Forewarning About Opiate Potentiators

Before we get started, its really important to note that. Opiate potentiation is not the same as tolerance reversal or prevention. The two are often mistaken for each other because they both can increase opiates effects (hence also described as potentiators).

However traditional potentiators are different in that they do not reverse or prevent tolerance, they work by merely increasing the amount of opiates in your blood plasma or they work by having similar analgesic effect which complements the opiates effects.

This means that potentiators will increase your tolerance to opiates, in the long run, unlike proglumide or memantine which would decrease it. The effect of true tolerance reversal agents like Proglumide also serves as potentiating opiates at the same time, but reduces tolerance at the same time (as long as doses are not going up).


Therefore, a highly advised strategy is to take tolerance preventative measures like Memantine and Proglumide with opiate potentiators to prevent tolerance developing, whilst achieving increased pain relief or other opiate effects.

Anti Tolerance Opiates

Do not recklessly mix and match potentiators as this can bring opiate levels up to dangerous or even fatal levels.

The Categories

In general opiate potentiators usually fall into one of these categories:

  • Antihistamines
  • CYP enzymes inhibitors
  • NMDA antagonists
  • Muscle-relaxants
  • Other CNS depressants
  • Phytochemicals

The Big List

There are literally dozens of chemicals that can potentiate opiates, many with similar mechanisms. We will start with the most well-known ones slowly move into the more novel ones as we go down the list.

Grapefruit Juice – The classic. Works by blocking the enzymes that metabolize opioids, thus increasing opiate concentration and duration. Usually, a 500ml of real 100% grapefruit juice will work fine. This is simple and works modestly for most people.

Cimetidine (also known as Tagamet) –  Works by occupying CYP enzymes that metabolize opioids (and other drugs), may not be great for the liver as it increases the workload on in. Anecdotally dosage is 800mg. Available over the counter. Works for about an hour. This is the choice for most people, but may affect the metabolization of codeine to morphine.

Diphenhydramine (Benadryl) – Less itchy and better effects. Inhibits histamine and increases the analgesic and mood properties of opiates to a small degree. In addition, they also inhibit a subset of CYP2D6.