Cross Tolerance and the GABA-A Receptor
In order to discuss cross-tolerance, lets revisit tolerance. Tolerance occurs when the receptors in your brain adapt to the drug dose you’re on and they no longer work as well as they once did. You may find you need to increase your dose to achieve the same effect. Tolerance is almost always associated with some degree of dependence when it comes to benzos.
Physical dependency refers to the need to continue taking the drug in order to avoid experiencing withdrawal symptoms. If anyone with a drug dependence stops taking that drug suddenly, that person will experience predictable and measurable symptoms, known as a withdrawal syndrome.
A similar term to tolerance is cross-tolerance which occurs when you take one type of medication and it causes you to develop a tolerance to another medication. Cross-tolerance between drugs in the same category occurs because of the similarity in the way each drug reacts within the brain. You can also develop cross-tolerance to drugs from different classes too; in the case of benzos, when they both affect the same receptors.
Here’s how it works
Benzodiazepines have a calming effect on your central nervous system by enhancing the calming neurotransmitter in your brain called GABA. This slows the nerve impulses in your body and can work in a sedative, muscle relaxant, anticonvulsant or anti-anxiety manner. However, with long term use (more than a few months) benzos become less effective over time and can interfere with other medications you are potentially taking.
You can also quickly develop cross-tolerance to drugs that belong to the same class. As an example, if you’re taking alpralozam for anxiety and are then prescribed lorazepam, you may already have a tolerance to lorazepam, causing it to not work as well as expected.
Basically, benzodiazepines result in a habituation to closely related drugs because these drugs affect the same receptors in your brain.
This means that benzos, alcohol, barbiturates, steroids and sedative and hypnotic drugs such as non-benzodiazepines (also known as baby benzos or Z drugs) can result in cross tolerance. Since these all share similar action, if you take a Z drug like zopiclone for sleep, you could develop a cross tolerance to benzo drugs like diazepam. The more closely related the two drugs are the stronger the cross tolerance effect will be.
Other drugs that can result in a cross tolerance with benzodiazepines include neuroactive corticosteroids, such as progesterone. This occurs due to their positive modulation on the GABA-A receptor.
If you develop cross-tolerance from other medications, you may start to experience benzo withdrawal symptoms, while still taking your medication exactly ‘as prescribed’.
Who Is Likely to Develop Cross-Tolerance?
For those on benzos, you’re most likely to develop cross-tolerance if:
you’ve been prescribed drugs from the same or similar classes, such as two different types of benzo
if you are taking medications with similar effects, like an anti-anxiety drug and a sedative/hypnotic
you drink alcohol while taking any of the drugs that affect your GABA-A receptors
if you take any other medications that hit the same GABA-A receptors in your brain including steroids, barbiturates, Z drugs and other sedatives.
Dangers of Cross-Tolerance
Cross-tolerance means that if you become dependent on one drug in the class, you’re more likely to develop dependence on the others. Someone who suffers from alcohol dependence/addiction is more likely to develop a dependence issue with benzos as well.
If you are taking benzos please do the research on all new medications to check if they affect the GABA-A receptor so you don’t end up taking something that makes you tolerant to your benzos, giving you more symptoms to manage.
Other common cross-tolerance associations include:
amphetamines (e.g ADHD drugs), which are cross-tolerant with caffeine (due to their common effects on dopamine receptors)
alcohol is also cross -tolerant with caffeine and nicotine.
heroin, morphine, and codeine are opiates so if a person is addicted to heroin, they will be cross-tolerant to other opiates such as codeine and methadone.
Cross-tolerance can be used as a medical tool. For example, benzodiazepines are sometimes utilized when detoxing from alcohol abuse to ease withdrawal symptoms. However, this can be extremely dangerous and can lead to relapse. That’s because this type of cross-tolerance can actually increase the cravings for the drugs we want to eliminate.
Benzos increase the depressant qualities of other sedative-type drugs, including alcohol; fatalities can more easily occur when these two types of drugs are combined.
Cross Tolerance Risks for Benzodiazepines
The list of drugs that can result in cross tolerance with benzodiazepines include:
All other benzodiazepines
Z drugs (like Sonata, Ambien, and Lunesta)
Barbiturates (such as Seconal, Nembutal, and Luminal)
Alcohol
Neuroactive corticosteroids (including progesterone)
Corticosteroids
Benzodiazepines are a real and present danger, and the issue of cross tolerance only heightens the risk. It means you can find yourself suffering tolerance withdrawal from your benzos because you were prescribed another medication that caused the cross-tolerance.
If you stop any of these substances abruptly e.g. benzodiazepines, alcohol, barbiturates, corticosteroids, neuroactive steroids, corticosteroids (and others), you may be at risk for similar withdrawal effects characterized by central nervous system hyper-excitability, resulting in symptoms such as increased anxiety and seizure susceptibility.
If your doctor prescribes a benzo drug, let them know about other medications you may be taking that could elevate your chances of experiencing problems.
Unfortunately it seems many medical people are unaware of these risks and interactions so please do your own research as well.