Reverse Tolerance and Drug Sensitization

Drug sensitization, or reverse tolerance, is the opposite of developing a tolerance to drugs or alcohol.

Alcohol Tolerance occurs when regular drinking or drug use causes changes in the brain’s function and structures, and the metabolism adapts to the regular presence of drugs in the body. As a result, it takes increasingly higher doses of a psychoactive substance to get the same effects that a smaller dose produced before, according to HAMS: Harm Reduction for Alcohol.

Reverse tolerance, on the other hand, occurs when it takes smaller doses of a drug to become intoxicated.

What Causes Reverse Tolerance?

According to clinical psychologist Michaele Dunlap, when people drink alcohol, their tolerance typically increases initially. But because the liver doesn’t become more tolerant to higher doses of alcohol, liver damage occurs over time, and it no longer produces the appropriate number of enzymes because the number of cells required to break down the alcohol have died. This reduction in liver function causes a decrease in tolerance, which may be a sign of late-stage alcoholism of a heavy drinker.

According to Sacramento State University, drug sensitization may also be affected by pharmacokinetics and pharmacodynamics. Pharmacokinetics, according to the National Institutes of Health, is the study of the absorption, metabolism, distribution, and excretion of a drug, while pharmacodynamics is the observed effects of a certain concentration of a drug and determines how a drug will affect a user and how long those effects will last. In other words, different people will react differently to various types of drugs.

Reverse Tolerance and Amphetamine Psychosis

According to a Japanese study, reverse tolerance may be related to the psychosis that sometimes occurs in people who chronically abuse amphetamines. In the study, drug sensitization was produced in rodents when they were given normal doses of amphetamines at intervals of longer than a day, rather than more frequently. This resulted in an increase in repetitive movements like head bobbing and sniffing. This study found that once reverse tolerance develops, it’s very difficult to reverse, even through treatment with antipsychotics.

Reverse Tolerance, Seizures, and Aggression

A Tufts University study found that the repeated dosing of stimulants or opiates can cause longer-lasting motor-activating effects. The study concluded that reverse tolerance to these drugs may increase the susceptibility to seizures. It also found that the repeated administration of alcohol can produce behavioral sensitization that results in more aggressive behavior when drinking.

Reverse Tolerance and Overdose

Addiction medicine expert David Sack, MD, notes that the development of tolerance to a drug can be reversed very quickly during even short periods of abstinence, and the risk of overdose is very high if a user returns to using drugs at the same dose they had become accustomed to before stopping.

The Latest Reverse Tolerance Research

Researchers from the University of California in San Francisco have linked reverse tolerance related to alcohol, opiates, nicotine, and antidepressants to a subtype of glutamate receptors in the brain, known as NMDA receptors, which are linked to developing a tolerance to drugs as well. An NMDA receptor antagonist known as MK-801, according to the study, appears to block some of the effects of drugs, and that, researchers say, could open the door to treatments that may help make drugs less appealing to those who have lost control over their substance use. It may also help reduce the effects of alcohol in those who have been abstinent for some time and then return to drinking.

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