Addiction Treatment Forum

Addiction Treatment Forum reports on substance use news of interest to opioid treatment programs and patients in medication-assisted treatment.

A.T.F. Volume IX #1 Winter 2000

by

 

  • Clinical Concepts – Naltrexone in Action Against Alcoholism
  • Research Review – Update: Stimulant Use Disorders
  • From the Editor
  • Events to Note
  • Brainstorm: The Hijacked Brain Part 3
  • Where to Get Info

 

Clinical Concepts – Naltrexone in Action Against Alcoholism

A brief newspaper article in January 1995 caught Lloyd Vacovsky’s eye. It briefly noted how naltrexone had recently been approved by the FDA for alcoholism, and that the drug appeared to be extremely effective.
“The article said naltrexone suppressed alcohol cravings, with only minor side effects, and curbed the effects of alcohol,” Vacovsky remembers. “I thought, if half of this is true, we should be putting the drug in our city’s drinking water!” Not long thereafter, he founded Assisted Recovery Centers of Arizona, a naltrexone-based alcoholism recovery program based in Phoenix.
‘Frequent Flyers’
At the time of the article, Vacovsky was a social worker at Central Arizona Shelter Services (CASS), the state’s largest non-profit facility for homeless persons. “I was frustrated by the recidivism rate of our clientele,” he says. “After getting them on their feet, many were back in just 3 months, following a cycle of drinking and drugging. Traditional programs, from AA to expensive residential treatment, just weren’t working for these ‘frequent flyers.'”
In February 1995, Vacovsky arranged a test of naltrexone in one alcoholic. “The night before, he was washing down whisky with malt liquor. It was his ‘going away blast.’ The next morning we started him on naltrexone and within an hour we could see a calmness wash over him as the compulsion to drink dissipated. With the craving suppressed, he was able to deal with other issues in his life.”
Based on this success, Vacovsky set about mustering support for naltrexone in the local medical community. “Their immediate response was ‘no way,'” he recalls. “They said we were pursuing ‘voodoo medicine’ and they wouldn’t consider a pharmacologic option for alcoholism treatment.”
Why weren’t they more receptive? Vacovsky explains, “There hadn’t been a new medication for treating alcoholism in nearly 47 years, since disulfiram [Antabuse®] in 1948. The mentality was that there wasn’t anything worthwhile available, plus an attitude that lasting sobriety was best achieved the old-fashioned way ­ no pain, no gain.”
Up to 80% Success
Eventually, the program director at CASS suggested that Vacovsky start a program on his own. So, in April 1996, he created Assisted Recovery to implement a naltrexone-based alcoholism treatment program at the CASS shelter, with the county providing medical services for patient examinations and prescriptions. By May 1998, Vacovsky left the program at the shelter to devote full time to Assisted Recovery.
Since then, Vacovsky’s organization has served more than 300 patients, plus another 200 at CASS. “The age range has been 18 to 82 years, with the majority in their 40s, and an equal mix of men and women,” he comments. “We serve the general public and the adult probation departments of three local counties.”
Among those persons compliant with the medication and actively participating in their recovery, Vacovsky claims up to 80% success ­ that is, patients abstinent from alcohol at the end of 6 months.
Dose Matters
The usual starting dose of naltrexone is 50 mg/day, but some patients are started at 25 mg/d. Dosages may be increased up to 100-150 mg/d until cravings are eliminated. Vacovsky notes that, although initial studies of naltrexone for alcoholism used a 50 mg/d dose for only 12 weeks, experience has shown that the 100 mg/d dose for 6 months seems to be the most effective. Interestingly, he has found that women often need higher doses than men.
Timing of the dose can be important. “Patients should take the medication at the time of day when cravings usually begin to appear,” Vacovsky advises. “For some, it’s first thing in the morning, for others it may be when they leave work ­ the ‘happy hour syndrome.'”
Patients are not required to detox before entering the program, but Vacovsky prefers that they be sober for up to 5 days, which reduces the incidence of potential naltrexone side effects. The most noticeable side effect appears to be fatigue. Nausea, headaches, and tremors can also occur; however, Vacovsky believes such symptoms are more often due to prolonged alcohol withdrawal.
He stresses that it is important to start treatment immediately when the person is ready, rather than expecting prior abstinence. “Naltrexone actually has a positive effect on detoxification, making it more bearable and allowing patients to be more functional.”
Patients are instructed not to drink while on naltrexone. Although, Vacovsky concedes, nearly three quarters of them do drink to test the effectiveness of naltrexone. “They find that naltrexone indeed works to dull the effects of alcohol and rarely will they even finish the first drink.”
Compliance, Honesty Critical
Success in the program depends heavily on compliance in taking naltrexone daily. The court program is closely monitored; probationers must stay on the program a full year and take the naltrexone every day under observation by Vacovsky’s staff, a probation officer, or other responsible person who would not be intimidated.
“For everyone else, we get an interested third party to help monitor compliance,” he says. “We find that an immediate indicator of an alcoholic’s commitment to sobriety and probable success is their being amenable to compliance monitoring.”
Vacovsky continues, “Patients also need to be honest about how the medication is helping them overcome alcohol cravings. Sometimes, the dosage needs adjustment.”
Furthermore, patients need to be counseled and educated on what to expect from naltrexone. “Many people are expecting a Valium effect, a buzz, or some other distinct feelings,” he observes. “Naltrexone is more like taking a vitamin in the subtlety of its effect. Absence of craving is the main symptom, and the person sometimes isn’t fully aware of that.”
Part of a Program
“Naltrexone isn’t a magic bullet ­ it’s very effective, but it needs to be used as part of a basic cognitive-behavioral therapy program,” Vacovsky insists. “Otherwise, there’s probably a 90% chance of failure.”
Assisted Recovery offers group sessions every day, at varying times, and patients are expected to attend at least two groups a week for a minimum of 6 months. They are permitted to attend sessions beyond the 6 months, and Vacovsky says, “many do return to visit and share their ongoing successes with the others.”
Naltrexone dramatically changes the rules in recovery, he believes. “When people aren’t craving alcohol on a daily basis, they are better able to listen to the group’s message. Our program focuses on today and tomorrow, and how to adjust to not having alcohol as a part of life.”
“Alcoholics very quickly learn that they’ve ‘lost their sandbox’ ­ that is, they can no longer stick their heads in the sand to avoid the problems they were self-medicating with alcohol. Among some patients there is a desire to sabotage the program by not taking the medication or overriding it by drinking, which doesn’t work because naltrexone blocks the effects.”
Most Assisted Recovery patients also attend Alcoholics Anonymous at one time or another, although Vacovsky believes naltrexone is most effective in naltrexone-based therapy groups. “We counsel patients that, when they attend AA meetings, they should be discrete about mentioning they are taking naltrexone.” While many AA groups have become enlightened, some individual members still oppose any pharmacologic therapy in recovery.
A Tool; Not a Cure
For its 6-month program, Assisted Recovery charges roughly $1,000. This includes medical services for initial intake and medication prescribing, and ongoing group sessions. Additionally, each person is responsible for purchasing the naltrexone, using insurance or personal funds.
Vacovsky believes patients must stay on the medication long enough so cravings do not return once it is discontinued. “At the end of 6 months they are weaned from naltrexone, reduced first to 50 mg/d, and then 50 mg every second or third day. Soon, patients realize they don’t need it anymore.” They are encouraged to keep a small supply of 50 mg tablets on hand to use in special circumstances when they feel they might be uncomfortable, such as attending an event where there will be drinking.
Assisted Recovery also uses naltrexone to treat persons formerly dependent on opioids, and they attend the same group therapy sessions as alcoholic patients. However, since naltrexone is an opioid antagonist it cannot be used by anyone actively taking opioids ­ e.g., heroin, methadone, certain painkillers ­ or it will precipitate sudden, severe withdrawal.
In parting, Vacovsky reiterates that naltrexone is a tool, not a cure. “It effectively suppresses alcohol (and opioid) cravings so other issues can be addressed. However, we need to keep in mind that the individual needs to find a better, happier life as a result of treatment or it won’t be worthwhile.”
For more information, Vacovsky can be contacted at 602-264-7897 or Lloydv@primenet.com. Web site is: www.assistedrecovery.com.
A.T. Forum also featured an article on naltrexone for alcoholism a year ago, which may be accessed at www.atforum.cwinter99.shtml#anchor1222388. Or, for a copy of the complete “Naltrexone Nexus” series, check the appropriate box on the feedback card in this issue.

 

Research Review – Updates: Stimulant Use Disorders

The treatment of stimulant use disorders is an emerging and exciting field. New knowledge of how these agents affect the human brain has spurred innovative treatment approaches, most of which are still in early stages of investigation.
Increasing Prevalence
Stimulant abuse in the United States has risen dramatically over the past 20 years. These drugs tend to be used more erratically than opioids or alcohol, although they may be used in dangerous combinations with other psychotropic agents that multiply each other’s effects.[1,2]
Cocaine (paste, powder, or freebase “crack”) is the most widely used and abused stimulant, although it has declined from its peak in the 1980s. Still, more than 2 million cocaine abusers in the U.S. alone need treatment.[3] Twice as many males as females use cocaine, but smokable crack is popular among young women, resulting in significant use during pregnancy.[1]
The user-desired effects of cocaine, particularly at lower doses, include: increased arousal, improved performance on certain tasks, and a sense of confidence and well-being. Higher doses produce euphoria of brief duration, followed by cravings for more drug.[1]
Besides cocaine, the stimulant class of drugs includes: amphetamine, methamphetamine, dextroamphetamine, and others.[1] Although some agents in this class serve legitimate medical purposes, they all share a propensity for abuse and dependency. Others are strictly illicit, like the “club drug” MDMA (methylenedioxymethamphetamine, also called “ecstasy”) that produces stimulant and other psychotropic effects.[4,5]
Methamphetamine abuse follows closely behind cocaine.[3] In 1997, there were an estimated 5 million methamphetamine users in the U.S. age 12 and over. Also called crank, speed, ice, and other names, deaths related to methamphetamine tripled between 1991 and 1996 and its production and use have spread rapidly across the country.[2,6]
Physiological Effects
Craving, depression, mood swings, anxiety, paranoia, sexual dysfunction, and cognitive deficits are well-recognized outcomes of stimulant abuse.[1,3,7] Impairments of manual dexterity, memory, problem solving, and other cognitive skills can last up to a month after the stimulant is last taken.[8,9] A recent recommendation is that all patients entering treatment be given neuropsychological screening tests to identify the extent of their deficits and treatment plans should take these into account.[9]
Acute physiological effects from excessive doses of stimulants include: rapid, erratic heartbeat, heart failure or other heart damage; cerebral hemorrhaging, seizures, stroke, and coma; diabetic ketoacidosis; and sudden death.[3,7,9,10] Recent research in extensive cocaine users found an increase in coronary aneurisms and blood thickening, causing a 24-fold increase in heart attacks and strokes. [11,12]
Escalating abuse of stimulants and repeated use in the same session can create tolerance to the positive effects (e.g., euphoria), while negative effects (e.g., dysphoria) steadily intensify. Intermittent stimulant use can cause sensitization in which repeated exposure eventually produces intense drug effects at lower doses than were required at an earlier phase of the addiction process.[1,3]
Neurological Changes
Stimulants appear to impair normal functioning of dopamine in the brain.[3] For example, the subjective and reinforcing effects of cocaine are associated with dysfunctions of dopamine mechanisms in the mesolimbic reward system, particularly the nucleus accumbens. It is believed that cocaine boosts dopamine release and blocks its reuptake by transporters. This leaves more dopamine saturating synaptic clefts to overstimulate critical brain sites. Figure 1 (See also, “The Hijacked Brain” in this issue). Reuptake of other monoamines ­ norepinephrine and serotonin ­ is also blocked, producing changes in these neurobiological systems.[1,7]
Figure 1 ­ Adapted from NIDA Research Report: Cocaine. Pub. No. 99-4342, 1999
Dopamine acts at 5 different “D” receptor subtypes; however, the exact contributions of D1-like (D1,D5) and D2-like (D2,D3,D4) receptor families is not well established.[7] Plus, there has been increasing evidence that cocaine’s effects are not solely attributable to dopamine. When dopamine production was curtailed in the brains of laboratory animals, they continued to seek cocaine, so other neurotransmitters also may serve as reinforcers of reward from stimulants.[13]
Recent research isolated a protein called Delta-FosB in the brain, which triggers addiction by regulating genes controlling the nucleus accumbens. It is believed that this agent also activates genes producing glutamate, which carries messages in brain cells that increase cocaine sensitivity and craving.[14]
Amphetamines increase dopamine levels by as much as 2,600%, primarily by stimulating presynaptic release of the neurotransmitter, rather than by reuptake blockade.[1,15] Amphetamine effects last for days in the body, and some degree of neurological impairment may last up to 2 years or more after cessation of the drug.[3]
It has been proposed that sensitization to cocaine and amphetamines results from increased synaptic connectivity due to repeated exposure to the drugs. Circumstances surrounding drug taking (environmental cues) can trigger this neuronal hypersensitivity and exert a powerful influence leading to physiological arousal and increased craving at the mere sight or thought of the drug.[1,3,16] To a degree, the brain may become “rewired” for stimulant addiction.
MDMA (ecstasy) appears to involve serotonin stimulation, and chronic abuse can lead to long-term damage to serotonin-containing neurons, causing persistent memory impairments. Other functional aspects of serotonin ­ mood, impulse control, sleep cycles ­ may be affected, and it is now believed that serotonergic dysfunction may persist for many years or even become permanent.[4,5]
Some psychostimulants are known to have paradoxical effects, such as methylphenidate (Ritalin), which exerts a calming effect in children with ADHD (attention-deficit hyperactivity disorder). New research in animals suggest that these stimulants act by facilitating therapeutic concentrations of serotonin, rather than affecting dopamine.[17]
Pharmacotherapy Horizons
Recently reported research demonstrated that the selective D1/D5 receptor antagonist ecopipam diminished the euphoric and anxiogenic effects of cocaine, and stemmed craving.[7] It has been suggested that low doses of D1 antagonists might be useful in blocking relapse or blunting effects of relapse when it occurs. D3 receptor partial agonists also have been effective in reducing cocaine craving, so a combination of drugs acting on D1 and D3 receptors might prove particularly powerful for treating cocaine addiction.[18]
An anti-cocaine vaccine, called “TA-CD,” is in early testing stages. Reports indicate that the vaccine successfully mounted an antibody response against free cocaine in the blood that lasted nearly 3 months. It is believed that antibodies to other stimulants might also be developed.[19]
Normally, stimulant drugs have molecules so tiny that they sneak past the body’s immune system. To create antibodies, researchers hook the stimulant molecule to a protein large enough to set off the immune system’s alarms.[19]
Another approach uses passive immunization, in which antibodies are injected without affecting the natural immune system. A protein called a “catalytic antibody” splits cocaine molecules in the blood into neutral fragments rendering them harmless.[20]
Vigabatrin, or gamma-vinyl-GABA (GVG) ­ a drug used outside the U.S. to treat epilepsy ­ appears to reduce the biochemical effects of stimulants, opioids, and ethanol that make these drugs addictive. Experiments in animals showed vigabatrin increased the amount of the neurotransmitter GABA (gamma-aminobutyric acid), improving communication between brain cells and attenuating production of dopamine. Moreover, the medication dramatically dampened the influence of environmental cuing that normally triggers intense drug craving. Clinical trials in human cocaine addicts were planned.[15]
On the horizon, a new drug ­ BP 897 ­ that targets the environmental cuing effects of cocaine has been tested in European laboratories. The medication appears to mildly stimulate the brain while regulating dopamine levels to ease cravings.[21]
Cocaine abuse also occurs in 40%-60% of patients entering opioid addiction treatment, and a controlled clinical trial found the tricyclic antidepressant desipramine helpful when combined with either methadone or buprenorphine. The combination facilitated opioid and cocaine abstinence, especially at higher desipramine plasma levels.[22]
To date, there have been no drugs approved by the FDA specifically for stimulant dependency pharmacotherapy. As research continues, this may change in the next few years.
1. O’Brien C. Cocaine and stimulants. Lecture presented at: University of Pennsylvania Medical School, October 6, 1995.
2. Methamphetamine abuse alert. NIDA Notes.1998;13(6):15.
3. Rawson RA (panel chair). Treatment for Stimulant Use Disorders. Treatment Improvement Protocol (TIP) Series 33. Rockville, MD: Center for Substance Abuse Treatment; 1999. DHHS Pub. No. (SMA) 99-3296.
4. Club Drugs. Community Drug Alert Bulletin. Bethesda, MD: National Institute on Drug Abuse; 1999. NIH Publication No. 00-4723.
5. Mathias R. “Ecstasy” damages the brain and impairs memory in humans. NIDA Note 1999;14(4):10-11,15.
6. A dangerous drug hits the heartland. Reader’s Digest. April 1999.
7. Romach MK, Glue P, Kampman K, et al. Attenuation of the euphoric effects of cocaine by the dopamine D1/D5 antagonist ecopipam (SCH 39166). Arch Gen Psychiatry. 1999;56:1101-1106.
8. Bolla KI. In: J Neuropsych Clin Neurosciences. Summer 1999.
9. Stocker S. Cocaine abuse may lead to strokes and mental deficits. NIDA Notes. 1998.;13(3):10-12.
10. Petitti D, Sidney S, Quesenberry C, et al. Reported in: Epidemiology. 1998;9(6):596.
11. Satran A, Henry TD. Presentation at: 72nd Scientific Sessions of the American Heart Association. November 1999.
12. Siegel AJ, et al. Evidence for drug-related blood doping and prothrombotic effects. Arch Int Med. 1999;159:1925-1930.
13. Garris PA, Kilpatrick M, Bunin MA, Michael D, Walker QD, Wightman RM. Dissociation of dopamine release in the nucleus accumbens from intracranial self-stimulation [letter]. Nature. 1999;398(6722):67-69.
14. Nestler E, et al. Reported in: Nature. September 16, 1999.
15. Brennan M. Evidence mounts that epilepsy drug could alleviate drug addiction. Chem & Eng News. August 23, 1999:8. Also see: Dewey S, et al. Synapse. 1999;34(11).
16. Robinson T, Kolb B. Presentation at: 5th Annual Wisconsin Symposium on Emotion, April 23, 1999.
17. Marx J. How stimulant drugs may calm hyperactivity. Science. 1999;283(5400):306.
18. Koob GF. Cocaine reward and dopamine receptors. Arch Gen Psychiatry. 1999;56(12).
19. Kostens K. Presentation at: 61st Annual Scientific Meeting of the College on Problems of Drug Dependence, Acapulco, Mexico, June 1999.
20. Travis J. War on drugs enlists an antibody. Science News.1998;154(15):239.
21. Pilla M, et al. Reported in: Nature. July 22, 1999.
22. Oliveto A, et al. Desipramine in opioid-dependent cocaine abusers maintained on buprenorphine vs methadone. Arch Gen Psychiatry. 1999;56:812-820.

From the Editor

Beneficent Booze? Just ask 007

How Much is Enough
What can help prevent heart disease, stroke, cancer, diabetes, liver disease, dementia, and cataracts? Alcohol. Ethanol to be precise; or, booze if you prefer.
That’s the conclusion proffered by more than a dozen research reports in just the past year, examining nearly 125,000 people and an untold number of laboratory rats. These have been mentioned in the News Updates at our Web site ­ www.atforum.com.
How much alcohol is necessary to do the job? Well, that’s puzzling.
Shaken, Not Stirred
Most of the studies advocate a cocktail or two a day ­ or a pint of beer or a few glasses of wine. And make that martini in a shaker. An article in the British Medical Journal (no less) demonstrated that such libations ­ as fictional secret agent 007 James Bond always required them ­ are richer in healthful antioxidants than the stirred variety.
As might be expected, heavy drinking cancels out all benefits, as risks of serious illness and premature death kick in. However, in many studies, social drinkers and abstainers don’t fare very well either. People who drink less than a few drinks each week appear to risk stroke and heart disease.
Jimmy Was Wrong
The net effect of all this research is ambiguity. For every study finding benefits of alcohol, another is less certain or qualifies the therapeutic effects ­ e.g., healthy for the heart; murder on the liver. One investigation found a drink per day decreased coronary heart disease by 25%, while other research demonstrated that drinking just a bit more increased risks of cardiogenic brain embolism.
Even James Bond had it wrong. Any amount of alcohol, shaken or not, raises levels of oxidants in the body. These pesky chemicals can damage major organs, including the brain, heart, and liver.
For example, red wine has been touted almost as a health food, in part because it contains antioxidants. Research showed that those antioxidants barely counteract harmful oxidant effects of the alcohol in wine.
Ask Right Question
An editorial in the New England Journal of Medicine (November 18, 1999) noted that there are numerous potential sources of error and bias in studies of alcohol consumption and health benefits. Readers were reminded that the pathophysiological mechanisms behind alleged medical benefits of alcohol remain obscure, and they were cautioned not to lose sight of the physical and social damage provoked by alcohol abuse and dependency.
There seems to be dire potential for results of beneficent booze research to be applied recklessly. For one thing, it’s a perilous rationalization for millions of alcoholics: “I’m only drinking for my health.”
Perhaps, a great deal of effort and money (who’s funding these studies?) have been directed at the wrong question, asking, “How much alcohol should people drink to be healthy?”
Better to ask: “Are there better ways to help people overcome their drinking problems?”
Survey ­ Patients Battling Prejudice
We are continuing our survey from the last issue of AT Forum on the challenges faced by patients in addiction treatment programs. There are several ways to respond: A. Provide your answers on the postage-free feedback card in this issue; B. Write or fax us [see info below]; or C. Visit our Web site to respond online. As always, your written comments will also help us discuss the results in our next issue.
Stewart B. Leavitt, PhD, Editor
stew202@aol.com
Addiction Treatment Forum
1750 East Golf Rd., Suite 320
Schaumburg, IL 60173
FAX: 847-413-0526
Internet: http://www.atforum.com

Events to Note

For additional postings & information, see: www.atforum.com

March 2000
Amer. Counseling Assn. Conference
March 20-25, 2000
Washington, DC
Contact: 800-347-6647; amiller@counseling.org; www.counseling.org/conference/default.htm
Treatment – Recovery for Deaf People
March 23-25, 2000
Minneapolis, MN
Contact Deb Guthmann: 612-672-4402;
dguthmann@aol.com
April 2000
14th Ann. ADAD Conference
April 9-11, 2000
Pueblo, Colorado
Contact Elizabeth Smith: 303-756-8380;
www.conferenceoffice.com/adad
AMTA – Conference 2000
April 9-12, 2000
San Francisco, CA
Contact: 609-423-7222 ext 350;
meetings@tmg.smarthub.com
ASAM Pain in Addiction Conf.
April 12, 2000
Chicago, IL
Contact: 301-656-3920; email@asam.org
www.asam.org
ASAM 31st Ann. Conference
April 13-16, 2000
Chicago, IL
Contact: 301-656-3920; email@asam.org; www.asam.org
May 2000
Critical Issues in Addiction
May 21-23, 2000
San Francisco, CA
Contact: 415-565-1904
June 2000
Medical Aspects of Addiction
June 8-10, 2000
Myrtle Beach, SC
Contact Timothy Fischer, MD: 803-536-4900;
Timothy_fischer@msn.com

[To post your event announcement in A.T. Forum and/or our Web site, fax the information to: 847/413-0526 or submit it via e-mail from http://www.atforum.com]

Brainstorm: The Hijacked Brain Part 3

Addictive psychotropic substances sometimes appear to take on lives of their own, capable of “stealing away” the brain and altering it irreversibly. Since the human brain is command central of all perceptions, thoughts, feelings, and actions, understanding addiction requires some knowledge of brain structure, function, and chemistry.
More Cells Than Milky Way Stars
The brain’s fundamental functional unit is the neuron, a cell with the sole purpose of conveying information both electrically and chemically. There are billions of neurons in the brain ­ more cells than there are stars in the Milky Way.[1]
It is believed that at birth a person possesses all the neurons he/she will ever have, unlike most other body cells that can divide and replenish themselves throughout life. Furthermore, as many as 200,000 brain cells normally die each day.[1] The implication is that the even more extreme neuronal degeneration and/or changes in cell structure brought about by substance abuse can never be repaired.
Yet, brain cells do possess remarkable abilities to rebuild and repair themselves; a capability called “plasticity.” For example, each of the 20 billion neurons in the brain’s cerebral cortex ­ the outer rind of the brain where higher intelligence and personality reside ­ may have up to 10,000 connections with other neurons. Plasticity allows these cells to constantly sprout new connections facilitating learning and memory. If this process runs amok, some researchers believe, a misdirected or faulty repair mechanism can result in disturbances of mental function, as happens with Alzheimer’s disease[2] and, possibly, with long-term drug abuse.
In an exciting new discovery, scientists at Princeton University found that thousands of freshly hatched neurons arrive each day in the cerebral cortex. Although the research was in monkeys, it challenges the long-standing belief that adults never generate new brain cells. It also may lead to new approaches for revitalizing memory and learning or for restoring dysfunctional neuronal processes wrought by addiction.[3]
Carrying the Message
A typical neuron consists of a cell body (containing a nucleus with the cell’s genetic information), a large number of short-branched filaments, dendrites, and one longer fiber, the axon. At the end of the axon are additional filaments sprouting like tree branches that connect with the dendrites of other neurons.[4] Figure 1.
Figure 1 ­ Adapted from Dowling. [1]
Inputs to nerve cells are usually via dendrites; axons carry output signals. These signals (called “action potentials”) surge along axons at up to 200 miles per hour.[1]
Signals are carried in the form of electrical impulses within neurons. However, when signals are sent from one neuron to another, they must typically bridge a gap, or synapse, from one cell membrane to another. At the synapse, the electrical signal within the neuron is converted to a chemical signal.
To do this, the terminal ends of axons contain chemicals called neurotransmitters. Impulses in the axon cause the release of neurotransmitters, which float cross the synapse and adhere to special receptors on the outer surfaces of nearby neurons or dendrites.
There are about 50 to 100 different neurotransmitters in the human body, each interacting with one or many receptors. To date, 35 types of receptors for neurotransmitters have been identified,[5] at which processes occur that alter the actions of receiving neurons.
The actions of neurotransmitters are complex. Some of these chemicals excite the receiving neuron, some inhibit the cell’s responsiveness, others have modifying effects to selectively increase or decrease the cell’s response ­ called neuromodulation.[1,4]
After a neurotransmitter is taken up by the receiving neuron’s receptors, a cascade of biochemical reactions may involve secondary or even tertiary chemical messengers. In this way, profound physiological and structural changes can be produced in a neuron that can last from seconds to days, or even longer. This phenomenon, occurring in millions or billions of affected neurons, may produce striking changes in perceptions, memory, behavior, or even personality.
Following the release of a neurotransmitter into the synaptic space, it must be “mopped up” to stop the reaction and allow fresh chemicals to exert effects. Usually, it is rapidly taken back into the axon terminals (a process called “reuptake”) by proteins called transporters. However, certain drugs block transporter function, causing transmitters to remain longer in the synaptic cleft and trigger physiological and/or psychological changes.[1] (See also, “Update: Stimulant Use Disorders” in this issue.)
Evil Tutors
A great deal of attention has been focused on synapses and their neurochemical schemes because most of what the brain does is by synaptic interactions. Many mental disorders (e.g., depression, anxiety, schizophrenia) may result from impaired synaptic mechanisms. Psychoactive drugs ­ including drugs of abuse or dependency ­ either increase neurotransmitter release, stimulate receptors, hinder reuptake of neurotransmitters, or inhibit enzymes that would otherwise break down the transmitters.[1,5]
According to researcher Avram Goldstein, all addictive drugs share a common characteristic in that they interact with receptors for some endogenous (i.e., naturally produced within the body) neurotransmitter.[6] The many endogenous neurotransmitters discovered thus far fall into one of four chemical classes: acetylcholine, amino acids, monoamines, and neuropeptides.[1] Table 1.
Evidence from both animal and human research suggests that commonly abused psychotropic drugs may deceive the brain, sometimes mimicking endogenous neurotransmitters, to over-stimulate or block natural processes involved in the brain’s reinforcement and reward systems. A danger is that the effects of abused substances can become more powerfully rewarding than the body’s inborn reinforcers. Like an evil tutor, the lesson of an addictive drug is that the brain should want more of it ­ whatever the costs.[4,7]
Unrestrained Reward
It is believed that reinforcement and reward are associated with a drug’s capacity to increase levels of the neurotransmitter dopamine in critical brain areas, particularly the nucleus accumbens (NAc). This mass of neurons lies along bundles of fibers called the mesolimbic dopamine system deep within the brain. It arises from the midbrain’s ventral tegmental area and substantia nigra and courses into the prefrontal cortex and striatum, respectively. Colloquially, this system is known as the “reward pathway.” [1,4,8-10] Figure 2.
Figure 2 ­ Mesolimbic Reward Pathway. Adapted from Leshner. [9]
Most addictive substances ­ e.g., opioids, cocaine, amphetamine, ethanol ­ appear to increase extracellular dopamine levels in the reward pathway, although the process can be indirect.[1,4,7,8] For example, exogenous opioids like heroin circuitously influence neurons within the reward pathway to release excess dopamine.
Dopamine neurons are normally held in check by other (inhibitory) neurons. In turn, endorphin, an endogenous neuromodulator, helps control the extent of this inhibition. A burst of endorphin slows the inhibition ­ allowing the floodgate to open a bit, so to speak ­ and extra dopamine is released. This is how naturally occurring opioid peptides ­ enkephalins and endorphins ­ act to produce feelings of satisfaction, good moods, and other intrinsic rewards.[11,12]
Heroin mimics endorphin interacting at mu-opioid receptors, overriding the natural control mechanisms and provoking a flood of excessive, euphoria-producing dopamine. The addicting power of heroin is considered due to severe overstimulation of the mesolimbic reward pathway, bringing about adaptive changes in neurons leading to withdrawal and craving in its absence that perpetuate drug use.[11,12] Whereas, addicts initially may take heroin to feel good, they end up taking it to avoid feeling bad.
In a figurative sense, psychotropic substances of abuse appear to “hijack” the brain’s natural reward system and alter certain aspects of its function.[10] As NIDA chief Alan Leshner has so often emphasized, the brains of addicts become different.[13]
It should be noted that opioids used in addiction treatment ­ i.e., methadone and LAAM ­ have different pharmacokinetic properties from heroin. These agents occupy mu-opioid receptors in a steady, stable state, allowing a normalization of dopamine function contrasting sharply with the repeatedly excessive “highs” and “lows” of heroin ­ they are not merely heroin substitutes.[6,12]
Beyond Dopamine
Whether or not the neurochemical disturbances of a “hijacked brain” ever can be rehabilitated to completely normal function remains a treatment conundrum. As Goldstein has noted, merely detoxifying addicts from a drug- dependent state is relatively easy; therefore, addiction should be easy to cure.[6] However, it has long been recognized that many addicts return to destructive drug use even after long-standing abstinence that should have normalized brain chemistry.
One author has proposed that understanding the entire milieu of addiction requires venturing into the realm of human cognitions ­ personal attitudes, beliefs, and goals ­ that play vital roles in drug abuse.[14] It also has been suggested that psychological counseling can actually alter brain chemistry, possibly restoring more normal functioning, and that there lies the merit in combining psychotherapy with pharmacotherapy in treatment.[1]
A guiding principle of modern neuropharmacology is to mimic, amplify, block, or reduce the availability of certain neurotransmitters believed as critical in the disorder being treated. Unfortunately, there appears to be no one-to-one matching of a single neurotransmitter system to a particular addiction,[15] and it seems unlikely that a single pharmacotherapeutic agent will “cure” addiction.
However, there have been some noteworthy successes in the pharmacologic treatment of addiction. For example, methadone and naltrexone have demonstrated efficacy in treating (yet, not curing) opioid and alcohol dependency, respectively.
Furthermore, new research suggests that dopamine may not be the “master molecule”[10] of addiction or, at least, not the only one. While bursts of dopamine triggered by drugs may attract the brain’s attention, modifications in glutamate signaling appear to produce more lasting changes in the brain, fostering compulsive drug-seeking.[7] Other studies propose that, although dopamine may play an early central role in feelings of satisfaction or euphoria, another chemical ­ possibly serotonin ­ could be the major messenger of continuous reward. In fact, dopamine may be only a neural harbinger of reward expectation, rather than reward itself.[16]
As science uncovers further intricacies of brain function, especially involving synaptic mechanisms and neurochemistry, more targeted and effective pharmacologic agents will undoubtedly be developed. And, if the brain can truly rejuvenate itself with fresh neurons and synaptic connections as new research implies, an understanding of how to harness and direct this plasticity may open entirely new frontiers of addiction treatment.
Table 1 ­ Neurotransmitters (Partial List) [1,4,6,11]
1. Dowling JE. Creating Mind: How the Brain Works. New York, NY: WW Norton; 1998.
2. Mesulam MM. Neuroplasticity failure in Alzheimer’s disease: bridging the gap between plaques and tangles. Neuron. 1999;24(3):521-529.
3. Gould E, Reeves AJ, Graziano MS, Gross CG. Neurogenesis in the neocortex of adult primates. Science. 1999;286:548-552.
4. O’Malley S (consensus panel chair). Naltrexone and Alcoholism Treatment. Treatment Improvement Protocol (TIP) Series 28. Rockville, MD: Center for Substance Abuse Treatment; 1998. DHHS Pub No. (SMA 98-3206.
5. Brick J, Erickson C. Drugs, the Brain, and Behavior. The Pharmacology of Abuse and Dependence. New York, NY: Haworth; 1998.
6. Goldstein A. Heroin addiction: neurobiology, pharmacology, and policy. J Psychoactive Drugs. 1991;23(2):123-133.
7. Wickelgren I. Teaching the brain to take drugs. Science. 1998;280(5372):2045-2047.
8. O’Brien CP. Pharmacological aspects of addiction. Lecture presented at: University of Pennsylvania Medical School; September 19, 1995; Pittsburgh, PA.
9. Leshner AI. Drug abuse and addiction are biomedical problems. Hospital Practice. 1997; April (Special Report):2-4.
10. Nash M. Addicted: Why do people get hooked? Time. May 5, 1997.
11. Nutt DJ. The neurochemistry of addiction. In: Graham AW, Schultz TK, eds. Principles of Addiction Medicine. 2nd ed. Chevy Chase, MD: American Society of Addiction Medicine, Inc;1998:51-55.
12. Goldstein A. Neurobiology of heroin addiction and methadone treatment. Presentation at:1997 National Methadone Conference; April 1997; Chicago, IL.
13. Leshner A. Addiction is a brain disease and it matters. Science. 1997;278:45-47.
14. Gazzaniga MS. [Editorial.] Science. 1997;275(5299):459-460.
15. Greenfield S. Brain drugs of the future. BMJ. 1998;317:1698-1701.
16. Garris PA, Kilpatrick M, Bunin MA, Michael D, Walker QD, Wightman RM. Dissociation of dopamine release in the nucleus accumbens from intracranial self-stimulation [letter]. Nature. 1999;398(6722):67-69.

Where to Get Info

Recovery 2000

Set your Internet browser to www.recovery2000.com for heaps of information on substance dependency, especially alcoholism and naltrexone therapy. This site is managed by the Treatment Research Center at the University of Pennsylvania and directed by Joseph Volpicelli, MD, PhD, one of the premier researchers of alcoholism and the use of naltrexone.

There is easy access to authoritative research articles and lectures-in-print on numerous addiction topics. The naltrexone FAQs are helpful for both patients and practitioners, and patient case studies provide insights into the clinical application of this underutilized medication. There are listings of treatment programs worldwide using naltrexone therapy, links to other sources of information on the Web, and a number of interactive surveys and self-tests.

Watch for a new book by Volpicelli and Maia Szalavitz coming from Popular Press early next summer: Recovery Options, The Complete Guide. Register at the Web site to be notified when the book is available.

 

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