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Understanding Opiate Potentiators and the Risks

The U.S. Department of Health and Human Services (HHS) publishes that any substance that enhances the effects of an opioid, such as other drugs, herbs, or chemicals, is a potentiator.


Other drugs or supplements may be taken in conjunction with an opioid to try and elevate the high or increase the euphoric effect. Some drugs may have similar mechanisms of actions to opioids, thus enhancing their impact, while others interfere with the absorption or metabolism of these medications.

Opiate potentiation can also be induced by chewing pills or tablets that are meant to be swallowed, crushing and snorting or smoking them, inserting pills or tablets into the rectum, or dissolving opioids and injecting them. These methods of ingestion all send the dose of the drug directly into the bloodstream for a faster and more intense impact on the system.


Opiate potentiation is extremely risky and should not be attempted without medical supervision and direction. In cases of extreme breakthrough pain where opioid tolerance is present, opiate potentiation may be necessary. However, due to the high abuse potential of these drugs, opiate potentiation is commonly a result of drug misuse.

Opiate potentiation amplifies the effects of opioids and, therefore, the odds for a life-threatening overdose. All potential side effects of opioid drugs are increased through potentiation, including a quicker rate of drug tolerance and dependence.

Opiate potentiation and misuse of opioid drugs are optimally managed through a specialized drug abuse and addiction treatment program. Treatment can offer therapeutic and pharmacological support to allow the drugs to safely process out of the body. Comprehensive therapy is recommended following detox.


Common opiate potentiators are used illicitly to elevate the euphoric effects of opioid drugs, including heroin and prescription painkillers.

The U.S. Food and Drug Administration (FDA) warns that grapefruit juice, as well as some orange juices, can block the action of the enzyme CYP3A4 in the small intestine, which typically helps to metabolize drugs. Therefore, mixing grapefruit juice with medications can inhibit the metabolism of these drugs, making them last longer and have greater effect.

Opioid pain medications contain FDA boxed warnings, the strongest possible warning they issue, on the hazards of mixing these drugs with other central nervous system depressants like benzodiazepines. When combined, benzodiazepines can potentiate all the effects of opioids, including depressed respiration, heart rate, and blood pressure. This can greatly increase the risk for a potentially fatal overdose, as it can make it hard for a person to breathe normally. It may even suppress respiration completely.

Over-the-counter (OTC) antihistamine medications, such as Benadryl, are commonly used to potentiate the effects of opioid drugs. OTC cough medications containing promethazine are also commonly illicitly mixed with opioids as a method of increasing euphoric effects, the journal Drug and Alcohol Dependence reports. The National Institute on Drug Abuse (NIDA) warns that antihistamines are central nervous system depressant drugs as well. As such, they can interact with opioids to cause respiratory depression that can be life-threatening.

Anticonvulsant drugs containing gabapentin or pregabalin are often used off-label to manage opioid cravings and withdrawal symptoms during detox. The American Journal of Psychiatry (AJP) reports that gabapentinoids are commonly misused in combination with opioids to create a more intense high, however. Gabapentinoids can also induce an opioid-like high when taken in high doses and can, therefore, potentiate opiates.

Herbal substances like St. John’s wort, which contains the active ingredient hypericin, can increase the pain-relieving effects of opioid drugs, making them candidates for opiate potentiation. The Journal of Pharmacological Sciences publishes that herbal remedies like this can increase the duration of analgesia from opioids and may also have antidepressant effects in patients who manage chronic pain.

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These products should be used only under the direction and supervision of a trained medical professional. The possible adverse side effects of opiate potentiation often outweigh any possible good from the combination.


Opioid overdose is a public health epidemic. HHS publishes that about 116 people die every single day in the United States as a result of an opioid-involved overdose.

Opiate potentiation in any form elevates the odds for an overdose. When two substances are combined that interact with each other to increase their effects, all effects are amplified, not just the potentially positive ones.

This means the depressant impact of opioids can be exacerbated, slowing down blood pressure and heart rate and lowering body temperature and respiration rate.

“An opioid overdose often results in difficulties breathing and sedation.

Sliced grapefruit on a wooden table

An opioid overdose, especially when multiple substances are involved, is a medical emergency requiring immediate professional help.

It may take more than one dose of naloxone, the opioid overdose reversal drug, to overturn an overdose involving opiate potentiation.”


Opiates are tightly controlled substances, as they are regularly misused and have a high rate of drug dependence and addiction. In 2016, the National Survey on Drug Use and Health (NSDUH) reports that more than 2.5 million Americans struggled with addiction involving an opioid drug.

Opiate potentiation can increase drug dependence faster and, therefore, intensify withdrawal symptoms when the substances process out of the body. Opiate withdrawal can be relatively intense, including both mood swings and emotional lows as well as significant cravings and flu-like symptoms.

Opioid misuse and opiate potentiation without medical intention and supervision can be managed through medical detox and a comprehensive addiction treatment program. Medical detox will allow the drugs to process out of the body in a safe environment, often using other medications to manage withdrawal symptoms. Therapeutic and supportive measures provided in a complete treatment program can aid in controlling cravings. Clients will learn how to cope with potential triggers to sustain abstinence throughout recovery.


(March 2018). Opioid Potentiators. Center for Medicare and Medicaid Services from

(July 2017). Grapefruit Juice and Some Drugs Don’t Mix. U.S. Food and Drug Administration from

(August 2016). FDA Drug Safety Communication: FDA Warns About Serious Risks and Death When Combining Opioid Pain or Cough Medications With Benzodiazepines; Requires its Strongest Warning. U.S. Food and Drug Administration from

(May 2015). Promethazine Use Among Chronic Pain Patients. Drug and Alcohol Dependence from

(December 2018). Is It Safe to Use Opioid Drugs with Other Medications? National Institute on Drug Abuse from

(June 2014). Potentiation to the Effect of Buprenorphine/Naloxone with Gabapentin or Quetiapine. American Journal of Psychiatry (AJP). from

(2014). PKC-Mediated Potentiation of Morphine Analgesia by St. John’s Wort in Rodents and Humans. Journal of Pharmacological Sciences from

(March 2018). What is the U.S. Opioid Epidemic? U.S. Department of Human Health and Services from

(September 2017). Key Substance Use and Mental Health Indicators in the United States: Results from the 2016 National Survey on Drug Use and Health. Substance Abuse and Mental Health Services Administration from




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