Tag: psychopharmacology

01/31/23

Never Enough and Adaptation

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In “Never Enough and No Free Lunch,” we looked at what Judith Grisel identified as the three laws of psychopharmacology from her book, Never Enough. She recalled a time when giving a brief lecture to a group of high school students on the opponent-process theory of Solomon and Corbit. A student leaped to his feet and cried out, “This changes my life!” She said she shared his sentiments and added that the theory was important because it largely “set the course” for how scientists think about and study addiction.

Richard Solomon and John Corbit proposed that every stimulus that disturbs the way we feel is counteracted by the nervous system in order to bring the body back to an emotional “set point” or homeostasis. In their description of the theory in a 1974 article for Psychological Review, “An Opponent-Process Theory of Motivation,” they said addiction did not differ in principle from any acquired motivational system. “We can easily describe opiate, alcohol, barbiturate, amphetamine, or cigarette addiction within the empirical framework of the analysis we have proposed.”

Grisel said Solomon and Corbit suggested that feeling states are maintained around a “set point” like body temperature is. Any feeling, such as being happy, depressed or excited, represents a disruption of the stable feeling state or homeostasis. The opponent-process theory suggests that “any stimulus that alters brain functioning to affect the way we feel will elicit a response by the brain that is exactly opposite to the effect of the stimulus.” The fact that our feeling states are so tightly constrained has important implications for understanding drug abuse. The brain learns by adapting to every drug that affects its function.

Some of these changes are relatively transient, like tachyphylaxis [an acute, sudden decrease of response to a drug after its administration, rendering it less effective] in an occasional drinker, but as learning is stronger with repetition, chronic exposure to a drug results in more lasting alterations. 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. . . .As the brain adapts to a drug of abuse and the drug becomes less effective at stimulating dopamine transmission, a user must take more and more to produce the same high. Engaged in a futile attempt replicate the initial experiences, an addict repeatedly administering the drug ensures more and more adaptation.

In the following charts, the A process is what the drug does to the brain and the B process is the brain’s response or adaptation to the drug, as it attempts to return the brain to its neutral, homeostatic state. State A can be pleasant or unpleasant, but whatever it is, State B is the opposite. The set point is the line in the middle. Large doses of a drug produce large A processes, and long-lasting stimulations produce long-lasting A processes.

When the brain is first exposed to a drug, the high or A process is not initially dampened by the B process of the brain trying to return to a neutral, homeostatic state. This leads to an initial peak experience followed by a leveling off. The A process in the brain is always the same if the same amount of the drug is used, but this is not true for the B process. Generated by an adaptive nervous system, the b process learns with time and exposure. “Repeated encounters with the stimulus (or use of the drug) result in bigger, faster, and longer-lasting B processes that are better able to maintain the homeostasis in the face of further stimulation.” Another thing to know is the B process can be triggered by environmental cues that signal an A process is coming. In other words, it can trigger the A process.

After many times of getting high, an adaptation results and there is hardly a bump in the feeling (euphoric) state. The drug then functions primarily as a way to hold off withdrawal and craving in the b process, in the face of the brain’s ability to counteract the A process until drug use is stopped, then withdrawal and craving begins in earnest. The classic illustration of this is with opioids like heroin.

This model also explains why the states of withdrawal and craving from a drug are always exactly opposite to the drug’s effects. If a drug makes you feel relaxed like benzodiazepines, withdrawal and craving are experienced as anxiety and tension. If a drug helps you wake up like caffeine, adaptation includes a lack of energy and enthusiasm. If it reduces the sensation of pain like opioids do, feeling pains you didn’t know you had will happen.

The common symptoms of addiction are tolerance, withdrawal and craving, and they are embedded in the consequences of the B process. Tolerance occurs because more drug is needed to produce an A process capable of overcoming an increasingly stronger b process. Withdrawal happens because the B process outlasts the drug’s effects (see the charts above). Craving is almost guaranteed by the opponent-process model, because any environmental cue that became associated with the drug (through classical conditioning) can trigger a B process because the learning cycle or ritual that included the cue or trigger was repeated many times as the person used drugs.

This happens because of what Jeffrey Schwartz called the Quantum Zeno Effect, in You Are Not Your Brain.  This means the brain areas activated by a drug are stabilized and held in place long enough so they can be wired together by Hebb’s Law. Hebb’s Law says neurons that fire together wire together. Once any sequence of neurons is wired together, the brain will respond to similar situations in a reliably “hard wired” way. So, any environmental cue that occurred repeatedly within the sequence of neurons or the ritual of “getting high” has the potential to become a trigger and initiate craving. In Never Enough, Judith Grisel gave a personal example of the incredible power of this cognitive memory process.

I was clean for close to two years and had been volunteering in my biopsychology professor’s laboratory to get some research experience. One part of the protocol required daily administration of an experimental drug into the subjects’ (rats) peritoneum, which is the sac that loosely constrains the abdominal organs. The standard procedure is to cup the rat gently in one hand, insert the needle with the other, and create negative pressure by pulling slightly back on the needle to be sure the injection isn’t going straight into a blood vessel. I thought I’d fully extinguished any personal associations by this time, but one day when I pulled back and the needle filled with blood, I heard clamorous ringing in my ears and a taste in my mouth that were characteristic of cocaine going into my vein. It was years later, in a completely different context, and I had not a whit of desire to use at that moment, but just seeing blood filling the syringe cause an instantaneous reaction. I let my colleague finish the injections and went back to my dorm sobered by the astounding power of memory.

The brain is so well organized to counteract things that cause it anxiety or unease, that it uses its learning skills to anticipate the disturbance a drug will cause rather than wait for the drug effects themselves. It starts a B process, from which you experience craving. In other words, the brain begins to dampen the drug effects before you even take the drug! So, there is a real potential for cue-induced relapse to occur and addicts need to become aware of this danger and develop a plan ahead of time, before the B process activates, to manage it if it occurs.

Originally posted on July 6, 2021

06/8/21

Never Enough and No Free Lunch

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By the time she was twenty-three, it had been several years since Judith Grisel had gone twenty-four hours without a drink, pill, fix, or joint. The fun and excitement from using was long gone. “Dying slowly a day at a time was turning out to be unbearably painful.” She’d finally reached the dead end of feeling she was incapable of living either with or without mind-altering substances. But after an unexpected encounter with her father, she decided to go to rehab, became a neuroscientist and eventually wrote a book on the neuroscience and experience of addiction called Never Enough.

In the Introduction of Never Enough, she said there were two factors that motivated her desire to recover. First, she began to wonder what it would be like to be sober. “I promised myself that if I wasn’t less miserable sober than I’d been loaded, I’d go back to using.” Second, she thought she could find a cure. She admitted later on, that in early recovery, she wanted to study addiction so she could use better. “If it’s a disease, and diseases can be cured, and I can cure it, then maybe I can still use.”

But as her knowledge and understanding grew, she discovered she had something to focus on that was not about using. Her growing knowledge about addiction also gave her more compassion for herself and others. She recognized she did not initiate drug use with a blank slate. “I started out with certain tendencies that make drugs for me so valuable and important, that really the courage and perseverance I’ve demonstrated over thirty years, both trying to study this and stay clean and sober, is something that I’m proud of.” She added that character traits that facilitated her addiction—bottomless curiosity, a willingness to take risks, and perseverance—contributed to the successes she’d had as a neuroscientist.

More than anything else, seeking and acquiring knowledge about drugs, addiction, and the brain have given me compassion for the desperate plight of people like me. The understanding I’ve gained has helped me stay clean by informing better choices. My hope is that by illuminating the seeming insanity of colluding in habits that are not only joyless but lethal, this book will contribute to a path of freedom for others.

When Never Enough was first published in 2019, Judith Grisel was interviewed on the NPR program, “Fresh Air.” She said during her interview that she was always interested in the mechanisms of things. She thought if she studied the biological basis of addiction and understood it, perhaps she could “fix” it. She had moments, one after another, of learning things that explained her experiences when using drugs. “There is a common sub strait for all addictions, in neurochemistry in dopamine pathways. And it made perfect sense to me that my dopamine pathways were especially attuned to hear signals from drugs and other things.”

One of the things she learned was that the more you use a drug to change the way you feel, the more your brain produces the exact opposite state. This is the case for every single drug. If you take a drug to feel awake, you will produce lethargy. If you take a drug to feel relaxed, you’ll produce anxiety and tension. A naive user will get a big experience of the drug. “But a regular user feels about normal.”

If you are familiar with 12 Step recovery, you have probably heard the saying; “A drug is a drug, is a drug.” While other recovering addicts are not behavioral neuroscientists like Judith Grisel, they are essentially saying the same thing here. In Never Enough, Grisel said there are three laws in psychopharmacology that apply to all drugs.  First, all drugs act by changing the rate of what is already going on in the brain. “They only work by interacting with existing brain structures.”

It follows that drugs can either speed up or slow down ongoing neural activity—and that’s it. Every drug has a chemical structure (a three-dimensional shape) that is complementary to certain structures in the brain and produces its effects by interacting with those structures.

The second law states all drugs have side effects. This happens because drugs do not target specific cells or circuits like neurotransmitters do. Drugs act at all accessible targets, meaning “they act whenever they encounter a receptive structure.” Drugs like nicotine, THC and heroin are called exogenous drugs, meaning they originate outside the body. They work because they mimic endogenous neurotransmitters. Endogenous means they are made inside your body.

For example, the neurotransmitter serotonin modulates mood, cognition, learning, memory, and other physical processes. It is involved with sleep, aggression, sex, and eating. Serotonin targets particular cells at particular times, depending on whether or not it is time to sleep, fight, etc. In contrast, if you take an SSRI, a selective serotonin reuptake inhibitor, it will influence all these behaviors at the same time, producing side effects in addition to potentially influencing your mood.

The third law is particularly important to addiction. It concerns how the brain responds to drugs, not how drugs act on the brain. “The brain is not just a passive recipient of drug actions but responds to the effects of the drugs.” In other words, there is a bidirectional, two-way street kind of relationship between a drug and the brain. “Repeated administration of any drug that influences brain activity leads the brain to adapt in order to compensate for the changes associated with the drug.” This is called adaptation. 

For the brain, the difference between normal rewards and drug rewards is like the difference between someone whispering into your ear and someone shouting into a microphone. Just as we turn down the volume on a radio that is too loud, the brain of someone who misuses drugs adjusts by producing fewer neurotransmitters in the reward circuit, or by reducing the number of receptors that can receive signals. As a result, the person’s ability to experience pleasure from naturally rewarding (i.e., reinforcing) activities is also reduced.  See the following illustration.

This reduction of receptors takes time to return to a pre-drug use homeostasis and in some cases may not be able to return completely. That is why a person who misuses drugs eventually feels flat, without motivation, lifeless, or depressed; they are unable to enjoy things that used to be pleasurable for them. Now, the person needs to keep making drugs to feel normal or experience a normal level of reward—which only makes the problem worse. The person will also need to take larger amounts of the drug to produce their high—an effect known as tolerance. Getting high is increasingly short-lived; and the purpose in using becomes to put off withdrawal.

The terrible truth for all those who love mind-altering chemicals is that if the chemicals are used with regularity, the brain always adapts to compensate. . . . 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. Getting high, if it occurs at all, is increasingly short-lived, and so the purpose of using becomes to stave off withdrawal.

This maxim applies to every effect of any drug that impacts the brain. At first, drugs produce good feelings because when they reach the brain, they impact the nucleus accumbens and other brain structures related to experiencing pleasure. But the brain is designed to return to its homeostatic “set point.” So, it counteracts the flood of dopamine released by the drug, which is interpreted as pleasure or the possibility of pleasure.

This is the driving force and curse of regular drug users. It results in an urge to use and reinforces the destructive cycle that underlies habitual drug use. With repeated exposure to the same stimulus over time, there are smaller and smaller changes in dopamine. Eventually, there is essentially no change in mesolimbic dopamine when exposed to a favored drug. But withholding it leads to a big drop in dopamine levels, which we experience as “a feeling of disappointment and craving.” The disappointment and craving experience anticipates that withdrawal is not far behind. Ultimately, according to Grisel, the most profound law of drug use is there is no free lunch.