ADDICTION, TOLERANCE, AND DEPENDENCE

ADDICTION, TOLERANCE, AND DEPENDENCE

While the buzz from opiates might sound alluring, it comes at a cost. Opiate drugs stimulate all opioid systems simultaneously, so there are many unwanted effects that accompany the desirable ones. One of these is the cycles of withdrawal that opiate users experience. People who take opiates for a while (weeks) can develop significant dependence and addiction and undergo withdrawal when they stop. Most opiate addicts use heroin or other opiates several times a day. With this pattern of use, tolerance develops to many of the actions of opiates, but it develops to different effects at different rates. In experimental studies, tolerance develops quickly to the ability of opiates to suppress pain. However, patients experiencing intense, chronic pain like that associated with ter­minal cancer can actually show little tolerance to the analgesic effects of opiates. Tolerance also develops fairly well to the suppression of breath­ing (this is why opiate users can tolerate higher and higher doses). How­ever, the constipation remains, and the pinpoint pupils are slow to change. The latter is fortunate because it provides a useful sign of OD in a comatose patient and can help identify even a long-time user. While tolerance develops to opiate-induced euphoria, the drug keeps providing enough pleasure that users still get high.

Part of the tolerance results from chemical changes in how cells respond to opiates. The normal chain of events initiated by opiates adapts to the continuous presence of the drug. The adaptation becomes so thor­ough that cells function normally even though the drug is present. Another part of tolerance is purely a conditioned response. Pharmacolo­gists have learned from animal studies that if you give animals a dose of heroin every day in the same room, they tolerate higher and higher doses. However, if you move them to a strange environment, the dose that they usually tolerated kills them: we think that conditioned responses permit their bodies to anticipate and counter the effects of the drug. This condi­tioning effect probably does apply to humans. Frequently, very experi­enced opiate users who OD do so because they took the drug in an unfamiliar environment.

Opiate withdrawal is miserable but not life-threatening (unlike alcohol withdrawal). Again, in Junkie, William Burroughs provides a good description:

The last of the codeine was running out. My nose and eyes began to run, sweat soaked through my clothes. Hot and cold flashes hit me as though a furnace door was swinging open and shut. I lay down on the bunk, too weak to move. My legs ached and twitched so that any posi­tion was intolerable, and I moved from one side to the other, sloshing about in my sweaty clothes.... Almost worse than the sickness is the depression that goes with it. One afternoon I closed my eyes and saw New York in ruins. Huge centipedes and scorpions crawled in and out of empty bars and cafeterias and drugstores on Forty-second Street. Weeds were growing up through cracks and holes in the pavement. There was no one in sight. After five days I began to feel a little better.

The earliest signs of withdrawal are watery eyes, a runny nose, yawn­ing, and sweating. When people have been using opiates heavily, they experience mild withdrawal as soon as their most recent dose wears off. As withdrawal continues, the user feels restless and irritable and loses his appetite. Overall, it feels like the flu. As withdrawal peaks, the user suffers diarrhea, shivering, sweating, general malaise, abdominal cramps, muscle pains, and, generally, an increased sensitivity to pain. Yawning and diffi­culty sleeping gradually become more intense over the next few days. The worst of the physical symptoms abates after a few days.

If flu symptoms were all that happened when addicts stopped using, treating heroin addiction would be easy. Unfortunately, there is another symptom that is more intangible but much longer lasting. There is a dysphoria (the just-feeling-lousy feeling), which may be the reverse of opiate-induced euphoria. They experience a craving for the drug that can be so strong that it becomes the only thing they can think about. The craving for a fix can last for months, long after the physical symptoms have abated. This is the symptom that usually triggers relapse.

Most of these withdrawal signs are the opposite of acute drug effects For example, opiates cause constipation, and diarrhea occurs when people go through withdrawal. The body of the addict adapts to maintain a level of intestinal tract movement despite the presence of the opiate that is con­stipating. Remove the opiate, and the underlying processes that were counteracting it to keep things normal suddenly find themselves unhin­dered. The character in the movie Trainspotting experienced this effect, which necessitated his mad dash for the bathroom in one scene. This rep­resents the sort of yin-yang response the body has to any disruption. (If you shiver and feel cold when you are withdrawing from opiates, what do opiates usually do to body temperature?)

Many addiction researchers think that once people are established addicts, the desire to avoid withdrawal maintains addiction more than the pleasurable effects of the drug. Obviously, when people first get addicted, they haven't been taking the drug long enough to go through intense with­drawal if they stop. However, after several months or years, the withdrawal is stronger and may contribute more to an addict's continued drug taking. If you know taking the drug will solve the problem, it seems an easy solu­tion, doesn't it? In the end, it is a combination of changes in the brain that create the overwhelming compulsion to keep using narcotics (or any other highly addictive drug). Researchers think that the craving for a drug may result from chemical changes in two parts of the brain that unfortunately combine their efforts: the parts of the brain that seek reward are chemically changed to respond strongly to drug cues, and the parts of the brain that create anxiety and bad feelings start firing as soon as the drug wears off.

NATURAL HIGH OUR OWN ENDORPHINS

NATURAL HIGH OUR OWN ENDORPHINS

Are the joys of nature (music, sex, meditation, whatever) as great as drugs? There may be a crumb of truth in this. The brain does produce its own opiates—the enkephalins and endorphins. If we inject these into animals, they cause the same effects as morphine or heroin. The big question is, are they released in circumstances in which we feel great? Can we learn to release them ourselves? 'Ihe latter question is a premise of the science fic­tion book Earth, by David Brin, which depicts a future world where drug abuse no longer exists: the new social outcasts are the brain addicts who have learned to release their own opioids.

Naturally released endorphins do affect behavior. One enterprising sci­entist showed that the release of endorphins went up in animals undergo­ing experimental acupuncture, lending credence to this ancient Chinese healing technique. How can we tell if we are releasing endorphins? First, we could give a drug like naloxone (Narcan) and see if the endorphin high stopped. This approach has actually been tested on people listening to their favorite music, who found that they didn't enjoy the music as much if they were treated with an opiate antagonist (and pleasure is in the ear of the beholder—it has to be music the listener likes, whether it is Bee­thoven or Florence and the Machine). However, playing the music instead of listening to it may be even more effective. A recent study that used increased pain threshold as a surrogate for endorphin activity in the brain showed that playing music or drumming elevated the pain threshold of the musician. How about runner's high? Do endorphins kick in at the end of a marathon? A recent experiment suggests that may happen. Scientists showed that endogenous opioids were released in the brains of people who had just completed a two-hour endurance run. Overall, endogenous opioids play an important role in suppressing pain and in promoting reward. Recent studies showed that animals with no beta-endorphins will not take care of their babies, implicating endor­phins as a critical element in nurturing behavior as well. These neu­rotransmitters are crucial to an important and related group of behaviors essential to human survival. Dynorphins also have an important role to play, telling us that stressful experiences make us feel bad, hopefully teaching us to avoid such experiences in the future.

WHAT MDMA DOES TO THE BRAIN AND BODY

WHAT MDMA DOES TO THE BRAIN AND BODY

MDMA users provide very consistent reports of the feelings that result from taking it. Almost all users say that it causes a feeling of empathy, openness, and caring. The enhancement of positive emotions has been described as a decrease in defensiveness, fear, the sense of separation from

others, aggression, and obsessiveness.

One first-time user reported the effects in this way: "What happens is, the drug takes away all your neuroses. It takes away your fear response. You feel open, clear, loving. I can't imagine anyone being angry under its influence, or feeling selfish, or mean, or even defensive. You have a lot of insights into yourself, real insights that stay with you after the experience is over. It doesn't give you anything that isn't already there. Ifs not a trip.

You don't lose touch with the world. You could pick up the phone, call your mother, and she'd never know." *

In both animals and humans, MDMA seems to cause a combination of amphetamine- and hallucinogen-like effects. MDMA does not cause overt hallucinations, but many people have reported enhanced perception of sensory stimuli and distorted time perception while under the influ­ence of the drug. It causes an amphetamine-like hyperactivity in people and animals, as well as the classic signs of stimulation of the fight-or­flight response. For instance, heart rate and blood pressure increase, and the smooth muscles of the breathing tubes (bronchioles) dilate. The pupils dilate, and blood flow to the muscles increases.

One way to test the qualities of an unknown drug is to give it to an ani­mal that is trained to recognize a certain class of drugs and see if it recog­nizes this one. This is called a drug discrimination test. When such tests are done with MDM A, some animals trained to recognize amphetamine also recognize MDNIA, while other animals trained to recognize LSD or other hallucinogens also recognize MDM A. This confusion almost never happens with other drugs. Amphetamine-like drugs are almost never confused with hallucinogens. This finding points out the unique behav­ioral effects of MDMA.

People report that MDMA decreases feelings of aggression, and animal studies confirm this impression. MDMA has contradictory effects on sex­ual function: while some people report greater sensory pleasure with stimulation, studies in animals and human self-report show a delay or inability to achieve orgasm. MDMA shares this effect with other drugs like SSRIs that raise synaptic serotonin. There is mixed information about whether MDMA is pleasurable and addictive the way cocaine is. Primates will take this drug voluntarily, and the general profile of the way the drug acts on the brain indicates that it has the potential to be addictive. How­ever, the typical pattern of human use is quite different from that of cocaine and amphetamine. While people clearly use it repeatedly, it is used most frequently in a specific environment, like rave dance parties. Although compulsive daily use as seen with cocaine or heroin is not typi­cal with MDMA, some people do experience tolerance to the effects of MDMA and increase the number of pills to compensate. A student in a focus group reported, "The more you do it the less good you feel while on it and the worse you feel coming down."unusual Overall, MDMA creates a very unal behavioral profile. The positive feelings that people report are most similar to the effects of fluoxetine (Prozac) and fenfluramine (the main component of the withdrawn diet pill Pondimin). This makes sense, as we will see in what follows, because these three drugs share some biochemical actions. Overall, MDMA doesn't fit into any other drug category, and the term entactogen, mean­ing "to touch within," has been coined to describe drugs such as this.

MDA is very closely related to MDMA in chemical structure, and though it shares the amphetamine-like effects, its effects on mood are dif­ferent. MDA acts more like a typical hallucinogen. NADE effects more closely resemble those of NI DMA, but it lacks the unusual empathic qual‑

ities of MDMA.