Never Enough: the neuroscience and experience of addiction (The Addicted Brain)

by Judith Grisel

As with every addict, my days of actually getting “high” were long past. My using was compulsive and aimed more at escaping reality than at getting off.

What was once a normal state punctuated by periods of high, inexorably transforms to a state of desperation that is only temporarily subdued by drug.

most research suggests that the psychedelic LSD does not stimulate the mesolimbic pathway. From this and related evidence, the majority of addiction researchers would argue that LSD is not an addictive drug.

So, if the pathway were somehow lesioned before a shot of alcohol or bump of cocaine, especially if these were among your initial experiences with those substances, you’d think the drugs were a complete waste of money (though you’d be sedated or behaviorally active, depending on which drug you had because those effects are produced elsewhere).

In recent years, new evidence has shown that dopamine in the mesolimbic pathway works not exactly by signaling pleasure but by signaling the anticipation of pleasure.

In general, the more predictable and frequent the dosing, the more addictive a drug will be.

1. All drugs act by changing the rate of what is already going on. 2. All drugs have side effects. 3. The brain adapts to all drugs that affect it by counteracting the drug’s effects.

Serotonin release in the normally functioning brain is targeted to particular cells at particular times, depending on whether it is time to sleep, time to fight, time to eat, and so on. But drugs that enhance or attenuate serotonin act in all these places at once rather than in precise circuits. Therefore, if you take such a drug to modify mood, it will also produce side effects in other motivated behaviors such as sleeping and sex.

The brain’s response to a drug is always to facilitate the opposite state; therefore, the only way for any regular user to feel normal is to take the drug.

Eventually, exposure to a favorite drug results in virtually no change in mesolimbic dopamine, but withholding it leads to a big drop, which we experience as a feeling of disappointment and craving. Thus the most profound law of drug use is this: there is no free lunch.

The first cigarette of the day is the best one because after the particular brain sites for nicotine’s effects have been activated, they become insensitive to subsequent exposures.

For some drugs, such as antidepressants, adaptation is actually the therapeutic point. Developing tolerance to selective serotonin reuptake inhibitors (SSRIs) may help to change a pathological affective “set point” so that being depressed is no longer the patient’s normal state.

I don’t suppose those refusing cocaine or even marijuana encounter the mix of incredulity and pity that those of us refusing alcohol regularly experience.

The first drug prescribed specifically to treat alcoholics was based on the premise of positive punishment. Antabuse interferes with the metabolism of alcohol and leads to a buildup of acetaldehyde, which is toxic. This metabolite produces uncomfortable physiological effects including flushing, sweating, and irregular heartbeat. Though it is still used to some benefit by highly motivated individuals, forty years of research have largely confirmed what most parents and pet owners already know: in general, punishment is not an especially effective way to change behavior. Some people live as if permanently taking Antabuse because of a natural deficiency in the enzyme that metabolizes acetaldehyde, caused by a common gene variation. These mutations are fairly rare in those with European descent but present in about half of northeast Asians. Within an hour after consuming alcohol, such people experience allergic-like reactions to the drug, including facial flushing, hives, and shortness of breath. Not surprisingly, this mutation decreases the tendency toward excessive drinking; however, it doesn’t totally prevent alcoholism, demonstrating the limited efficacy of punishment on behavior.

Unfortunately, many people are dependent on benzodiazepines and need them just to function normally. Though they might have begun taking anxiolytics to help them cope with a specific event or stressor, adaptation to these drugs is robust and inevitable, guaranteeing a particularly anxiety-ridden day if one skips a dose.

Rats will readily learn to run up an alley for a cocaine infusion. In one study, they have this opportunity once a day for fourteen consecutive days, but instead of going faster each day, as they would with other drugs such as heroin, they begin quickly and just before reaching the infusion source are apt to turn and run the other way. They usually go back and forth several times—“Yes! I want it” / “No! I don’t”—suggesting to researchers what every addict already appreciates: that cocaine addiction is a mix of positive and negative motivational states and that the negative consequences sensitize. Some have hypothesized that this quirky and unfortunate adaptation may account for the association between cocaine use and anxiety disorders, which emerge with frequent use and grow worse as the addiction progresses.

Instead, caffeine is an antagonist at adenosine receptors (just as Narcan is an antagonist at opiate receptors). Adenosine may be familiar in its role in adenosine triphosphate, or ATP, a primary source of energy. But adenosine also serves as a neurotransmitter and is thought to build up over the day, accumulating in synapses where it binds to its receptors, precipitating a state of drowsiness. When caffeine is on board, adenosine signaling is blocked and as a result temporarily prevents or relieves drowsiness and maintains or restores alertness.

(As a rule of thumb, it takes about five half-lives to get rid of about 95 percent of any drug,

It seems that MDMA causes non-repairable damage, especially to serotonergic neurons,

Every drug that acts on the central nervous system to change the way we feel will cause an opponent process. For most drugs discussed in this book, it’s likely that with abstinence the b process will dissipate and the brain return somewhere near its nascent state. Unfortunately, it doesn’t look as if this is going to be the case with stimulants, and particularly for those abusing amphetamines or ecstasy.

A singular fact about psychedelics is that the majority of scientists who study abused substances don’t think these are addictive. Though highly regulated across the globe, the compounds LSD, mescaline, DMT, and psilocybin are certainly much less harmful than many other substances and may even confer benefit. Despite political and social opposition and a dearth of research (due to regulatory constraints), the scientific community remains curious about the effects of these compounds and open-minded concerning the potential therapeutic benefit they may afford.

The use of LSD in the drug scene can thus be seen as a profanation of a sacred substance.

Because of their lasting halo, I tend to agree with Hofmann and others that psychedelics are a tool for the path but not themselves a path. To think otherwise is like mistaking the finger pointing at the moon for the moon itself.

As a side note, I was struck while reading the early literature that the single exception to humans being the sole species to show any interest in volunteering to test psychedelics were nonhuman primates who—only when deprived of normal external stimulation, including social interactions—would sometimes prefer to sit alone in their cages and self-administer psychedelics, lost in what, I can only imagine.

My takeaway from psychedelics is the light they shone on what is always available but somehow usually obscured.

The universality of drug taking across the animal kingdom has suggested to some that such activity may reflect a biological drive, like that for food or sex.

“Why me?” There seemed plenty of reasons that I shouldn’t be one of those people who couldn’t control their use. I thought I was smarter . . . or more resolute . . . or more deserving.

Almost by definition, we’re more inclined to think of our use as the solution to our troubles than the cause. Sure, I met some of the criteria some of the time, but my ability to fool teachers, clinicians, and law enforcement stemmed from an ability to fool myself.

After about thirty years of highly motivated focus on the research, I’d say there are four primary reasons people like me develop addictions. Well, actually five, but I’m saving the gloomy news for last. The four are these: an inherited biological disposition, copious drug exposure, particularly during adolescence, and a catalyzing environment. It’s not necessary to have all four, but once some threshold is reached, it’s like breaching a dam—virtually impossible to rebuild. So, with enough exposure to any addictive drug, any one of us will develop the hallmarks of addiction: tolerance, dependence, and craving. But if the biological predisposition is very high, or use starts during adolescence, or certain risk factors are present, less exposure will do the trick.

In other words, the experiment suggested that if your parent used THC before you were conceived, you may be at increased risk for developing a mood disorder or an addiction.

the older one is when one begins getting high—on anything from alcohol to amphetamine—the less likely one’s use is to become addictive.7