Cross-Tolerance Can Lead to Dangerous Dosing

Cross-Tolerance Can Lead to Dangerous Dosing

Sydney recalls the days when she used to be able to get the relaxed and carefree feeling she was looking for when drinking by consuming just two or three beers. But now, ten years later, even after consuming five or six beers, Sydney finds that she still isn’t able to reach that same level of relaxation.

Sydney has come to recognize that her relaxation goal has been thwarted by a process called tolerance, which often occurs with regular consumption of alcohol or other depressant drugs, such as opiates or amphetamines, among others. But Sydney did not realize her tolerance toward alcohol would also increase her tolerance for many of the other drugs in the depressant category, including opiate-based medications and even some anesthetics. So imagine her surprise when this became an issue for Sydney when she was preparing to undergo elective surgery.


Sydney faced a dilemma known as cross-tolerance. Even though she had never abused opiate drugs, her body had developed a tolerance to them because they are similar in chemical composition and have similar brain effects as alcohol. So her doctor had to carefully gauge and monitor her pain medications after surgery. And because Sydney had also become cross-tolerant to certain anesthetic medicines, the amount of anesthesia needed for her during surgery was increased, which increased her overall risk; so this too, needed to be dealt with.

Fortunately, Sydney had been honest with her anesthesiologist when he asked her about her drug and alcohol use, and he was able to choose an appropriate anesthesia and monitor it so that her increased risk was managed. But like Sydney, many drug and alcohol users are not aware of the potential for cross-tolerance and the risks it entails.

…like Sydney, many drug and alcohol users are not aware of the potential for cross-tolerance and the risks it entails.-Lesley Wirth

How Does Cross-Tolerance Develop and What is Its Effect?

Cross-tolerance between drugs in the same category (ex: depressants) occurs because of the similarity in the way each drug reacts within the brain. Depressants affect the brain chemicals dopamine and serotonin by attaching to the receptor (receiving) sites on nerve cells, effectively taking over the space where these mood regulating chemicals would normally attach to the cell.

In addition, depressant drugs also take over the mood-regulating functions normally provided by the dopamine or serotonin that they replace. Because there is then a reduction in the normal amount of dopamine and serotonin available to the person, if they stop taking the substitute (a depressant drug such as alcohol or opioid medicine), they then suffer the consequences of having insufficient levels of mood regulating chemicals available to them and often experience depressed mood, anxiety or other symptoms like headache, nausea and vomiting that are typically associated with drug withdrawal.

Which Drugs Are Most Often Associated With Cross-Tolerance?

Cross-tolerance most often occurs between chemically related drugs, but it can also occur between two chemically dissimilar drugs that share similar functions within bodily systems.

The more closely related two drugs are in chemical composition or bodily function, the stronger the possibility for cross-tolerance and the stronger the cross-tolerance effects. Valium, Librium and Xanax are benzodiazepines, a category of prescription drugs that affect brain receptors called GABA receptors. These and other benzodiazepines can easily become cross-tolerant. And since alcohol also affects GABA receptors, there is some cross-tolerance with alcohol (but not as much since alcohol affects many different receptors, not just GABA). Heroin, on the other hand, does not affect GABA receptors, so there is no cross-tolerance reaction between heroin and benzodiazepines.

Heroin, morphine, and codeine are opiates, and affect the brain’s opioid receptors. If a person is addicted to heroin, they will be cross-tolerant to other opiates such as codeine and methadone. Even though methadone is used to treat heroin withdrawal, because of its cross-tolerance tendency, it can become addictive itself. So careful monitoring and a slow weaning off of this drug are often required when it is used to treat heroin addiction.

Other common cross-tolerance associations include amphetamines (such as ADHD drugs), which are cross-tolerant with pseudoephedrine (found in nasal decongestants and cough syrup) and caffeine, via their common effects on dopamine receptors. Alcohol is also cross -tolerant with caffeine and nicotine, making it necessary to consume more of each in order to get the desired effect.

Dangers of Cross-Tolerance

Benzodiazepines, including Xanax, Klonopin, Ativan and Valium, are among the most commonly prescribed mental health medications. By themselves, they are generally safe and effective for treating anxiety, insomnia and other symptoms. Even though they are sometimes used as part of an alcohol detoxification program, combining benzodiazepines and alcohol can lead to deadly results. Benzodiazepines increase the depressant qualities of other sedative-type drugs, including alcohol; fatal overdoses can more easily occur when these two drugs are taken together.

Unfortunately, many addicts self-medicate with benzodiazepines in combination with alcohol, as the combination enhances the “high.” According to a 2012 study on polydrug abuse by Columbia University researchers J.D. Smith, S. Mogali and S. Comer, reported in the journal Drug and Alcohol Dependence, the abuse of benzodiazepines has surged in recent years, nearly tripling between 1998 and 2008.

In addition to being combined with alcohol, benzodiazepines are often taken with opioid drugs, such as methadone, to reinforce the reward effects of these drugs as well. But the increased high comes with a significant risk. Chances of drug overdose and death, caused by depression of the respiratory system, are significantly higher when multiple drugs are combined.  The Columbia study, Polydrug Abuse: A review of Opioid and Benzodiazepine Use, reported that 71-98% of fatal overdoses involved the use of more than one drug in combination.

Benzodiazepines increase the depressant qualities of other sedative-type drugs, including alcohol; fatal overdoses can more easily occur when these two drugs are taken together.-Lesley Wirth

Impact of Cross-Tolerance on Detox and Recovery

The dangers of combining drugs and the risks of cross-tolerance are well established. Yet, medications that may become addictive (such as methadone) are often prescribed to diminish the symptoms associated with detox and withdrawal. Current research is indicating that pharmaceutical solutions using mood-altering drugs, often part of the initial detox treatment phase, may not be the best option for ongoing recovery treatment.

As the evidence increases, it is becoming clear to both treatment providers and those they treat that they would be well advised to consider non-pharmacologic options, such as mindfulness, stress reduction training, nutrition and wellness education, as long-term treatment options.



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