What is Cross Tolerance and What Drugs Cause it?

Ongoing or heavy substance abuse can lead to tolerance, meaning your body becomes dependent on the substance to function. While many people understand that this can happen with one substance, some are surprised to learn that people can develop cross-tolerance to other drugs after using a substance.

Cross-tolerance means that by developing tolerance to one substance, you also have tolerance to others. For example, people who use heroin and build tolerance to it may have tolerance to all opioids. This would be relevant if they were taking prescription opioid painkillers, as they may need to take higher doses to get pain relief.

If you or someone in your life has developed cross-tolerance between substances, it may be a sign that you need help to safely stop using drugs and avoid future relapse. Reach out to the Arise Treatment Center staff to learn more about identifying and treating cross-tolerance or to find support at any stage of your recovery journey.

Understanding Cross-Tolerance Within Drug Classes

Anyone who uses drugs and develops tolerance is at risk of developing cross-tolerance to other substances. However, experts believe that cross-tolerance occurs because of changes in a person’s enzymes and neurotransmitters, making it more likely to develop across classes of drugs.

Here are some of the most common classes of drugs associated with cross-tolerance.


Psychedelic drugs like psilocybin mushrooms, peyote, and LSD work similarly in the brain, increasing the likelihood of developing cross-tolerance. People who take one type of psychedelic and build a tolerance to it may find that they need higher doses of other psychedelics to achieve the desired results.

People with a tolerance to hallucinogenic drugs may also be more likely to develop cross-tolerance to drugs that use certain brain pathways to affect serotonin, including marijuana, ketamine, DMT, and PCP.


Developing tolerance to any opioid makes it likely you’ll have tolerance to all opioids. Cross-tolerance among opioids is one of the most significant reasons behind the current opioid epidemic. People who take prescription opioids may later seek more potent opioids, such as heroin, to get the euphoric effects they want.

People who develop tolerance to prescription opioids typically need to take higher doses of other opioids to feel the desired effects when compared to people who have no history of opioid use. This puts opioid users at greater risk for overdose as they seek more potent drugs over time.


People who develop tolerance to one stimulant drug, such as ecstasy,  are more likely to need higher doses of other stimulants like cocaine. Understanding this is critical for people who use stimulant medications like Ritalin to manage attention deficit disorders.


Sedative substances like barbiturates, benzodiazepines, sleep medications, and alcohol work similarly in the brain. These substances bind to specific receptors, resulting in decreased central nervous system (CNS) activity. Because these drugs work in the same way, cross-tolerance across sedative drugs is common. This is important to consider for people who take sedative medications to manage anxiety or help with sleep.

People who use any substances must consider the effects of cross-tolerance and the increased risk of addiction, overdose, and other complications.

Cross-Tolerance Between Different Drug Classes

While it’s much more common for cross-tolerance to develop within a class of drugs, it’s also possible for people to build cross-tolerance between different drug classes.

Here are some of the most common instances where cross-tolerance can develop between different types of drugs.

Cannabis and sedative drugs

The cannabinoids that cause marijuana users to feel calm and relaxed work by depressing CNS activity. People who develop tolerance to marijuana may have cross-tolerance with some sedatives, including alcohol and barbiturates.

Alcohol and Nicotine

Drinking alcohol and smoking cigarettes often go hand-in-hand. Many people who drink heavily also smoke, and nicotine addiction often runs parallel with alcohol abuse. Research has revealed that nicotine’s stimulant effects may counteract the sedative effects of alcohol. Experts believe this could lead to cross-tolerance between both substances.

Nicotine and stimulants

Nicotine is a unique substance because it has both stimulant and depressant effects. People who regularly consume nicotine by smoking, vaping, or chewing may have cross-tolerance with several other types of substances, including stimulants like Ritalin and Adderall and caffeine.

Cross-tolerance can be dangerous and cause complications during detox and treatment. People who seek addiction treatment must be honest about all substances they use and seek care from a licensed center offering evidence-based, medically-supported treatment.

Find Treatment Now

Addiction to multiple substances can complicate recovery, but moving forward into a healthier future is still possible. Located in Vista, California Arise Treatment Center is one of the country’s leading drug and alcohol addiction treatment and behavioral health providers. With a team of passionate professionals who are dedicated to helping those struggling with substance abuse, our main goal is to provide exceptional long-term wellness to our clients as well as their families.

Getting the care you need doesn’t need to be complicated. Call our admissions staff today to get started. Reach out to the knowledgeable team at Arise Treatment Center now to explore our effective, comprehensive substance abuse treatment programs.


  1. Science Direct: Cross-Tolerance, Retrieved August 2023 from https://www.sciencedirect.com/topics/medicine-and-dentistry/cross-tolerance
  2. National Library of Medicine: Opioid Tolerance Development: A Pharmacokinetic/Pharmacodynamic Perspective, Retrieved August 2023 from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2628209/
  3. National Library of Medicine: Nicotine and amphetamine: differential tolerance and no cross-tolerance for ingestive effects, Retrieved August 2023 from https://pubmed.ncbi.nlm.nih.gov/7367453/


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