Learn / Understanding Cross-Tolerance: Effects on Medication and Substance Use

Understanding Cross-Tolerance: Effects on Medication and Substance Use

Kayla Gill
 April 10th, 2024|   Clinically Reviewed by 
Rajnandini Rathod

Have you ever felt like tolerance to one drug affects your response to a seemingly unrelated substance? This is cross-tolerance: building tolerance to one substance as a result of using another. And the mechanisms in our brain that cause cross-tolerance to develop show just how interconnected our body’s adaptations are.

Cross-tolerance has a host of implications for everyday life. It affects overdose risk from drug use, complicates addiction recovery, and can even influence the effectiveness of medications for pain management, psychiatry, and chronic disease treatment. 

Here, we explore what cross-tolerance is and how it develops. We’ll also take a look at what the medical community is currently doing to prevent, manage, and treat cross-tolerance for people who use substances or take medications. 

What Is Cross-Tolerance?

The American Psychological Association (APA) defines cross-tolerance1 as “a condition in which tolerance to one drug results in a lessened response (i.e., increased tolerance) to a related drug.”

Cross-tolerance develops when the use of one substance leads to a reduced response to another substance with a similar way of taking effect. This happens due to the body’s adaptation to repeated exposure to a particular type of substance, leading to brain changes that affect your sensitivity. For example, people who develop a tolerance to opioids might also be less sensitive to other substances that affect their opioid receptors, such as certain prescription pain medications.

The APA notes that “Cross-tolerance may be seen with amphetamines, benzodiazepines, hallucinogens, and opiates, among other drugs.”

Other types of substance cross-tolerance include:

  • Alcohol and marijuana 
  • Alcohol and opiates2 
  • Opioids and other opioids
  • Benzos and other sedatives or painkillers 

There’s also evidence to show that you can build cross-tolerance between different psychedelics,3 like LSD (acid) and psilocybin (mushrooms), or mescaline and LSD. This may be because both substances use similar substances to produce effects on the brain. “These two drugs cause psychic disturbances by acting on some common mechanism, or on mechanisms acting through a common final pathway,” say researchers.

Cross-Tolerance in Substance Use

If you use drugs recreationally, cross-tolerance can impact their effectiveness and the risks they carry. 

Cross-tolerance may lessen the desired effects of certain drugs. If you build a tolerance to one drug, you may find it harder to achieve the same level of euphoria or intoxication with a different drug that acts on similar receptors.

Potential for Overdose

Cross-tolerance poses a significant risk of overdose.4 People with higher tolerance may consume higher quantities of a substance, unaware that their tolerance to one substance doesn’t always extend to another. Miscalculating doses in this way increases the risk of toxicity and overdose.

Cross-Tolerance and Polydrug Use

Tolerance can also increase the risks of polydrug use (using multiple drugs at a time). People with cross-tolerance might combine different substances to compensate for reduced effects. This complicates the chemical reactions in your body, increasing the risks of adverse drug reactions, unpredictable interactions, and overdose.

Challenges in Addiction Recovery

Cross-tolerance complicates addiction treatment, as people might require higher doses of medication to achieve therapeutic effects. This can pose challenges in managing withdrawal symptoms and cravings during recovery.

Increased Relapse Risk

People with cross-tolerance can also be at an increased risk of relapse. If you’ve become less sensitive to the effects of one substance, you may be more likely to look for alternatives, which can work against your efforts to stay sober.

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How Cross-Tolerance Can Impact the Effectiveness of Your Medication

Cross-tolerance increases the risks of taking certain medications, especially if you use medication regularly for conditions like pain management, a psychiatric disorder, or chronic disease treatment. 

Pain Management

Cross-tolerance complicates the prescription of opioids and other pain-relieving medications. If you’ve developed cross-tolerance through the use of opioid medications, it may reduce their analgesic effects. That means you need higher doses to achieve the same pain relief, increasing the risk of opioid addiction and other negative side effects.

Response to Psychiatric Medications

If you take medication for a psychiatric condition,5 cross-tolerance can change your response to your medication. People with a history of tolerance to one class of psychotropics may need to have their dosage adjusted, or use a different medication to achieve therapeutic effects.

Impact on Chronic Disease Management

Cross-tolerance can impact the effectiveness of medications used to manage chronic diseases such as hypertension, diabetes, or heart conditions. Reduced responsiveness can compromise the ability to control your symptoms and manage the progression of the disease.

Overmedication and Increased Side Effects

Cross-tolerance can lead to overmedication as you require higher doses to achieve the intended therapeutic effects. This increases the likelihood of adverse side effects and complications, including overdose.

Treatment Resistance

People with cross-tolerance may develop treatment resistance, where medications lose their effectiveness over time. This poses a significant challenge in managing chronic conditions, and may mean you’ll need to explore alternative treatment approaches.

Managing Cross-Tolerance and Reducing Its Effects

Strategies Used in Professional Settings

If you’re seeking rehab for substance addiction, your program should create an individualized treatment plan that takes your cross-tolerance and need for medication management into account. Your rehab will need to carefully assess your substance use history to tailor treatment effectively. Ideally, they should have a psychiatrist or other specialized medical doctor on their clinical team

In an addiction treatment program, or as part of your normal medical or psychiatric care, you should receive a regular medication review.6 In this review, your doctor can check for cross-tolerance and ensure your medications work together effectively without excessive side effects. 

If you’re in recovery and have a history of cross-tolerance, you should receive continuous monitoring and support by qualified professionals. A comprehensive recovery strategy includes regular assessments, adjustments to treatment plans, and ongoing therapy.

Rehab programs often include an educational component to help people understand how addiction works in the mind and body. This may include education about cross-tolerance to help you make informed decisions about your recovery.

Tips for Patients and People Who Use Substances

If you’re concerned about cross-tolerance, it’s important to get guidance from medical care professionals.

If you’re addicted to multiple substances, or want to recover from substance addiction while taking medication, seek professional help via an addiction treatment program that includes medical treatment. Be transparent with your treatment team about substance use patterns so they can tailor treatment plans effectively. Rehab admissions staff can also help you understand what the available treatment options are, and which ones may be most appropriate for you. 

If you use multiple substances and don’t plan on quitting, or don’t feel ready to quit yet, learning harm reduction techniques can help you stay safe and prevent overdose. These are reputable harm reduction resources: 

If your prescribing doctor isn’t already doing so, request regular medication reviews to maintain therapeutic benefits without relying on increased dosing.

The Science Behind Cross-Tolerance

Chemical Processes in the Body

Your brain has an amazing ability to adapt. Unfortunately, that also means it can adapt to repeated exposure to certain substances. This happens on a cellular level, influencing your neurotransmitter (brain chemical) systems, receptor (sites in your brain that receive chemicals) function, and neural plasticity (the ability of your brain to change).

Prolonged exposure to a specific substance can alter your baseline levels of certain neurotransmitters. This includes feel-good chemicals like GABA and dopamine.7 You also become less sensitive to the effects of these chemicals, meaning you need higher doses of a substance to elicit the same response. This is how tolerance is formed.

As your body strives to maintain internal stability in response to chronic substance exposure, it may activate certain mechanisms to counteract the substance. This might include releasing extra enzymes that help metabolize the substance, for example.

With cross-tolerance, these mechanisms of tolerance-building apply to multiple substances. That is, the tolerance you build to one substance affects your tolerance for another. This usually happens between substances that share common receptor systems or pathways. For example, opioids and prescription painkillers can cause cross-tolerance,8 because they work by affecting your opioid receptors.

Risk Factors for Cross-Tolerance

A number of factors can affect your likelihood of developing cross-tolerance:

  • Inherent sensitivity: Some people’s neurotransmitter systems are more sensitive than others. People with naturally high or low sensitivity to certain substances may have different levels of tolerance.
  • Substance type and similarity: Cross-tolerance is more likely to occur between substances that have similar chemical structures or act on the same receptors. 
  • Polydrug use: Using multiple substances increases the risk of cross-tolerance. That’s because exposure to different substances at the same time can lead to overlapping adaptations in neural pathways.
  • Frequency and duration of use: Regular and prolonged use of substances contributes to the development of cross-tolerance, because they influence the extent to which your body adapts to substances. If you have a pattern of bingeing on substances intermittently, this can also accelerate the development of tolerance.
  • Individual metabolism: Your metabolism affects how substances are processed and cleared from the body, and therefore affects the speed at which cross-tolerance develops.
  • Underlying conditions: People with underlying mental health conditions may be more susceptible to cross-tolerance. 
  • Age and developmental stage: Teens and young adults may be more vulnerable to the development of cross-tolerance due to ongoing neural development. Substance exposure during this critical period can have lasting effects on the maturing brain.
  • Environmental factors: Stressful environments and chronic stress can amplify the risk of cross-tolerance. Environmental factors, like exposure to trauma or adverse life events, can prompt addictive behaviors that shape neural adaptations.
  • Rapid tolerance building: Research shows that building tolerance to a substance quickly9 can be a predictor of chronic tolerance and cross-tolerance.

How Research Helps Us Understand Cross-Tolerance

Ongoing research on cross-tolerance plays a pivotal role in our understanding of the complex interactions between substances and the human body. These studies help professionals develop more effective strategies to manage and treat cross-tolerance. 

Implications for Heroin Addiction Recovery

Buprenorphine is an opioid medication that’s used to treat heroin addiction. Because heroin and other opioids are so physically addictive, quitting them cold-turkey can be dangerous. With medication-assisted treatment, patients take a prescribed opioid instead, then taper off under the guidance of their doctor. A recent study finds that for people who regularly use heroin, cross-tolerance to buprenorphine10 is associated with intravenous drug use and a faster return to opioid use.

Effects on Anesthesia 

Cross-tolerance can also affect how effective anesthesia is, which is especially important to know for performing major surgeries. Emerging research looks into how building tolerance to certain substances, like opioids, impacts the effects of anesthesia.11  

Cross-Tolerance Between ADHD Medications

As increasing numbers of people, especially teens and young adults, are taking medication for ADHD, new research explores important considerations for these drugs. One study shows that cross-tolerance and “tolerance build-up” can result from stimulants prescribed to treat ADHD12 when multiple medications are used.

Future Directions 

As the behavioral health community strives to learn more about cross-tolerance, continued research looks at mapping neural pathways, identifying genetic markers, and understanding substance-specific adaptations. Researchers are also further exploring the associations between cross-tolerance and certain mental health conditions.

The more we learn about how cross-tolerance develops, the better medical professionals will be able to prevent, treat, and manage its effects. In the future, this could look like earlier intervention, more precise treatment, and more effective treatment methods. 

Get the Medical Support You Need to Stay Safe

If you use medication regularly to manage pain, chronic disease, or a psychiatric disorder, cross-tolerance can have serious implications for how effective your medications is and what side effects it has.

And if you use multiple substances in combination, or take different substances in sequence, your tolerance to each of those substances can impact your tolerance to others. That poses significant challenges to preventing adverse reactions and managing your risk of overdose. It can also complicate the addiction recovery process and require additional medical support. 

Thankfully, our understanding of cross-tolerance is evolving as scientific research continues.   

If you take multiple medications, it’s a good idea to request regular medication reviews from your prescribing doctor or a qualified psychiatrist. And if you’re ready to get help for an addiction and cross-tolerance is a concern for you, plenty of treatment centers have medical professionals on staff who can ensure your recovery is as safe as possible. 

See our list of medical treatment rehabs to search by conditions treated, insurance accepted, and more, and start your recovery journey today.

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