1007/s00213-011-2272-x

While some pain killers need to be injected into the damaged tissue in order to work, topical anesthetics only need to be spread on the surface. The earliest examples of "topical" anesthetics contained cocaine, but now a new systematic review has shown that newer agents that don't contain cocaine can effectively treat pain caused by torn skin. This makes these pain killers an attractive choice for doctors who need to sew-up a patient's skin wound.

This finding was reached after a team of Cochrane researchers analyzed data from 32 randomized control trials that together involved 3128 patients.

Wiping or placing an anesthetic cream, gel or patch onto damage skin can be easier to perform and less painful to the patient than injecting a pain killer through a needle. The first versions of this form of pain killer used cocaine. That, however, makes the pain killer difficult to use in practice, because there are concerns over possible harms and in many countries cocaine use is tightly controlled. Consequently the pharmaceutical industry has produced a range of non-cocaine topical anesthetics.

"The research clearly showed that cocaine-free topical anesthetics can substantially reduce pain without triggering serious side effects," says the study's lead researcher Anthony Eidelman, who works at the Olathe Medical Center in Kansas. He adds that because the trials varied widely in the ways that they were performed and the ways that pain was measured, his team was unable to draw any more detailed conclusions.

"We need to encourage people to do more research using non-cocaine topical anesthetics, but this time perform the research in ways that are sufficiently rigorous. These agents look promising at the moment, but it would be great to confirm their value with high-quality research," says Eidelman.

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Journal Reference:

1. Anthony Eidelman, Jocelyn M Weiss, Cristy L Baldwin, Ikay K Enu, Ewan D McNicol, Daniel B Carr. Topical anaesthetics for repair of dermal laceration. , DOI: 10.1002/14651858.CD005364.pub2

 Researchers at The Scripps Research Institute have developed a highly successful vaccine against a heroin high and have proven its therapeutic potential in animal models.

The new study, published recently online ahead of print by the American Chemical Society's Journal of Medicinal Chemistry, demonstrates how a novel vaccine produces antibodies (a kind of immune molecule) that stop not only heroin but also other psychoactive compounds metabolized from heroin from reaching the brain to produce euphoric effects.

"In my 25 years of making drug-of-abuse vaccines, I haven't seen such a strong immune response as I have with what we term a dynamic anti-heroin vaccine," said the study's principal investigator, Kim D. Janda, the Ely R. Callaway, Jr. Chair in Chemistry and a member of The Skaggs Institute for Chemical Biology at Scripps Research. "It is just extremely effective. The hope is that such a protective vaccine will be an effective therapeutic option for those trying to break their addiction to heroin."

"We saw a very robust and specific response from this heroin vaccine," said George F. Koob, chair of the Scripps Research Committee on the Neurobiology of Addictive Disorders and a co-author of the new study. "I think a humanized version could be of real help to those who need and want it."

A Worldwide Epidemic

While injection drug abuse is a debilitating worldwide epidemic, heroin abuse and addiction are especially destructive, with costs estimated at $22 billion in the United States due to loss of productivity, criminal activity, medical care, and social welfare, the authors say in their study.

Heroin abuse and addiction are also driving forces in the spread of HIV through needle sharing.

Using an approach termed "immunopharmacotherapy," Janda and his Scripps Research colleagues previously created vaccines that used immune molecules to blunt the effects of other abused drugs such as cocaine, methamphetamine, and nicotine. Human clinical trials are under way for the cocaine and nicotine vaccines.

Attempts by other researchers over the past four decades to create a clinically viable heroin vaccine, however, have fallen short, in part due to the fact that heroin is an elusive target metabolized into multiple substances each producing psychoactive effects.

An Innovative Approach

To overcome this problem, in the new study the Scripps Research team used a "dynamic" approach, targeting not only heroin itself, but also the chemical it quickly degrades into, 6-acetylmorphine (6AM), and morphine.

"Heroin is lipophilic and is rapidly degraded to 6AM," said G. Neil Stowe, a research associate in Janda's laboratory who is first author of the new study. "Both readily cross the blood-brain barrier and gain access to the opioid receptors in the brain."

The researchers linked a heroin-like hapten (a small molecule that elicits an immune response) to a generic carrier protein called keyhole limpet hemocyanin or KLH, and mixed it with Alum, an adjuvant (vaccine additive), to create a vaccine "cocktail." This mixture slowly degraded in the body, exposing the immune system to different psychoactive metabolites of heroin such as 6AM and morphine.

"Critically, the vaccine produces antibodies to a constantly changing drug target," said Stowe. "Such an approach has never before been engaged with drug-of-abuse vaccines."

To compare the results of a non-dynamic approach, the team also prepared a vaccine simply targeting morphine, a substance related to heroin. Both vaccines were then injected into rats and the effects were examined in Koob's laboratory.

Promising Results

The results showed that the rats rapidly generated robust polyclonal antibodies in response to the dynamic heroin vaccine.

In addition, the study found that addicted rats were less likely to "self-administer" heroin by pressing on a lever after several booster shots of the vaccine. Only three of the seven rats that received the heroin vaccine self-administered heroin. In contrast, all of the control rats, including those given the morphine vaccine, self-administered the drug.

The effect of the heroin vaccine "was very dramatic; as dramatic as we have ever seen in experiments of this kind," said Koob. "To have an animal vaccinated and not show a response to heroin is pretty amazing."

The team also found that the heroin vaccine was highly specific, meaning that it only produced an antibody response to heroin and 6AM, and not to the other opioid-related drugs tested, such as oxycodone as well as drugs used for opioid dependence — methadone, naltrexone, and naloxone. "The importance of this," said Janda, "is that it indicates these vaccines could be used in combination with other heroin rehabilitation therapies."

The Scripps Research team has recently begun an exciting collaboration with researchers at the Walter Reed Army Institute of Research to see if it is feasible to develop a dual-purpose vaccine against HIV and for the treatment of heroin addiction in a single shot, Janda said.

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Journal Reference:

1. G. Neil Stowe, Leandro F. Vendruscolo, Scott Edwards, Joel E. Schlosburg, Kaushik K. Misra, Gery Schulteis, Alexander V. Mayorov, Joseph S. Zakhari, George F. Koob, Kim D. Janda. A Vaccine Strategy that Induces Protective Immunity against Heroin. Journal of Medicinal Chemistry, 2011; 110630091316074 DOI: 10.1021/jm200461m

New discoveries by researchers at the University of Wisconsin-Milwaukee (UWM) offer potential for development of a first-ever pharmacological treatment for cocaine addiction.

A common beta blocker, propranolol, currently used to treat people with hypertension and anxiety, has shown to be effective in preventing the brain from retrieving memories associated with cocaine use in animal-addiction models, according to Devin Mueller, UWM assistant professor of psychology and a co-author with James Otis of the research.

This is the first time that a therapeutic treatment has been shown to block the retrieval of memories associated with drug addiction, a major reason many addicts experience relapse, says Mueller.

The research is published in the August issue of the journal Neuropsychopharmacology.

Cocaine is one of the worst drug addictions to kick, with about 80 percent of those trying to quit experiencing a relapse within six months.

"Right now, there are no FDA-approved medications that are known to successfully treat cocaine abuse," says Mueller, "only those that are used to treat the symptoms of cocaine withdrawal, which are largely ineffective at preventing relapse."

The effects of propranolol were long-lasting and could be permanent, he says, even without subsequent doses and even in the presence of stimuli known to induce relapse.

Currently, "exposure therapy" is used to help recovering addicts suppress their drug-seeking behavior. In this therapy, the patient is repeatedly exposed to stimuli that provoke cravings but do not satisfy them. Done repeatedly over time, the patient experiences less craving when presented with those stimuli.

The success of exposure therapy, however, is limited. Combining therapy with the use of propranolol, says Mueller, would boost the effectiveness of the treatment.

Propranolol was chosen for the memory study because it has been used before to ease some withdrawal symptoms experienced by recovering cocaine addicts. Those using the drug were able to continue exposure therapy for longer periods than those without the drug.

But Mueller adds that propranolol has never been tested for use with memory extinction before.

In order to develop a drug treatment for overcoming relapse, the next step in the research is to determine where in the brain propranolol acts to mediate the retrieval of cocaine-associated memories.

The study was funded by the National Institute on Drug Abuse, one of the National Institutes of Health, and by the UWM Research Growth Initiative.

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Journal Reference:

1. James M Otis, Devin Mueller. Inhibition of β-Adrenergic Receptors Induces a Persistent Deficit in Retrieval of a Cocaine-Associated Memory Providing Protection against Reinstatement. Neuropsychopharmacology, 2011; 36 (9): 1912 DOI: 10.1038/npp.2011.77

— If the obvious reasons for avoiding recreational drug use aren't off-putting enough, physicians have yet another detrimental consequence to add to the list — crusty, purplish areas of dead skin that are extremely painful and can open the door to nasty infections.

The condition is called purpura. Typical causes include a range of rare disorders, but it is also associated with the use of cocaine. Not just any cocaine, though: Physicians, researchers and health officials believe cocaine contaminated with a de-worming drug commonly used by veterinarians is the culprit. The drug, called levamisole, was found in 30 percent of confiscated cocaine in 2008 and 70 percent in 2009, according to the U.S. Drug Enforcement Administration.

In the Journal of the American Academy of Dermatology, physicians highlight six new and very similar patient cases of purpura, mostly on and around the ears, following cocaine use. The cases — four seen in Rochester, N.Y., and two in Los Angeles — closely resemble two additional cases in San Francisco that were reported previously in the journal. In each case an extensive battery of blood tests ruled out the usual causes of purpura.

The cases were reported by the University of Rochester Medical Center and the University of California, Los Angeles.

Because testing for traces of levamisole in the blood is complex and unreliable, researchers cannot say for sure that it is the direct cause of purpura in these instances. But, due to the striking similarity of these cases, and the presence of another condition caused by levamisole called agranulocytosis — low blood counts that up the risk of infection — in the majority of the patients, doctors say there is strong reason to suspect the drug and to focus greater attention on what could become a widespread health concern.

"We believe these cases of skin reactions and illnesses linked to contaminated cocaine are just the tip of the iceberg in a looming public health problem posed by levamisole," said the study authors.

According to Mary Gail Mercurio, M.D., an author and associate professor in the Department of Dermatology at the University of Rochester Medical Center, "When we first started seeing these patients they all had a similar clinical picture, but they were really an enigma because they weren't falling into any other pattern we'd seen before. When a colleague at the National Institutes of Health mentioned levamisole contamination, we did toxicity screens and lo-and-behold, all the patients came up positive for cocaine. We had our diagnosis."

Drug enforcement officials have detected levamisole — which was once used to treat colon cancer — in cocaine since 2003, but have watched it increase rapidly in recent years. The Drug Enforcement Administration says that the drug, which is inexpensive, is used more and more as a diluting agent in order to stretch supplies. Study authors report that levamisole is known to increase dopamine, a neurotransmitter that helps control the brain's reward and pleasure centers, causing experts to believe it is also added to cocaine to further enhance or prolong the user's high.

Researchers don't know how levamisole causes purpura, which occurs when vessels become plugged and blood can't flow to the skin, leading to skin death and the resulting purplish, crusty appearance. Cocaine alone constricts blood vessels, which is probably the first step, but how levamisole contributes is not yet understood, Mercurio said.

Both smoking and snorting tainted cocaine can lead to purpura and both men and women can be affected. Treatment options include steroids to prevent inflammation, but stopping the exposure to cocaine is the best medicine: Mercurio and the other study authors observed that once patients stopped using cocaine, the purpura and low blood counts improved.

"We've seen a lot of cases in Rochester alone, so it is important to alert the gatekeepers of medicine, the primary care physicians who are in the trenches every day, of this diagnosis," said Mercurio. "This is one of those entities that with familiarity and recognition can go a long way in helping physicians to quickly make a diagnosis and intervene without embarking on an elaborate workup where nothing will pan out."

In addition to Mercurio, Catherine Chung, M.D., a resident in the Department of Dermatology at the Medical Center, also contributed to the research. Ghinwa K. Dumyati, M.D., associate professor in the Department of Medicine, identified two of the four patients from Rochester, and these patients were recently discussed in the internal medicine literature. From the University of California Los Angeles, Paul C. Tumeh, M.D., Ron Birnbaum, M.D., Belinda H. Tan, M.D., Ph.D., Linda Sharp, M.D., Erin McCoy, M.D., and Noah Craft, M.D., Ph.D., also participated.

It's well known that drunk driving can have fatal consequences, but a new study suggests that alcohol is not the only drug that's a danger on the road.

It might make sense that drugs like marijuana or amphetamines would impair drivers and lead to crashes. But few studies have actually looked specifically at the impact of other drugs on traffic deaths — even as there is an increasing push to pass "drugged driving" laws nationally. In the new study, reported in the July issue of the Journal of Studies on Alcohol and Drugs, researchers found that of U.S. drivers who died in a crash, about 25% tested positive for drugs. The most common drugs were marijuana and stimulants, including cocaine and amphetamines, which each accounted for almost one quarter of the positive tests.

It's not clear whether the drugs were to blame for the crashes, the researchers say. Some people who use illegal drugs may simply be reckless drivers in general, for instance.

On the other hand, a recent government study found that of U.S. drivers who were randomly pulled over, 14% tested positive for drugs. The fact that drug use was almost twice as high among drivers in fatal crashes suggests that drugs do contribute to road deaths.

"The suspicion is there, because when you look at drivers who've been in fatal crashes, the percentage using drugs is a good deal higher," said study co-author Robert B. Voas, Ph.D., of the Pacific Institute for Research and Evaluation in Calverton, Maryland.

For the general public, the message is simple.

"Don't drink or don't consume drugs when you're going to drive," said Eduardo Romano, Ph.D., the lead author on the study.

The issue is more complicated, though, when it comes to lawmaking, according to the researchers.

With alcohol, drivers' blood levels can be easily tested, and because studies have found that levels above a certain limit — .08% — impair driving, that blood alcohol concentration is the legal limit in all U.S. states. With other drugs, however, there are no agreed-upon levels that impair driving, and testing drivers is not straightforward. For one, certain drugs can linger in the body for days or weeks after they are used. Right now, states differ in how they tackle drugged driving. More than a dozen have drugged-driving "per se" laws. In most states, that means "zero tolerance" for any detectable amount of certain drugs in a driver's blood or urine. The specific drugs that are prohibited vary by state.

Last year, the White House announced that it would be encouraging more states to adopt drugged-driving per se laws.

So it is important, Romano and Voas say, for researchers to keep studying how various drugs might impair drivers.

The current findings are based on a government reporting system that collects data on all U.S. traffic deaths. All states report drivers' blood alcohol levels, whereas 20 test for drugs.

Between 1998 and 2009, there were more than 44,000 fatally injured drivers with drug-test information — one quarter of whom tested positive for drugs. Marijuana and stimulant drugs including cocaine and methamphetamine were the most commonly implicated.

It turned it out that stimulants were linked to all types of crash fatalities — whether from speeding, failure to obey other traffic laws, inattention, or forgoing seatbelts. Marijuana, on the other hand, was tied only to speeding and seatbelt non-use. That lays out the possibility that stimulants are particularly impairing, but that's not yet clear, the researchers say.

Whatever the effects of different drugs, alcohol still appears to be the biggest roadway hazard.

This study found that, in general, other drugs seemed to be key only when drivers had not been drinking as well. That is, when someone drinks and does drugs, the alcohol is the main reason for impaired driving.

"Alcohol is still the largest contributor to fatal crashes," Romano said.

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Journal Reference:

1. Eduardo Romano, Robert B. Voas. Drug and Alcohol Involvement in Four Types of Fatal Crashes. Journal of Studies on Alcohol and Drugs, 2011; 

Researchers at the University of Cambridge have identified abnormal brain structures in the frontal lobe of cocaine users' brains which are linked to their compulsive cocaine-using behaviour.

Their findings were published June 21, in the journal Brain.

Led by Dr Karen Ersche, the Cambridge researchers scanned the brains of 120 people, half of whom had a dependence on cocaine. They found that the cocaine users had widespread loss of grey matter that was directly related to the duration of their cocaine abuse (i.e. the longer they had been using cocaine, the greater the loss of grey matter), and that this reduction in volume was associated with greater compulsivity to take cocaine.

The scientists also found that parts of the brain reward system where cocaine exerts its actions (the basal ganglia) were significantly enlarged in cocaine users; but the size of the enlargement was not related to the duration of cocaine use. The researchers believe this may suggest that alterations in the brain's reward system predate cocaine abuse, possibly rendering these individuals more vulnerable to the effects of the drug.

Dr Ersche, of the Behavioural and Clinical Neuroscience Institute (BCNI) at the University of Cambridge, said: "This research gives us important insight into why some people are more vulnerable to drug addiction. Not only is this important for the future development of more effective therapeutic interventions for people who have become dependent on drugs, it will also inform improved strategies to prevent drug addiction in the first place."

Cocaine, one of the most addictive drugs on the illicit drug market, exerts its effects on the brain by changing the way a person thinks and feels. People addicted to cocaine feel an overwhelming, uncontrollable need for the drug, even in the face of aversive consequences.

Dr Ersche added: "People with cocaine dependence describe their out-of-control drug use as a 'compulsion' to use cocaine. Our current work has laid the foundation for a better understanding of cocaine dependence and why this compulsion occurs."

The researchers also showed that changes in other brain structures of chronic cocaine users were linked to debilitating attention problems.

Dr Ersche added: "Our findings are important because they show a clear relationship between the brain, the duration of cocaine use and some of the common attention problems that people with cocaine dependence report. These data show that cocaine dependence is a disorder of the brain, which is very relevant information for the treatment of people who are trying to beat their addiction."

The researchers will next explore whether there is an inherited vulnerability to develop cocaine dependence. Although cocaine is a highly addictive drug, not everyone who uses develops an addiction. They will research whether people with an enlarged brain reward system are more at risk of becoming dependent on cocaine as well as what the effects of recreational cocaine use has on the brain.

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Journal Reference:

1. KD Ersche, A Barnes, PS Jones, S Morein-Zamir, TW Robbins, and ET Bullmore et al. Abnormal structure of frontostriatal brain systems is associated with aspects of impulsivity and compulsivity in cocaine dependence. Brain, 2011