Naltrexone (low-dose)

Naltrexone, in its low-dose application, is an opioid antagonist that Ray Peat recommended as a short-term intervention to disrupt pathological cycles driven by endorphins. 3 Peat explained that endorphins, the body's endogenous opioids, are produced as a protective emergency response to stress signals, particularly lactic acid generated during hypothyroidism and fatigue. 2 He described these accumulated endorphins as limiting physiological functions in a protective, localized "hibernation" state, and he argued that low-dose naltrexone or naloxone could clear these endorphins, sometimes lifting a person out of depression or a lethargic state within two or three days. 2

The dosing strategy Peat advocated was sharply distinct from the standard 50 mg dose used for addiction. He consistently cited effective doses of 1 to 4 milligrams, noting that some individuals find a therapeutic effect with even a hundredth of a milligram. 3 Sarah Murray specified that the effective range is between 2 and 5 milligrams, and Peat confirmed that if the drug is working, the effect is noticeable after the first few milligrams. 2 He emphasized that the treatment should be brief, typically lasting only a few days, and he did not recommend continuous use. 4 Peat advised repeating these short courses only two or three times a year if needed, with a waiting period of two weeks or more to assess whether the process should be repeated. 2

Mechanistically, Peat connected the need for naltrexone to a fundamental energy deficit. He taught that the hypothyroid state increases lactic acid production at the expense of carbon dioxide, and this lactic acid is the primary driver of endorphin production. 2 Therefore, while naltrexone could break the immediate cycle of opioid-driven torpor, Peat considered the basic treatment to be a good diet and thyroid supplementation to restore oxidative metabolism and keep endorphins down. 3 He also noted that exogenous opioids like fentanyl can activate inflammatory histamine pathways, creating a self-perpetuating cycle that a short course of naltrexone can interrupt by blocking the morphine or endorphin effect. 8

Peat observed that the balance of endorphins could manifest in lateralized physical symptoms, with some individuals developing all their symptoms on one side of the body due to the predominant type of endorphin being produced. 1 He referenced a study where demented patients given large doses of naloxone for several weeks showed cognitive improvement simply from blocking endorphins, and he related this to the way naloxone withdrawal in old rats could cause either exaggerated skin flushing or no flush at all, depending on their baseline body temperature. 2 While Peat considered the drug safe for short-term use, he cautioned against the long-term use of other dopamine agonists like pramipexole, which he did not consider safe. 2