Epigenetics and Addiction

Turning off the genes for substance abuse.

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

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

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

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

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

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


Image Credit: Science in School

addiction drugs dopamine

The Chemistry of Cocaine Addiction

Crack, free-base, and powder

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

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

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

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

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

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

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

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

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

Photo Credit: Legal Drug Alternatives

addiction drugs

Neuroaddiction and the Reward Pathway

How addictive drugs fool Mother Nature

"The addicted brain is distinctly different from the nonaddicted brain,” writes Alan Leshner, the former director of the National Institute of Drug Abuse (NIDA). “Changes in brain structure and function is what makes it, fundamentally, a brain disease. A metaphorical switch in the brain seems to be thrown as a result of prolonged drug use.”

Addiction is both a cause and a consequence of these fundamental alterations in brain function. If physical abnormalities in the brain are at the root of the problem, then any treatment program worth its weight ought to be dealing—directly or indirectly--with these differences in brain state. Writing in Lancet, researcher Charles O’Brien has suggested a similar orientation: “Addiction must be approached more like other chronic illnesses--such as diabetes and chronic hypertension--than like an acute illness, such as a bacterial infection or a broken bone."

All of this suggests that we are not likely to win a war on drugs, achieve zero tolerance, or become chemical-free any time soon. The drug problem is an artifact of the basic design of the mammalian brain. Humankind is extraordinarily susceptible to drug abuse anywhere and everywhere certain drugs are widely available—and all because of a “design quirk” in the reward pathways of the central nervous system.

Any sufficiently powerful receptor-active drug is, in its way, fooling Mother Nature. This deceit means, in a sense, that all such drugs are illicit. They are not natural, however organic they may be. Yet, the human drive to use them is all-pervasive. We have no real built-in immunity to drugs that directly target specific receptors in the limbic and cortical pleasure pathways. The act of “liking” something is controlled by the forebrain and brain stem. If you receive a pleasant reward, your reaction is to “like” it.

If, however, you are anticipating a reward, and are, in fact, engaging in behaviors motivated by that anticipation, it can be said that you “want” it. The wholly different act of wanting something strongly is a mesolimbic dopamine-serotonin phenomenon. We like to receive gifts, for example, but we want food, sex, and drugs. As Nesse and Berridge put it, “The ‘liking’ system is activated by receiving the reward, while the ‘wanting’ system anticipates reward and motivates instrumental behaviors. When these two systems are exposed to drugs, the “wanting” system motivates persistent pursuit of drugs that no longer give pleasure, thus offering an explanation for a core paradox in addiction."

Under the biochemical paradigm, a runaway appetite for non-stop stimulation of the reward pathway is a prescription for disaster. The harm is physical, behavioral, and psychological--as are the symptoms. Peer pressure, disciplinary difficulties, contempt for authority--none of these conditions is necessary for drug addiction to blossom. What the drug itself does to people who are biologically vulnerable is enough. No further inducements are required.

Even this brief summation of the ways in which addictive drugs alter neurotransmission should serve to demonstrate that these substances have more in common than we ordinarily assume. All these drugs are of course rewarding, so it is perhaps not too surprising, for all their differences, that they work the limbic reward pathways. All these drugs share common mechanisms of action, which is why they are addictive.

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


addiction drugs

Amphetamine Blues

How meth addiction happens.

If alcohol’s impact on brain cells is wide-ranging and diffuse, and marijuana’s impact is selective and subtle, the impact of cocaine and amphetamine is much more straightforward. “There is certainly lots of evidence for common neurological mechanisms of reward across a wide variety of drugs,” said Dr. Robert Post, chief of the biological psychiatry branch at NIMH.

Animals will readily administer cocaine and amphetamine, Dr. Post once explained to me, but when researchers surgically block out areas of the brain that are dense with dopamine receptors, the picture changes dramatically. “The evidence definitely incriminates dopamine in particular,” said Dr. Post. “In animal models, if you make selective lesions in the dopamine-rich areas of the brain, particularly the nucleus accumbens in the limbic system, the animals won’t self-administer either amphetamine or cocaine.”

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 won’t do, of course.

At the heart of the meth high is a chemical paradox. The entire range of stimulative effects hits the limbic system within seconds of being inhaled or inject, and the focused nature of the impact yields an astonishingly pleasurable high.

But the long-term result is exactly the opposite. 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.

The release of dopamine and serotonin in the limbic structure called the nucleus accumbens lies at the root of active drug addiction. It is the chemical essence of what it means to be addicted. The pattern of neural firing that results from this surge of neurotransmitters is the “high.” 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.

One reason why 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 drug may no longer be working as well as it once did, the alternative--the psychological and physical cost of withdrawal--is even worse. When addicts talk about “chasing a high,” the metaphor can be extended to the losing battle of neurotransmitter levels. In the jargon used by Alcoholics Anonymous, addicts generally have to get worse before they can get better.

Speed, then, is diabolically 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, where they repeatedly stimulate their receptors. By mechanisms less well identified, cocaine accomplishes the same feat. Speed also interferes with the return of dopamine, norepinephrine, and serotonin molecules to their storage sacs, a procedure known as reuptake blocking—the same mechanism by which the so-called selective serotonin reuptake inhibitors (SSRI) antidepressants increase the availability of serotonin in the brain.

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

addiction drugs

“Drug Foods” and Addiction

Amino acid restoration therapy

Addicts frequently resort to sugar foods and other high-carbohydrates snacks as a substitute drug addiction, therapists frequently report. Since diet has a direct effect on neurotransmission in the brain, food of this type may play a role in keeping drug cravings alive.

Dr. Candace Pert, one of the founders of modern neuroscience, believes that the pain of drug withdrawal and the stress of associated cravings could be drastically lessened through attention to nutritional needs. “Recovery programs,” she writes in her book Molecules of Emotion: Why You Feel the Way You Feel, “need to take into account this multi-system reality by emphasizing nutritional support and exercise. Eating fresh, unprocessed foods, preferably organic vegetables, and engaging in mild exercise like walking to increase blood flow through the liver can speed the process up.”

Other alternative researchers speak of the body’s “natural stimulant capacity,” and suggest that proteins and raw vegetables replace drugs and “drug foods” like coffee, chocolate, and sugar.

Since the 1990s, various researchers have been experimenting with amino acid combinations, developing therapeutic “cocktails” composed of precursors for dopamine, serotonin, endorphin, norepinephrine, and other brain chemicals. Kenneth Blum, the co-author of numerous controversial dopamine-alcohol studies at the University of Texas, worked with a neurotransmitter restoration cocktail called SAAVE, composed of phenylalanine, glutamine, tryptophan, pyridoxal-5-phosphate, and various enzymes.

However, tryptophan has been difficult to obtain in the U.S. for years now, ever since the FDA told consumers to stop taking tryptophan after the supplement was linked to an outbreak of a rare blood disorder called eosinophilia-myalgia syndrome (EMS). The Centers for Disease Control eventually reported 24 deaths. A specific bacillus the Japanese had cultivated to use as a “factory” for the production of tryptophan had gone haywire, and, through a process akin to fermentation, produced a pathogen responsible for the outbreak.

If we are what we eat, then it behooves us all to eat a little more carefully—especially since some of the things we eat are either drugs, or else natural substances that exert a similar effect. For example, cigarette smoking puts additional demands on the body’s store of vitamin C. This is another good reason why pregnant women should not smoke, and need to eat foods rich in vitamin C. Otherwise, they may be depriving the fetus of ascorbic acid.

By elevating key neurotransmitter levels through amino acid “loading,” and by inhibiting the enzyme-induced degradation of these amino acids, amino acid restoration therapy may be “a useful adjunct to psychotherapy in achieving sobriety, not only in an inpatient setting but as a crucial element for continued recovery,” Blum believes. Blum eventually sold his patent rights to NeuroGenesis, Inc., which continues to market variations of his product.

Other researchers say that the ratio of the precursor amino acid to other amino acids present in the body is too complicated, and too little understood, to allow amino acid replacement therapy to be effective at present. Tryptophan, for example, must compete with other amino acids for entry into the brain. The serotonin uptake blockers, on the other hand, apparently produce a decrease in blood concentrations of neutral amino acids, which lessens the competition across the blood-brain barrier. Nonetheless, amino acid replacement therapy is being tried experimentally at clinics around the country.

Marijuana Withdrawal

For Some Users, Cannabis Can Be Fiercely Addictive.

(Note: more than 1200 comments below)

See Also:
Is Marijuana Addictive? (>143 posts)
Marijuana Withdrawal Revisited. (>108posts).
Feds Fund Study of Marijuana Withdrawal. (>39 posts)

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.

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

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

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

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

As Dr. DeChiara of the Italian research team suggested in Science, “this overlap in the effects of THC and opiates on the reward pathway may provide a biological basis for the controversial ‘gateway hypothesis,’ in which smoking marijuana is thought to cause some people to abuse harder drugs.” America's second favorite drug, De Chiara suggests, may prime the brain to seek substances like heroin. In rebuttal, marijuana experts Lester Grinspoon and James Bakalar of Harvard Medical school have protested this resumed interest in the gateway theory, pointing out that if substances that boost dopamine in the reward pathways are gateways to heroin use, than we had better add chocolate, sex, and alcohol to the list.

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

In 2005, an article in the American Journal of Psychiatry concluded that, for patients recently out of rehab, “Postdischarge cannabis use substantially and significantly increased the hazard of first use of any substance and strongly reduced the likelihood of stable remission from use of any substance.”

A selected bibliography of science journal references can be found HERE.

See also:
Marijuana Withdrawal Rivals Nicotine
Marijuana Withdrawal Revisited
Feds Fund Study of Marijuana Withdrawal

NOTE: THERE ARE MORE THAN 1, 200 COMMENTS BELOW. CLICK "NEWER" FOR ADDITIONAL COMMENT PAGES, OR "NEWEST" FOR THE LATEST POSTS.




addiction drugsmedical marijuana

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. The amines are of great interest, because both mood-altering drugs and addictive drugs show a very straightforward affinity for receptors sites designed for endogenous amines.

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.

Thus far, no other substance found the central nervous system has as many diverse receptor actions as 5-HT. The average adult has only about 10 milligrams of serotonin in his or her body. It is involved, to one degree or another, in appetite, sleep, mood, memory, learning, endocrine regulation, smooth muscle contractions, migraine headaches, motility of the GI tract, blood platelet homeostasis, so on. Serotonin also plays a large role in initiating and shaping certain kinds of behavior, especially behaviors of a sexual or hallucinatory nature. In animal models, lower serotonin levels correlate with higher levels of violence.

A receptor-selective agent like Sumatriptan, a popular migraine medication, works by binding selectively to a serotonin receptor subtype involved in arterial circulation and dilation. The difference between serotonin-active drugs like sumatriptan, and similarly serotonin-active drugs LSD or Ecstasy, is that the former locks exclusively into these “5-HT1” receptors, and nowhere else. The ergot alkaloids are all over the serotonin system, causing general surges of their own.

Psychedelic drugs like LSD and Ecstasy (chemically known as indoleamines) and mescaline (phenethylamines) make up the two major classes of hallucinatory drugs. They are both partial agonists at 5-HT receptors, boosting serotonin particularly in the cerebral cortex and the locus coeruleus. There is also some enhancement of glutamine activity as well. Other 5-HT agonists, like ondansetron (trade name Zofran), do not have that effect. Ondansetron helps block the nausea of chemotherapy by blocking serotonin activity in the GI tract. Vomiting is a serotonin-mediated reflex. In this case, it is the 5-HT3 receptor subtype that is of note. Ondansetron’s selective affinity for that subtype makes it a useful anti-emetic.

Dopamine, like serotonin appears to be strongly involved in mediating craving-- drug hunger, as well as real hunger. This yields a partial answer to one of addiction’s mysteries: Why would a drug addict, an alcoholic, continue to use when the adverse effects of continued use have long ago swamped whatever euphoric sense of well being, or even just plain normalcy, that once was obtained through the drug? One answer might be that dopamine causes human beings to pay attention to stimuli that are potentially rewarding. Even in the absence of any possibility of reward--on a desert island, in a rehab clinic--dopamine dysregulation could kindle episodes of fierce craving, because such episodes had led in the past to a renewed ingestion of the drug in question-- all the fiercer, these cravings, this drug hunger, whenever the addict was exposed to direct cues, like seeing the drug, or being in places where the addict had used before.

Scientists have managed to record a rise in dopamine levels in lab rats simply by cueing the rats to anticipate a pleasurable event--food, sex, sweet drinks. For example, you could condition the rats to a ringing bell before dinner, and soon the rats would be showing elevated dopamine levels at the sound of the bell only--with no reward at all. Anticipation of reward was all it took. Or you could give one of the male rats a good close look at a suitable female through a mesh panel, and the male rat’s dopamine levels would surge, presumably in anticipation of possible carnal pleasures, and dopamine levels would spike even higher, of course, once the divider was removed.

Serotonin/dopamine dysfunctions cause physical discomfort, anxiety, and panic--what a renowned neuropharmacologist has termed “spiraling distress”—which continues to occur even in the complete absence of the addictive drug. Take the drug away, and the brain begins its complex and minutely ordered repertoire of compensatory effects--unpleasant sensations as read out by the addict.

Finding a way to override serotonin- and dopamine-mediated mid-brain commands is one of the keys 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 certain areas of the brain. “Why are we so surprised that when you take a poison a thousand times, it makes some changes in your head?” wondered James Halikas, who was co-director of the chemical dependency treatment program at the University of Minnesota during the crack heyday of the late 1980s and early 1990s. “It makes sense that poisons change things.”

addiction drugs

addiction drugs

Food Addiction

Carbohydrates on the Brain, Food Rehab in the Future

Earlier this month, Yale University hosted the first-ever conference on Food and Addiction. Dr. Nora Volkow of the National Institute on Drug Abuse told the collection of experts on nutrition, obesity and drug addiction that “commonalities in the brain’s reward mechanisms” linked compulsive eating with addictive drug use. “Impaired function of the brain dopamine system could make some people more vulnerable to compulsive eating,” Volkow said.

Moreover, animal studies and brain imaging research in humans strongly support the notion of food addiction. In particular, research has pointed toward a form of food addiction known as “carbohydrate-craving obesity.” Dr. Mark Gold, chief of addiction studies at the McKnight Institute at the University of Florida, and a well-known authority on cocaine abuse, argued that “failed diets and attempts to control overeating, preoccupation with food and eating, shame, anger, and guilt look like traditional addictions.”

Conference organizer Kelly Brownell, director of the Rudd Center for Food Policy and Obesity at Yale, conceded that “it wasn’t obesity experts who got interested in addiction, it was the addiction scientists who got interested in food.” Brownell suggested that psychologists have been slower to grasp the import of food addiction “in part because of a bias that obesity is all about failure and personal responsibility, so why look at biology?”

As Dr. Gold summed it up, “It turns out that food and drugs compete for the same reward system in the brain.”

SOURCES:

--“Yale Hosts Historic Conference on Food and Addiction.” Yale University Office of Public Affairs. July 9, 2007. http://www.yale.edu/opa/newsr/07-07-09-01.all.html

--Hellmich, Nancy. “Does food ‘addiction’ explain explosion of obesity?” USA Today, July 9, 2007.

--“Yale Hosts Historic Conference on Food Addiction.” Medical News Today. 11 July 2007. www.medicalnewstoday.com

--Hathaway, William. “Experts Chew Over Eating as Addiction.” The Hartford Courant. July 11, 2007. http://www.courant.com/news/health