The Losing Battle For Perpetual Reward

Or why you can't stay high forever.

The amphetamine high, like the cocaine high, is a marvel of biochemical efficiency. Stimulants work 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 or speed—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 meth binge. The rapid movements, sniffing, and sudden rearing at minor stimuli are not that much different in principle from the outward signs of meth intoxication among higher primates.

Chemically, cocaine and amphetamine are very different compounds. Psychoactively, however, they are very much alike. Of all the addictive drugs, smoked cocaine and speed have the most direct and most devastatingly euphoric effect on the dopamine systems of the brain. 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.

In clinical settings, cocaine users have a hard time distinguishing between equal doses of cocaine and Dexedrine, administered intravenously. As we know, it is the shape of the molecule that counts. The amphetamines are shaped like dopamine and norepinephrine, two of the three reward chemicals. Speed, then, is well suited to the task of artificially stimulating the limbic reward pathway. Molecules of amphetamine displace dopamine and norepinephrine in the storage vesicles, squeezing those two neurotransmitters into the synaptic gap and keeping them there. By mechanisms less well identified, cocaine accomplishes the same feat. Both drugs also interfere with the return of dopamine, norepinephrine, and serotonin molecules to their storage sacs, a procedure known as reuptake blocking. Cocaine works its effects primarily by blocking the reuptake of dopamine.

Amphetamine was once one of the most widely prescribed drugs in the pharmacological cornucopia. It exists in large part now as a recreational drug of choice, abuse, and addiction. The same is true of cocaine. It was replaced as a dental anesthetic long ago, in favor of non-addictive variants like Novocain. The same tragic list of statistical side effects that apply to abusers of alcohol, heroin and nicotine also apply to stimulant abusers: Increased risk of car accidents, homicides, heart attack, and strokes.

In the late 1990s, scientists at Johns Hopkins and NIDA showed 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. It is also easy to understand the typical symptoms of cocaine and amphetamine withdrawal: lethargy, depression, anger, and a heightened perception of pain. 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.

With the arrival of smokable forms of cocaine and amphetamine, the race to pin down the biology of stimulation became even more urgent. Stimulants in smokable form—crack and ice—are even more rapidly addictive for addiction-prone users. “The reason has to do with the hydraulics of the blood supply,” a researcher at the University of Minnesota explained to me. “High concentrations are achieved with each inhalation, and sent right upstairs to the brain—but not all of the brain simultaneously. The target of the flow of blood is the limbic system, whereas the remainder of the brain is exposed to much milder concentrations.”

This extraordinarily concentrated jolt to the reward center is the reason why smokable cocaine and speed are able to pack such a wallop. The entire range of stimulative effects hits the ventral tegmental area and associated reward regions of the brain in seconds, and the focused nature of the impact yields an astonishingly pleasurable high.

But the long-term result is exactly the opposite. It may sound dour and religious, but the scientific fact of the matter is that continuous chemical pleasure extracts its fee in the end: The body’s natural stock of these neurotransmitters starts to fall as the brain, striving to compensate for the artificial flooding of the reward center, orders a general cutback in production. At the same time, the receptors for these neurotransmitters become excessively sensitive due to the frequent, often unremitting nature of the stimulation.

“It’s clear that cocaine causes depletion of dopamine, norepinephrine, serotonin—it is a general neurotransmitter depleter,” said my research source. “That may account for many of the effects we see after someone has stopped using cocaine. They’re tired, they’re lethargic, they sleep; they may be depressed, moody, and so on.” Continued abuse of stimulant drugs only makes the problem worse. One reason why cocaine and amphetamine addicts will continue to use, even in the face of rapidly diminishing returns, is simply to avoid the crushing onset of withdrawal. Even though the drugs may no longer be working as well as they once did, the alternative—the psychological cost of withdrawal—is even worse. In the jargon used by Alcoholics Anonymous, addicts generally have to get worse before they can get better.

When addicts talk about “chasing a high,” the metaphor can be extended to the losing battle of neurotransmitter levels.

[First published September 28, 2011]

Graphics Credit: http://www.keepcalm-o-matic.co.uk

Hunting For the Marijuana-Dopamine Connection

Why do heavy pot smokers show a blunted reaction to stimulants?

Most drugs of abuse increase dopamine transmission in the brain, and indeed, this is thought to be the basic neural mechanism underlying the rewarding effects of addictive drugs. But in the case of marijuana, the dopamine connection is not so clear-cut. Evidence has been found both for and against the notion of increases in dopamine signaling during marijuana intoxication.

Marijuana has always been the odd duck in the pond, research-wise. Partly this is due to longstanding federal intransigence toward cannabis research, and partly it is because cannabis, chemically speaking, is damnably complicated. The question of marijuana’s effect on dopamine transmission came under strong scrutiny a few years ago, when UK researchers began beating the drums for a theory that chronic consumption of strong cannabis can not only trigger episodes of psychosis, but can be viewed as the actual cause of schizophrenia in some cases.

It sounded like a new version of the old reefer madness, but this time around, the researchers raising their eyebrows had a new fact at hand: Modern marijuana is several times stronger than marijuana in use decades ago. Selective breeding for high THC content has produced some truly formidable strains of pot, even if cooler heads have slowly prevailed on the schizophrenia issue.

One of the reports helping to bank the fires on this notion appeared recently in the Proceedings of the National Academy of Sciences (PNAS). Joanna S. Fowler of the Biosciences Department at Brookhaven National Laboratory, Director Nora Volkow of the National Institute on Drug Abuse (NIDA), and other researchers compared brain dopamine reactivity in healthy controls and heavy marijuana users, using PET scans. For measuring dopamine reactivity, the researchers chose methylphenidate, better known as Ritalin, the psychostimulant frequently prescribed for attention-deficit hyperactivity disorder (ADHD). Ritalin basically functions as a dopamine reuptake inhibitor, meaning that the use of Ritalin leads to increased concentrations of synaptic dopamine.

In the study, heavy marijuana users showed a blunted reaction to the stimulant Ritalin due to reductions in brain dopamine release, according to the research. “The potency of methylphenidate (MP) was also reported to be stronger by the controls than by the marijuana abusers." And in marijuana abusers, Ritalin caused an increase in craving for marijuana and cigarettes.

 “We found that marijuana abusers display attenuated dopamine responses to MP including reduced decreases in striatal distribution volumes,” according to the study’s conclusion. “The significantly attenuated behavioral and striatal distribution volumes response to MP in marijuana abusers compared to controls, indicates reduced brain reactivity to dopamine stimulation that in the ventral striatum might contribute to negative emotionality and drug craving.”

Down-regulation from extended abuse is another complicated aspect of this: “Although, to our knowledge, this is the first clinical report of an attenuation of the effects of MP in marijuana abusers, a preclinical study had reported that rats treated chronically with THC exhibited attenuated locomotor responses to amphetamine. Such blunted responses to MP could reflect neuroadaptations from repeated marijuana abuse, such as downregulation of DA transporters.”

 Animal studies have suggested that these dopamine alterations are reversible over time.

Another recent study came to essentially the same conclusions. Writing in Biological Psychiatry, a group of British researchers led by Michael A.P. Bloomfield and Oliver D. Howes analyzed dope smokers who experienced psychotic symptoms when they were intoxicated. They looked for evidence of a link between cannabis use and psychosis and concluded: “These findings indicate that chronic cannabis use is associated with reduced dopamine synthesis capacity and question the hypothesis that cannabis increases the risk of psychotic disorders by inducing the same dopaminergic alterations seen in schizophrenia.” And again, the higher the level of current cannabis use, the lower the level of striatal dopamine synthesis capacity.  As for mechanisms, the investigators ran up against similar causation problems: “One explanation for our findings is that chronic cannabis use is associated with dopaminergic down-regulation. This might underlie amotivation and reduced reward sensitivity in chronic cannabis users. Alternatively, preclinical evidence suggests that low dopamine neurotransmission may predispose an individual to substance use.”

The findings of diminished responses to Ritalin in heavy marijuana users may have clinical implications, suggesting that marijuana abusers with ADHD may experience reduced benefits from stimulant medications.

Photo Credit: http://www.biologicalpsychiatryjournal.com/

The Year in Drugs

Top Posts at Addiction Inbox.

By the look of it, readers had marijuana on their minds in 2012. Of the posts at Addiction Inbox with the highest number of page views, an overwhelming majority are concerned with marijuana, and specifically, with marijuana addiction, withdrawal, and brain chemistry. Of the 9 most heavily trafficked posts of the year, only one involved alcohol. Readers were also interested in the safety of e-cigarettes, and the mysteries of neurotransmitters like serotonin and dopamine. Happily, all the top posts were patently science-oriented articles.

See you in the New Year.

•  Marijuana Withdrawal

For Some Users, Cannabis Can Be Fiercely Addictive.

For a minority of marijuana users, commonly estimated at 10 per cent, the use of pot can become uncontrollable, as with any other addictive drug. Addiction to marijuana is frequently submerged in the welter of polyaddictions common to active addicts. The withdrawal rigors of, say, alcohol or heroin tend to drown out the subtler, more psychological manifestations of cannabis withdrawal.

•  Serotonin and Dopamine: A Primer

The Molecules of Reward

Serotonin and dopamine are part of a group of compounds called biogenic amines. In addition to serotonin and dopamine, the amines include noradrenaline, acetylcholine, and histamine. This class of chemical messengers is produced, in turn, from basic amino acids like tyrosine, tryptophan, and choline.

•  Marijuana Fact and Fiction

Why cannabis research is a good idea.

There is little doubt among responsible researchers that marijuana--although it is addictive for some people--is sometimes a clinically useful drug. However, there is little incentive for commercial pharmaceutical houses to pursue research on the cannabis plant itself, since they cannot patent it.

• Anandamide: The Brain’s Own Marijuana

Anxiety and the THC receptor.

Several years ago, molecular biologists identified the elusive brain receptor where THC, the active ingredient in marijuana, did its work. Shortly after that discovery, researchers at Hebrew University in Jerusalem identified the body’s own form of THC, which sticks to the same receptors, in pulverized pig brains.

•  The Mysteries of the Blunt

Why do so many smokers combine tobacco with marijuana?

People who smoke a combination of tobacco and marijuana, a common practice overseas for years, and increasingly popular here in the form of “blunts,” may be reacting to ResearchBlogging.orgsome unidentified mechanism that links the two drugs. Researchers believe such smokers would be well advised to consider giving up both drugs at once, rather than one at a time, according to an upcoming study in the journal Addiction.

•  Are E-Cigarettes a Good Idea or a Bad Idea?

A group of nicotine researchers argue for an alternative.

Electronic cigarettes are here to stay. If you're not familiar with them, e-cigarettes are designed to look exactly like conventional cigarettes, but they use batteries to convert liquid nicotine into a fine, heated mist that is absorbed by the lungs. Last summer, even though the FDA insisted on referring to e-cigarettes as “untested drug delivery systems,” Dr. Neal Benowitz of the University of California in San Francisco--a prominent nicotine researcher for many years--called e-cigarettes “an advancement that the field has been waiting for.”

•  Cannabis Receptors and the “Runner’s High”

Maybe it isn't endorphins after all.

A perennial favorite, the runner’s high post shows what long-distance running and marijuana smoking have in common. Quite possibly, more than you’d think. A growing body of research suggests that the runner’s high and the cannabis high are more similar than previously imagined….Endocannabinoids—the body’s internal cannabis—“seem to contribute to the motivational aspects of voluntary running in rodents.” Knockout mice lacking the cannabinioid CB1 receptor, it turns out, spend less time wheel running than normal mice. 

• Topamax for Alcoholism: A Closer Look

Epilepsy drug gains ground, draws fire as newest anti-craving pill.

A drug for seizure disorders and migraines continues to show promise as an anti-craving drug for alcoholism, the third leading cause of death in America, the Journal of the American Medical Association (JAMA) reported in its current issue.

•  Is Marijuana Addictive?

The argument continues.

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.


Graphics Credit:  http://1.bp.blogspot.com (Creative Commons)

Reward and Punish: Say Hello to Dopamine’s Leetle Friend

  Dopamine recruits a helper to track drug rewards.

Ah, dopamine. Whenever it seems like researchers have finally gotten a bead on how that tricky molecule modulates pleasure and reward, and the role it plays in the process of drug and alcohol addiction, along come new findings that rearrange its role, deepening and complicating our understanding of brain function.

We know that the ultimate site of dopamine activity caused by drugs is the ventral tegmental area, or VTA, and an associated structure, the nucleus accumbens. But dopamine neurons in the VTA actually perform two distinct functions. They discriminate acutely between the expectation of reward, and the actual reward itself. Pavlov showed how these dual functions are linked, but the manner in which dopamine neurons computed and then dealt with the differences between expectation and reward—a controversial concept known as reward prediction error—was not well understood.

We all know about reward and punishment, however. Years ago, behaviorism’s emphasis on positive and negative reinforcement demonstrated the strong connection between reward, punishment, and learning. As Michael Bozarth wrote in “Pleasure Systems in the Brain,” addictive drugs “pharmacologically activate brain reward mechanisms involved in the control of normal behavior. Thus, addictive drugs may be used as tools to study brain mechanisms involved in normal motivational and reward processes.”

But how does the evolutionary pursuit of pleasure or avoidance of punishment that guarantees the survival of an organism—fighting, fleeing, feeding, and… fornicating, in the well-known “4-F” configuration—become a pathological reversal of this function? To begin with, as Bozarth writes, “the direct chemical activation of these reward pathways does not in itself represent any severe departure from the normal control reward systems exert over behavior…. Simple activation of brain reward systems does not constitute addiction!”

What does, then? Bozarth believes addiction results from “motivational toxicity,” defined as deterioration in the “ability of normal rewards to govern behavior.” In an impaired reward system, “natural” rewards don’t alter dopamine function as strongly as drug rewards. “Direct pharmacological activation of a reward system dominates the organism’s motivational hierarchy at the expense of other rewards that promote survival,” Bozarth writes. The result? Drug addicts who prefer, say, methamphetamine to food.

How does an addict’s mind become so addled that the next hit takes precedence over the next meal? A group of Harvard-based researchers, writing in Nature, thinks it may have a handle on how the brain calculates reward expectations, and how those calculations go awry in the case of heavy drug and alcohol use.

The dopamine system somehow calculates the results of both failed and fulfilled expectations of reward, and uses that data in future situations. Cellular biologists, with some exceptions, believe that dopamine neurons effectively signal some rather complicated discrepancies between expected and actual rewards. Dopaminergic neurons were, in effect, computing reward prediction error, according to the theory. They were encoding expectation, which spiked when the reward was better than expected, and fell when the reward was less than expected. As Scicurious wrote at her blog, Neurotic Physiology “If you can’t predict where and when you’re going to get food, shelter, or sex in response to specific stimuli, you’re going to be a very hungry, chilly and undersexed organism.” (See her excellent and very readable post on dopamine and reward prediction HERE. )

But nobody knew how this calculation was performed at the cellular level.

Enter research mice.

As it turns out, dopamine is not the whole story. (A single neurotransmitter rarely is.) Dopaminergic neurons account for only about 55-65% of total neurons on the VTA. The rest? Mostly neurons for GABA, the inhibitory transmitter. “Many addictive drugs inhibit VTA GABAergic neurons,” the researchers note, “which increases dopamine release (called disinhibition), a potential mechanism for reinforcing the effects of these drugs.” By inhibiting the inhibitor, so to speak, addictive drugs increase the dopamine buzz factor.

The researchers used two strains of genetically altered mice, one optimized for measuring dopamine, the other for measuring GABA. The scientists conditioned mice using odor cues, and offered four possible outcomes: big reward, small reward, nothing, or punishment (puff of air to the animal’s face). Throughout the conditioning and testing, the researchers recorded the activity of neurons in the ventral tegmental area. They found plenty of neurons with atypical firing patterns. These neurons, in response to reward-predicting odors, showed “persistent excitation” during the delay before the reward. Others showed “persistent inhibition” to reward-predicting odors.

It took a good deal of sorting out, and conclusions are still tentative, but eventually the investigators believed that VTA dopamine neurons managed to detect the discrepancy between expected and actual outcomes by recruiting GABA neurons to aid in the dendritic computation. This mechanism may play a critical role in optimal learning, the researchers argue.

Furthermore, the authors believe that “inhibition of GABAergic neurons by addictive drugs could lead to sustained reward prediction error even after the learned effects of drug intake are well established.” Because alcohol and other addictive drugs disrupt GABA levels in the brain’s reward circuitry, the mechanism for evaluating expectation and reward is compromised. GABA, dopamine’s partner in the enterprise, isn’t contributing properly. The ability to learn from experience and to accurately gauge the likelihood of reward, so famously compromised in active addiction, may be the result of this GABA disruption.

Naoshige Uchida, associate professor of molecular and cellular biology at Harvard, and one of the authors of the Nature paper, said in a press release that until now, “no one knew how these GABA neurons were involved in the reward and punishment cycle. What we believe is happening is that they are inhibiting the dopamine neurons, so the two are working together to make the reward error computation.” Apparently, the firing of dopamine neurons in the VTA signals an unexpected reward—but the firing of GABA neurons signals an expected reward. Working together, GABA neurons aid dopamine neurons in calculating reward prediction error.

In other words, if you inhibit GABA neurons through heavy drug use, you screw up a very intricate dopamine feedback loop. When faced with a reward prediction error, such as drug tolerance—a good example of reward not meeting expectations—addicts will continue taking the drug. This seems nonsensical. If the drug no longer works to produce pleasure like it used to do, then why continue to take it? It may be because dopamine-active brain circuits are no longer accurately computing reward prediction errors. Not even close. The research suggests that an addict’s brain no longer registers negative responses to drugs as reward errors. Instead, all that remains is the reinforcing signals from the dopamine neurons: Get more drugs.

[Tip of the hat to Eric Barker (@bakadesuyo) for bringing this study to my attention.]

Cohen, J., Haesler, S., Vong, L., Lowell, B., & Uchida, N. (2012). Neuron-type-specific signals for reward and punishment in the ventral tegmental area Nature DOI: 10.1038/nature10754

Photo Credit: http://www.zazzle.com 

A Few Words About Glutamate

Meet another major player in the biology of addiction.

The workhorse neurotransmitter glutamate, made from glutamine, the brain’s most abundant amino acid, has always been a tempting target for new drug development. Drugs that play off receptors for glutamate are already available, and more are in the pipeline. Drug companies have been working on new glutamate-modulating antianxiety drugs, and a glutamate-active drug called acamprosate, which works by occupying sites on glutamate (NMDA) receptors, has found limited use as a drug for alcohol withdrawal after dozens of clinical trials.

Glutamine detoxifies ammonia and combats hypoglycemia, among other things. It is also involved in carrying messages to brain regions involved with memory and learning. An excess of glutamine can cause neural damage and cell death, and it is a prime culprit in ALS, known as Lou Gehrig’s disease. In sodium salt form, as pictured---> it is monosodium glutamate, a potent food additive. About half of the brain’s neurons are glutamate-generating neurons. Glutamate receptors are dense in the prefrontal cortex, indicating an involvement with higher thought processes like reasoning and risk assessment. Drugs that boost glutamate levels in the brain can cause seizures. Glutamate does most of the damage when people have strokes.

The receptor for glutamate is called the N-methyl-D-aspartate (NMDA) receptor. Unfortunately, NMDA antagonists, which might have proven to be potent anti-craving drugs, cannot be used because they induce psychosis. (Dissociative drugs like PCP and ketamine are glutamate antagonists.) Dextromethorphan, the compound found in cough medicines like Robitussin and Romilar, is also a weak glutamate inhibitor. In overdose, it can induce psychotic states similar to those produced by PCP and ketamine. Ely Lilly and others have looked into glutamate-modulating antianxiety drugs, which might also serve as effective anti-craving medications for abstinent drug and alcohol addicts.

As Jason Socrates Bardi at the Scripps Research Institute writes: "Consumption of even small amounts of alcohol increases the amount of dopamine in the nucleus accumbens area of the brain—one of the so-called ‘reward centers.’ However, it is most likely that the GABA and glutamate receptors in some of the reward centers of the basal forebrain—particularly the nucleus accumbens and the amygdala—create a system of positive reinforcement.”

Glutamate receptors, then, are the “hidden” receptors that compliment dopamine and serotonin to produce the classic “buzz” of alcohol, and to varying degrees, other addictive drugs as well. Glutamate receptors in the hippocampus may also be involved in the memory of the buzz.


Writing in The Scientist in 2002, Tom Hollon made the argument that “glutamate's role in cocaine dependence is even more central than dopamine's.” Knockout mice lacking the glutamate receptor mGluR5, engineered at GlaxoSmithKline, proved indifferent to cocaine in a study published in Nature.

In an article for Neuropsychology in 2009, Peter Kalivas of the Medical University of South Carolina and coworkers further refined the notion of glutamine-related addictive triggers: "Cortico-striatal glutamate transmission has been implicated in both the initiation and expression of addiction related behaviors, such as locomotor sensitization and drug-seeking," Kalivas writes. "While glutamate transmission onto dopamine cells in the ventral tegmental area undergoes transient plasticity important for establishing addiction-related behaviors, glutamatergic plasticity in the nucleus accumbens is critical for the expression of these behaviors."

The same year, in Nature Reviews: Neuroscience, Kalivas laid out his “glutamate homeostasis hypothesis of addiction.”

A failure of the prefrontal cortex to control drug-seeking behaviors can be linked to an enduring imbalance between synaptic and non-synaptic glutamate, termed glutamate homeostasis. The imbalance in glutamate homeostasis engenders changes in neuroplasticity that impair communication between the prefrontal cortex and the nucleus accumbens. Some of these pathological changes are amenable to new glutamate- and neuroplasticity-based pharmacotherapies for treating addiction.

This kind of research has at least a chance of leading in the direction of additional candidates for anti-craving drugs, without which many addicts are never going to successfully treat their disease.


Graphics credit: http://cnunitedasia.en.made-in-china.com/

A Six-Pack of Prior Posts

Don’t fear the chemistry. 

This isn’t a top 10 list, just a compilation of five previous posts here at Addiction Inbox that have continued to draw reader interest since they were first published. If there is a theme running through this set, it is neurochemistry at its most basic level. Take a look, if any of the subjects interests you. (My most popular post of all, on Marijuana Withdrawal, has turned into a self-help message board. I note it here, but leave it off the list, as it has become a blog of its own for all practical purposes.)
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1) Don’t let anyone tell you that the basic notions involved in neurotransmitter action in the brain are over everyone’s head. This post about serotonin and dopamine basics has always been popular, partly because serotonin and dopamine have gone from obscure abstractions to pop buzzwords. But I think it also shows a growing awareness of brain science and its real-world applications among interested readers.

“…. Addictive drugs have molecules that are the right shape for the amine receptors. Drugs like LSD and Ecstasy target serotonin systems. Serotonin systems control feeding and sleeping behaviors in living creatures from slugs to chimps. Serotonin, also known as 5-HT, occurs in nuts, fruit, and snake venom. It is found in the intestinal walls, large blood vessels, and the central nervous system of most vertebrates. The body normally synthesizes 5-hydroxytryptamine, as serotonin is formally known, from tryptophan in the diet….”

Serotonin and Dopamine: A primer on the molecules of reward
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2) Continuing on the chemistry theme, this post on anandamide, the brain’s own form of internal marijuana, has garnered steady attention since 2008. It may be coincidental, but the post also makes mention of serotonin and dopamine.

“…Several years ago, molecular biologists identified the elusive brain receptor where THC, the active ingredient in marijuana, did its work. Shortly after that discovery, researchers at Hebrew University in Jerusalem identified the body’s own form of THC, which sticks to the same receptors, in pulverized pig brains. They christened the internally manufactured substance “anandamide,” after the Sanskrit ananda, or bliss…”

Anandamide, the Brain’s Own Marijuana: Anxiety and the THC receptor.
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3) Interest in the anti-craving drug Topamax, an anti-seizure medication used to treat alcoholism, remains strong with blog readers, although the drug has not become the universal blockbuster many advocates had hoped.

“…Dr. Bankole Johnson, chairman of Psychiatry and Neurobehavioral Sciences at the University of Virginia, told Bloomberg News that Topamax does everything researchers want to see in a pharmaceutical treatment for alcoholism: “First, it reduces your craving for alcohol; second, it reduces the amount of withdrawal symptoms you get when you start reducing alcohol; and third, it reduces the potential for you to relapse after you go down to a low level of drinking or zero drinking…"

Topamax for Alcoholism: A Closer Look. Epilepsy drug gains ground, draws fire as newest anti-craving pill
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4) One of the most popular posts to date was this examination of neurological questions surrounding marijuana and memory loss. Inquiring minds, uh, forget the question. Oh yeah: Does the strain of dope you smoke determine how forgetful you’ll become?

“…As far as memory goes, THC content didn't seem to matter. It was the percentage of cannabidiol (CBD) that controlled the degree of memory impairment, the authors concluded. "The antagonistic effects of cannabidiol at the CB1 receptor are probably responsible for its profile in smoked cannabis, attenuating the memory-impairing effects of THC. In terms of harm reduction, users should be made aware of the higher risk of memory impairment associated with smoking low-cannabidiol strains of cannabis like 'skunk' and encouraged to use strains containing higher levels of cannabidiol..." 


Marijuana and Memory: Do certain strains make you more forgetful?
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5) Finally, a popular post focusing on the biochemistry of nicotine in e-cigarettes, the new, smokeless nicotine delivery system. Are they safe? The latest in harm reduction strategies, or starter kits for youngsters?

“…You may never have heard of it—but it’s the newest drug in town. It’s called an electronic cigarette, or “e-cigarette.” Electronic cigarettes use batteries to convert liquid nicotine into a fine, heated mist that is absorbed by the lungs. No smoke, but plenty of what makes cigarettes go, if you don’t account for taste—or ashtrays and smoke rings….”

E-Cigarettes and Health: Smokeless nicotine comes under scrutiny.

Photo Credit: http://www.livingim.com/

On Chemical Imbalances in the Brain

Maybe it’s not such a bad theory after all.

The brain, as always, bats last. It compensates, reregulates, and adjusts. One of the major ways it accomplishes this is through the neuroadaptive phenomenon called downregulation. When we take drugs continuously, the brain compensates for the artificial flood of, or sensitivity to, serotonin, dopamine, and other neurotransmitters by cutting back on its own production, and the receptors on the cell surfaces ultimately degrade. This is, in fact, what can happen in a case of active addiction, or with the habitual use of any receptor-active drug. The phrase “chemical imbalance,” as a means of describing this process, fell out of favor as soon as Pfizer started using the analogy in its television advertising for zoloft.

Call it a receptor imbalance, then. Call it neuronal dysregulation, if that helps. The concern with downregulation is that, over time, chronic use of serotonin reuptake blockers or dopamine-active drugs of abuse can lead to both a decrease in the number of receptors and a desensitization of existing receptors. The brain does not stay idle during these artificial rains of neurotransmitters. As explained by Peter Kramer in Listening to Prozac: “The chronic, constant, reliable presence of high levels of neurotransmitter causes the cell to downregulate—reducing the number of receptors, by drawing them back into the cell membrane, where they become inactive, or by otherwise uncoupling them from further events.”

The brain adjusts to the constant bombardment of addictive drugs. Downregulation and upregulation are not well understood. If significant downregulation takes place, then conceivably, there could be a rebound effect. Even withdrawal from non-addictive drugs can be difficult and stressful, as the brain upregulates to account for the new biochemical dispensation. Drugs of abuse, and the drugs used against them, share one important trait—they both illustrate the adage that too much of a good thing is a bad thing.

The entire field of addiction medicine has its detractors, of course. In particular, the SSRI medications have been a prominent target since their inception. Dr. Peter Breggen, Dr. Joseph Glenmullen, and other critics have been particularly vocal in their objections to the use of serotonin-active drugs. They argue that psychoactive drugs cause assorted brain dysfunctions, and that such medications do far more harm than good. But these jeremiads aside, there are legitimate issues surrounding the use of many of the receptor-active drugs that addicts and alcoholics may encounter, or may request—whether treatment consists of a formal in-patient clinic or an informal arrangement with a family practitioner. Since addiction and mental illness overlap, a percentage of addicts are likely to encounter antidepressant and other psychoactive drugs during treatment. Drawing on work by Robins, Kessler, and Regier, Dr. Lance Longo, Medical Director of Addiction Psychiatry at Sinai Samaritan Medical Center, wrote as far back as 2001: “Approximately half of individuals with bipolar disorder or schizophrenia and approximately one third of those with panic disorder or major depression have a lifetime substance use disorder. In general, among patients with alcoholism, nearly half have a lifetime history of coexisting mood, anxiety, and/or personality disorders.”

The optimistic view of anti-addiction drugs says that depressive and addictive episodes feed on themselves. The more you get that way, the more you get that way, so if you can somehow give the brain a giant holiday from being serotonin- and dopamine-impaired, it will naturally adjust, compensate, rewire. It will teach itself. It will learn how not to be addicted and depressed all the time. In this view, what the addict/depressive needs is normalcy, a period of feeling better, a chance to sort things out, adjust behavior, become productive, and build confidence. While all of this is happening, under the influence of an antidepressant or an anti-craving drug, the patient learns to experience a different kind of world on a daily, even minute-to-minute basis. Like training wheels, the medications give the brain its first chance in a long time, possibly ever, to operate within the normal parameters of serotonin, dopamine, norepinephrine, and GABA metabolism.

Okay, “chemical imbalance” is a very imprecise description of all this. But branding it as a “myth” has the potential of doing far more damage, by discouraging active addicts from seeking medical treatment.

Adapted from The Chemical Carousel: What Science Tells Us About Beating Addiction by Dirk Hanson.

Graphics Credit: http://bentobjects.blogspot.com/2007/11/slight-chemical-imbalance.html

Gambling and Parkinson’s Disease

An addendum to the previous post.

Today, a group of Australians taking medications for Parkinson's Disease have filed a class action suit against makers of the drugs, according to a report in the Sydney Morning Herald.

 The Australian newspaper said that "The group includes people who sustained losses of hundreds of thousands of dollars and were involved in family breakdowns as a result of compulsive gambling allegedly linked to drugs they took between 1997 and last year. Most of the claimants developed gambling addictions but a few exhibited compulsive sexual behavior such as looking at pornography on the Internet.”

The drugs involved are dopamine agonists Cabaser and Permax. An agonist binds to particular receptor sites and mimics the action of the substance that normally occupies the site.

A study published in the May issue of Archives of Neurology concluded that, “Dopamine agonist treatment in PD (Parkinson's Disease) is associated with 2- to 3.5-fold increased odds of having an ICD (impulse control disorder)."

According to the study, 13% of the patients were adversely affected by the drugs, exhibiting impulse control problems with gambling (5 percent), sexual behavior (3.5 percent), shopping (5.7 percent) and binge eating (4.3 percent).

The case is not without precedent, according to the Herald. In 2008, “a jury in Minnesota awarded $8.2 million to a man who became a compulsive gambler after using Mirapex (made by Boehringer Ingelheim) to treat his Parkinson's disease. Other lawsuits are being considered in Canada, Britain and France.”


Photo Credit: http://gamingzion.com/

Triple Play for Addicts

Why cigarettes, alcohol and gambling are such a perfect fit.

The newer views of addiction as an organic brain disorder cast strong doubt on the longstanding assumption that different kinds of people become addicted to different kinds of drugs. By 1998, the Archives of General Psychiatry had already flatly stated the reverse: “There is no definitive evidence indicating that individuals who habitually and preferentially use one substance are fundamentally different from those who use another.” This quiet but highly influential breakthrough in the addiction paradigm has paid enormous dividends ever since.

From a genetic standpoint, the implication was that an addiction to alcohol, heroin, or speed did not necessarily “breed true.” The sons and daughters of alcoholics could just as easily grow up to be heroin addicts, and vice versa, due to the same brain anomalies.

There are numerous examples at hand. Recovering alcoholics and heroin addicts tend to be notorious chain-smokers, for one. Many prominent nicotine researchers lean toward the theory that those Americans who continue to be hard-core smokers, unwilling or unable to stop, may represent a biological pool of people who are genetically prone to addiction. Alcohol researcher George Vaillant,  who directed the seminal Harvard Medical School longitudinal studies, sees it the same way: “Alcoholism is a major reason that people don’t stop smoking. Those who keep on smoking after age 50 tend to be alcoholics.” 

There you have it. Throw a lasso around America’s cigarette smokers, and you are likely to snare the lion’s share of “drug abusers” and “problem drinkers” as well. This may also explain why there is such a huge overlap between gamblers and alcoholics, and between gambling and cigarette addiction. It is no secret to anyone who has been inside a casino that a striking percentage of the patrons are also smokers and drinkers. If gambling were truly capable of producing the hallmark symptoms of addiction, we would also expect to see such manifestations as continued use despite adverse circumstances, escalating use, and various forms of self-destructive behavior. It depends on whether the dopamine/serotonin patterns produced by addiction, involving midbrain dopamine neurons with divergent connections to the frontal cortex and other forebrain regions, are the same in compulsive gamblers as in alcoholics and other addicts. Many researchers simply do not believe that the alterations in neurotransmission brought about by behaviors are as powerful as the chemical surges produced by drugs, and therefore cannot result in a state technically called addiction. Others disagree.

Nonetheless, human neurostudies continue to show intriguing dopamine patterns during gambling and certain other forms of game playing. Part of what drives the destructive gambling cycle appears to be the intense, dopamine-driven arousal produced by the anticipation of reward—the jackpot.  Recent research has focused on the part played by midbrain dopamine in the anticipation of reward, otherwise known by addicts as “waiting for the man.” In the world of gaming, it is known as the classic “gambler’s fallacy—the expectation that after a series of losses, a win is “due.” Statistics say otherwise, and gamblers certainly know all about house percentages. Yet, the expectation effects of beating those odds may produce the same anticipatory effect on a disordered metabolism as drug-related activities. A very small, speculative, and intriguing study at Duke University suggested that dopamine agonists given for Parkinson’s disease might sometimes be a catalyst for excessive gambling behaviors in elderly patients, even those who had never shown an interest in gambling before.

As for shopping and sex, even an informed guess seems premature at this point.

Photo Credit: http://www.health.com/

Impulsivity and Addiction

The perils of a hypersensitive dopamine system.

The brooding, antisocial loner, the one with impulse control problems, a penchant for risk-taking, and a cigarette dangling from his lip, is a recognizable archetype in popular culture. From Marlon Brando to Bruce Lee, these flawed heroes are perhaps the ones with restless brain chemicals; the ones who never felt good and never knew why (“What are you rebelling against?” “What’ve you got?”).

A recent study at Vanderbilt University, published in Nature Neuroscience, used PET scans and fMRI imaging to suggest that impulsivity and other “antisocial” traits “predicted nucleus accumbens dopamine release and reward anticipation-related activity in response to pharmacological and monetary reinforcers, respectively.”

In other words, the Vanderbilt researchers maintained that so-called “psychopathic traits” like impulsivity and risk taking are linked to addiction and gambling by means of an overly active dopamine system. PET scans of dopamine responses to a low dose of amphetamine showed that “individuals who scored high on a personality assessment that teases out traits like egocentricity, manipulating others, and risk taking had a hypersensitive dopamine response system,” according to a press release from the National Institute on Drug Abuse (NIDA), which funded the study.

Putting a different spin on the matter, NIDA director Nora Volkow said: “By linking traits that suggest impulsivity and the potential for antisocial behavior to an overreactive dopamine system, this study helps explain why aggression may be as rewarding for some people as drugs are for others.”

Lead author Joshua Buckholtz of Vanderbilt said that “the amount of dopamine released was up to four times higher in people with high levels of these traits, compared to those who scored lower on the personality profile.  Buckholtz suggested that a pattern of exaggerated dopamine responses “could develop into psychopathic personality disorder.”

Dr. Robert Cloninger, a prominent addiction researcher, has asserted in the past that children who show a high propensity for risk-taking, along with impulsivity, or “novelty-seeking,” are more likely to develop alcoholism and other addictions later in life.

And, in interviews with the late psychologist Henri Begleiter for my book on addiction science, Begleiter insisted that addicts were stuck with a package of symptoms he called behavioral dysregulation. “Disinhibition, impulsivity, trouble fitting into society—you have certain behavioral disorders in kids who later develop into alcoholics and drug addicts,” he said. The behavior itself doesn’t cause the addiction. The dysregulated behavior is a symptom of the addiction.”

“When you talk to these people, as I have,” Begleiter said, “you see that the one thing they pretty much all report is that, under the influence of the drug, they feel much more normal. It normalizes their central nervous systems. Initially, what they have is a need to experience a normal life.”

So, it wasn’t ducktails, pool halls, tattoos, casual sex, or lack of parental involvement that caused addiction to alcohol and cigarettes and pot, and maybe cocaine and speed and heroin. It wasn’t just the “bad kids.” Irrational anger, impulsive decisions, certain compulsive behaviors like gambling—these behaviors were symptoms of the same group of related disorders that included drug and alcohol addiction, and which involved specific chemicals and areas of the brain related to reward, motivation, and memory.

The trait of impulsivity is a possible marker for addiction that may help explain why it is usually impossible to persuade addicts to give up their drugs by sheer force of logic—by arguing that the drugs will eventually ruin their health or kill them. “They tell me it’ll kill me,” sang Dave Van Ronk, “but they don’t say when.”

Consider the always-instructive case of cigarette smoking. In 1964, the Surgeon General’s Report on Smoking and Health laid out the case for the long-term ill effects of nicotine quite effectively—and millions of people quit smoking. A stubborn minority did not, and many of them still have not. Are they simply being hedonistic and irresponsible? Or are the long-term negative consequences, so dramatically clear to others, simply not capable of influencing their thinking to the same degree? Biochemical abnormalities similar to those predisposing certain people to addiction may also prevent them from comprehending the long-term results of their behavior.

Buckholtz, J., Treadway, M., Cowan, R., Woodward, N., Benning, S., Li, R., Ansari, M., Baldwin, R., Schwartzman, A., Shelby, E., Smith, C., Cole, D., Kessler, R., & Zald, D. (2010). Mesolimbic dopamine reward system hypersensitivity in individuals with psychopathic traits Nature Neuroscience, 13 (4), 419-421 DOI: 10.1038/nn.2510

Graphics Credit: http://www.nature.com/neuro/journal/

The Nucleus Accumbens

Final destination for addictive drugs.

The release of dopamine and serotonin in the nucleus accumbens lies at the root of active drug addiction. The pattern of neural firing that results from this surge of neurotransmitters is the “high.” It is the chemical essence of what it means to be addicted. Part of the medial forebrain bundle (MFB), which mediates punishment and reward, the nucleus accumbens is the ultimate target for the dopamine released by the ingestion of cocaine, for example.

The release of dopamine and serotonin in the nucleus accumbens appears to be the final destination of the reward pathway—the last act in the pleasure play. If you think about a drug, take a drug, or crave a drug, you are lighting up the nucleus accumbens with a surge of electrochemical activity. These are essentially the same pathways that regulate our food and water-seeking behavior. By directly or indirectly influencing the molecules of pleasure, drugs and alcohol trigger key neurochemical events that are central to our feelings of both reward and disappointment. In this sense, the reward pathway is a route to both pleasure and pain.

Alcohol, heroin, cigarettes, and other drugs caused a surge of dopamine production, which is then released onto the nucleus accumbens. The result:  Pleasure. When scientists pipe a dopamine-mimicking substance into the nucleus accumbens, targeting dopamine D2 receptors, withdrawal symptoms are blocked in morphine-addicted rats. Similarly, when scientists block dopamine receptors in the accumbens, the morphine-dependent rats exhibit withdrawal symptoms.

When you knock out large slices of the nucleus accumbens, animals no longer want the drugs. So, one cure for addiction has been discovered already—but surgically removing chunks of the midbrain just won’t do, of course.

Dopamine is more than a primary pleasure chemical—a “happy hormone,” as it has been called. Dopamine is also the key molecule involved in the memory of pleasurable acts. Dopamine is part of the reason why we remember how much we liked getting high yesterday. The nucleus accumbens (also known as the ventral striatum) seems to be involved in modulating the emotional strength of the signals originating in the hippocampus. This implicates the hippocampus in relapse, even though this area of the brain does not light up as strongly during actual episodes of craving.

The fact that we know all this is nothing short of amazing, but it is part of a larger perspective afforded by the insights of contemporary neurobiology. We know, for example, that the emotion of fear arises, in large part, through chemical changes in a peanut-sized limbic organ called the amygdala. Does this information make fear any less, shall we say, fearful? It merely locates the substrate upon which the sensation of fear is built.

Studies of the nucleus accumbens have demonstrated abnormal firing rates in scanned addicts who were deep into an episode of craving. The craving for a reward denied causes dopamine levels in the nucleus accumbens to crash dramatically, as they do when users go off drugs. Dopamine, serotonin, and norepinephrine activity soars just as dramatically when a drug user relieves withdrawal symptoms by relapsing. Drug hunger in abstinent addicts is not all in the head, or strictly psychological. Craving has a biological basis.  

Finding a way to override serotonin- and dopamine-mediated mid-brain commands is the essential key to recovery from addiction. One of the aims of a biological understanding of addiction is to tease out the mechanisms by which the reinforcing effects of addictive drugs become transformed into long-term adaptive changes in the brain.

Graphics credit: http://thebrain.mcgill.ca/

Adapted from The Chemical Carousel: What Science Tells Us About Beating Addiction by Dirk Hanson © 2008.

The Addiction Inbox Top Ten

A rundown of the most popular posts.

What are readers of Addiction Inbox interested in? Although scarcely scientific, a look at the most-viewed posts here over the past couple of years is indicative of general interest—or at least indicative of the general drift of Google searches on topics related to addiction and drugs.

Ranked by overall page views, from most to least, here are the ten most-visited blog posts on Addiction Inbox:

1. Marijuana Withdrawal

The most popular post on Addicton Inbox by a considerable margin. With almost 700 reader comments, this post has evolved into a message board for people having problems related to marijuana dependence and withdrawal. Very interesting first-person stuff attached to a rather straightforward post. Continues to grow like Topsy.

2. Is Marijuana Addictive?

A continuation of the discussion of marijuana withdrawal, or, as the director of the National Institute on Drug Abuse (NIDA) Nora Volkow calls it, “cannabis withdrawal syndrome.” 100 reader comments thus far.

3. Serotonin and Dopamine: A Primer

Sometimes you just gotta get back to basics.  Inquiring readers want to know.

4. E-Cigarettes and Health

A lively debate on the new, smokeless nicotine delivery system. Electronic cigarettes use batteries to convert liquid nicotine into a heated mist that is absorbed by the lungs. The latest in harm reduction strategies, or starter kits for youngsters?

5. Topamax for Alcoholism: A Closer Look

Another good response to a medical post about a drug for seizure disorders and migraines that shows promise as an anti-craving drug for alcoholism. People are getting more accustomed to hearing about medications for addiction.

6. Bill to Legalize Marijuana Offered in U.S.

Not a big surprise.

7. Marijuana Withdrawal Rivals Nicotine

Another comment-heavy post concerning a controversial study of withdrawal effects from smoking cigarettes and pot.

8. Anandamide: The Brain’s Own Marijuana

Something of a merger here between two consistently popular topics--cannabis and brain science. After the Sanskrit “ananda,” meaning bliss.

9. Food Addiction and Dopamine

Readers seem to take seriously the notion that certain forms of overeating are substance addictions.  This post focused on sugar's drug-like effect on the nucleus accumbens, a dopamine-rich brain structure in the limbic system.

10. Coffee Addiction

Increased tolerance, craving, and verifiable withdrawal symptoms--the primary determinants of addiction--are easily demonstrated in victims of caffeinism.

What’s a Neurotransmitter, Anyway?

A brief guide for the perplexed.

A neurotransmitter is a chemical substance that carries impulses from one nerve cell to another. Neurotransmitters are manufactured by the body and are released from storage sacs in the nerve cells. A tiny junction, called the synaptic gap, lies between brain cells. (Think of Michelangelo’s Sistine Chapel, with the finger of Adam and the finger of God not quite touching, yet conveying energy and information.)

Neurotransmitters squirt across the synaptic gap, and this shower of chemical messengers lands on a field of tiny bumps attached to the surface of the nerve cell on the other side of the synaptic gap. These bumps are receptors, and they have distinctive shapes. Picture these receptors, brain researcher Candace Pert has suggested, as a field of lily pads floating on the outer oily surface of the cell.

Neurotransmitter molecules bind themselves tightly to these receptors. The fact that certain drugs of abuse also lock tightly into existing receptors, and send messages to nerve cells in the brain, is the key to the mystery of addiction.

The fact that certain drugs essentially “fool” receptors into receiving them is one of the most important and far-reaching discoveries in the history of modern science. It is the reason why even minute amounts of certain drugs can have such powerful effects on the human nervous system. The lock-and-key arrangement of neurotransmitters and their receptors is the fundamental architecture of action in the brain. Glandular cells are studded with receptors, and many of the hormones have their own receptors as well. If the drug fits the receptor and elicits a response, it is called an agonist. If it simply blocks the receptor site without stimulating a response, it is an antagonist. Still other neurotransmitters have only a secondary effect, causing the target cell to release other kinds of neurotransmitters and hormones.

Two of the most important neurotransmitters are serotonin and dopamine. The unfolding story of addiction science, at bottom, is the story of what has been learned about the nature and function of such chemicals, and the many and varied ways they effect the pleasure and reward centers in our brains.

In 1948, three researchers—Maurice Rapport, Arda Green, and Irvine Page—were looking for a better blood pressure medication. Instead, they managed to isolate a naturally occurring compound in beef blood called serotonin (pronounced sarah-tóne-in), and known chemically as 5-hydroxytryptamine, or simply 5-HT. The researchers determined that serotonin was involved in vasoconstriction, or narrowing of the blood vessels, and in that respect resembled another important chemical messenger in the brain—epinephrine, better known as adrenaline.

Even though there is at most 10 milligrams of the substance in our bodies, serotonin turned out to be one of nature’s signature chemicals—a chemical of thought, movement and behavior, as well as digestion, ejaculation, and evacuation. The body’s all-purpose neurotransmitter, involved in sleep, mood, appetite, among dozens of other functions. The cortex, the limbic system, the brain stem, the gut, the genitals, the bowels: serotonin is a key chemical messenger in all of it.

Another key neurotransmitter—dopamine—is considered to be one of the brain’s primary “pleasure chemicals,” and is found in areas of the brain linked to experiences of joy and reward.

Dopamine pathways play a role in carrying signals related to attention, movement, problem solving, pleasure, and the anticipation of rewarding experiences. Dopamine is one of the reasons why, after you have a pleasurable experience with food, drink, sex, or certain drugs, you are likely to feel a desire to repeat the experience. Dopamine is implicated in not just the drug high, but in the craving that accompanies withdrawal as well.

Feelings of pleasure, or joy, are natural drug highs. The fact that they are produced by chemical alterations in brain state does not make the fear or the pleasure feel any less real.

Excerpted from The Chemical Carousel: What Science Tells Us About Beating Addiction by Dirk Hanson © 2008


Photo Credit: NIDA

addiction drugs dopamine

A Drug for Kleptomania?

Naltrexone curbs shoplifting.

It seems like such an unlikely finding: In a University of Minnesota study of kleptomania—the compulsion to steal—a popular medicine used to treat both heroin addiction and alcoholism drastically reduced stealing among a group of 25 shoplifters. The drug, naltrexone, blocks brain receptors for opiates. It is one of the few drugs available for the treatment of alcoholism, and continues to gain momentum as a treatment for opiate addiction.

In an article for the April issue of Biological Psychiatry, Jon Grant and colleagues at the University of Minnesota School of Medicine record the results of their work with 25 kleptomaniacs, most of them women. All of the participants had been arrested for shoplifting at least once, and spent at least one hour per week stealing. The 8-week study is believed to be the first placebo-controlled trial of a drug for the treatment of shoplifting.

In the April 10 issue of Science, Grant said that “Two-thirds of those on naltrexone had complete remission of their symptoms.” According to Samuel Chamberlain, a psychiatrist at the University of Cambridge in the U.K., the study strongly suggests that “the brain circuits involved in compulsive stealing overlap with those involved in addictions more broadly.” The study, in short, strengthens the hypothesis that the shoplifting “high” may have much in common with the high produced by heroin or alcohol.

Researchers are also working with the drug memantine as a treatment for compulsive stealing.

The finding lends additional evidence to the theory that shoplifting is a dopamine- and serotonin-driven disorder under the same medical umbrella as drug addiction and alcoholism. Preliminary research has shown that naltrexone may also have an effect on gambling behavior.

If so-called “behavioral addictions” continue to display biochemical similarities with “chemical addictions,” the move to broaden the working definition of addiction will continue to intensify. And the same sorts of questions that plague addiction research will be replayed in the behavioral sphere: What level of shoplifting constitutes the disorder called kleptomania? Isn’t the medicalization of shoplifting just a way to excuse bad behavior? Is medical treatment more effective than jail time? From a legal point of view, what is the the difference between kleptomania and burglary?

In his book, America Anonymous, Benoit Denizet-Lewis quotes lead study author Jon Grant: “With all addictions, a person’s free will is greatly impaired, but the law doesn’t want to entertain that.... Why shouldn’t someone’s addiction be considered as a mitigating factor, especially in sentencing?”

Photo Credit: Napo Hampshire Branch

addiction drugs

Guest Post: Things Go Better with Meth

The Pepsi Challenge with controlled substances.

[Today’s post comes to us from Neurological Correlates, a blog devoted to the neuroscience of dysfunctional behavior. It was written by Swivelchair, who refers to himself as “an anonymous biopharma worker." It’s an excellent blog, one of the few that focuses on the biological basis of addiction.]
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Things go better with meth, as compared to cocaine, if you’re dopamine transporter challenged, anyway.

By Swivelchair

Methamphetamine is taken up more quickly, and lasts longer than cocaine. (Fowler et al, Abstract below).

And here’s something from Microgram Bulletin, October 2008, Published by the Drug Enforcement Administration Office of Forensic Sciences Washington, D.C. 20537: The DEA South Central Laboratory (Dallas, Texas) recently received a submission of approximately 4972 fake “kidney beans” (total net mass 3,210 grams), all containing a fine tan powder, suspected heroin. The “beans” were actually small plastic packets that had been painted to resemble kidney beans... Analysis of the powder... confirmed 90.3% heroin hydrochloride.

The perhaps undeniable point: probably the self-selecting population of people who are first drawn to drugs, and then become irretrievably addicted, are those who lack sufficient dopamine transport to feel fulfilled (or other insufficiency, depending on the choice of drug). They are, in essence, self-medicating, rather than using drugs for recreational use. I mean, you don’t load up kidney beans for recreational drug users.

I’m reminded of a friends’ younger brother, from a locally well-known family, whose arrest was reported as bringing in “the largest amount” of cocaine in those parts. His remark: He was a wholesaler, and the newspaper quoted street (”retail”) values, so the report inflated his inventory value. This was purely about money for him — he made far more money selling coke than any job he was qualified to do (which was, well, probably none, unless being a bon vivant and sparkling raconteur with insufficient money to fund a high rent party lifestyle qualifies as a profession, which it may). If the US were to decriminalize drug use, and fund a program to make an agonist which was not addictive (a la the whole methadone thing), probably we could solve much of the crime problem in the Western Hemisphere.
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“Fast uptake and long-lasting binding of methamphetamine in the human brain: comparison with cocaine.” Fowler JS, Volkow ND, Logan J, et. al. Medical Department, Brookhaven National Laboratory, Upton, NY 11973

Abstract from Neuroimage. 2008 Dec; 43(4):756-63.

“Methamphetamine is one of the most addictive and neurotoxic drugs of abuse. It produces large elevations in extracellular dopamine in the striatum through vesicular release and inhibition of the dopamine transporter. In the U.S. abuse prevalence varies by ethnicity with very low abuse among African Americans relative to Caucasians, differentiating it from cocaine where abuse rates are similar for the two groups. Here we report the first comparison of methamphetamine and cocaine pharmacokinetics in brain between Caucasians and African Americans along with the measurement of dopamine transporter availability in striatum.

Methamphetamine’s uptake in brain was fast (peak uptake at 9 min) with accumulation in cortical and subcortical brain regions and in white matter. Its clearance from brain was slow (except for white matter which did not clear over the 90 min) and there was no difference in pharmacokinetics between Caucasians and African Americans. In contrast cocaine’s brain uptake and clearance were both fast, distribution was predominantly in striatum and uptake was higher in African Americans. “Among individuals, those with the highest striatal (but not cerebellar) methamphetamine accumulation also had the highest dopamine transporter availability suggesting a relationship between METH exposure and DAT availability. Methamphetamine’s fast brain uptake is consistent with its highly reinforcing effects, its slow clearance with its long-lasting behavioral effects and its widespread distribution with its neurotoxic effects that affect not only striatal but also cortical and white matter regions. The absence of significant differences between Caucasians and African Americans suggests that variables other than methamphetamine pharmacokinetics and bioavailability account for the lower abuse prevalence in African Americans.”

Related Links

PET studies of d-methamphetamine pharmacokinetics in primates: comparison with l-methamphetamine and ( –)-cocaine. [J Nucl Med. 2007] PMID:17873134

Long-term methamphetamine administration in the vervet monkey models aspects of a human exposure: brain neurotoxicity and behavioral profiles. [Neuropsychopharmacology. 2008] PMID:17625500

Graphics Credit: methamphetaminetx.com

addiction drugs dopamine

Modafinil May Be Addictive

NIDA study casts doubt on safety of “brain booster” drug.

Despite the headlines, most new drugs are not addictive. Very few medications show the distinctive side effects associated with clinical drug addiction: tolerance, withdrawal, and continued use despite adverse consequences. Such drugs are relatively rare—so it was with interest and alarm that addiction specialists confronted a small pilot study, led by Dr. Nora Volkow of the National Institute on Drug Abuse (NIDA), which appeared to demonstrate that the sleep drug modafinil has addictive potential.

Modafinil, sold as Provigil, has found increasing off-prescription use for the treatment of ADHD and other psychiatric disorders. The drug is also being used as a so-called “cognitive enhancement” drug or “brain booster,” particularly among college students and military field personnel. Modafinil had even shown early promise as a drug for the treatment of cocaine addiction.

In the March 18 issue of the Journal of the American Medical Association (JAMA) , the researchers reported on levels of extracellular dopamine in the brains of 10 healthy men on either placebo or modafinil.

According to the researchers, “Modafinil acutely increased dopamine levels and blocked dopamine transporters in the human brain. Because drugs that increase dopamine have the potential for abuse, and considering the increasing use of modafinil for multiple purposes, these results suggest that risk for addiction in vulnerable persons merits heightened awareness.”

Scientists were initially excited about a drug which showed stimulant properties but did not appear to have a direct effect on the dopamine pleasure systems of the brain—a finding that set it apart from drugs like amphetamine and cocaine. However, as reported online by Heidi Ledford of Nature, “Animal studies showed that rodents that lack dopamine receptors are unresponsive to the drug, and in 2006, researchers found that modafinil affects dopamine levels in the brains of rhesus macaques.”

Dr. Volkow stressed that patients taking modafinil for recognized medical conditions such as narcolepsy should continue to do so, while doctors should monitor modafinil patients for signs of dependency.

Still, dopamine is not all there is to addiction. As reported in Nature, Bertha Madras of Harvard Medical School notes that some drugs that boost dopamine have other properties that make them aversive, and therefore not addictive. “The full spectrum of the pharmacology of the drug is what drives the abuse potential,” she said.

[The following added 8.00 pm 3-18-09]: In addition, Corpus Callosum has an excellent in-depth look at why the results of the study should be interpreted conservatively.]

addiction drugs dopamine