Low-Dose Naltrexone and Diphenhydramine Interaction: What Patients and Clinicians Need to Know

Is there a known interaction between low-dose naltrexone and diphenhydramine?

The naltrexone label is written for the 50 mg tablet, and it advises caution when naltrexone is given with other drugs [1]. The caution is general and not limited to opioids; diphenhydramine is not an opioid.

Low-dose naltrexone is a different product from that tablet. No FDA-approved low-dose naltrexone product exists. LDN means naltrexone at roughly 0.5 to 6 mg a day, most often 4.5 mg, made by compounding pharmacies and used off-label [4]. FDA says compounded drugs are not FDA-approved and that it does not verify their safety, effectiveness or quality before they are marketed [9]. The approved labels give no guidance on LDN doses [1][4]. Read more about low-dose naltrexone.

Does diphenhydramine blunt the effect of LDN?

No source we found shows that diphenhydramine blocks or reduces the effect of naltrexone. The prescribing information for diphenhydramine describes it as an H1 antihistamine with anticholinergic and sedative effects that also inhibits CYP2D6 [3][5].

The naltrexone tablet label names interactions involving opioid-containing medicines, disulfiram and thioridazine; diphenhydramine is not among them [1].

How LDN works is itself unsettled. Proposed mechanisms include Toll-like receptor 4 antagonism on microglia, brief opioid-receptor blockade with compensatory upregulation of endogenous opioid signaling, and opioid growth factor receptor effects. A 2026 narrative review that screened 105 studies describes these mechanisms as largely theoretical and speculative [4]. An argument that diphenhydramine interferes with LDN therefore rests on a mechanism that has not been established.

What is known about sedation with each drug

Diphenhydramine's over-the-counter Drug Facts label says marked drowsiness may occur, says to avoid alcoholic drinks, states that alcohol, sedatives and tranquilizers may increase drowsiness, and says to be careful when driving a motor vehicle or operating machinery [2]. The prescription injection label states that diphenhydramine has additive effects with alcohol and other CNS depressants (hypnotics, sedatives, tranquilizers), and lists sedation, sleepiness, dizziness and disturbed coordination among its most frequent reactions [3].

The naltrexone tablet label lists dizziness in 4% and somnolence in 2% of about 570 people with alcoholism in an open-label safety study [1]. LDN trials commonly report insomnia, vivid dreams, nausea and dizziness, described as mostly mild and transient [4].

Diphenhydramine's effect on driving has been measured. In a randomized, double-blind, four-way crossover study in the Iowa Driving Simulator, 40 licensed drivers aged 25 to 44 with seasonal allergic rhinitis took a single dose of diphenhydramine 50 mg, fexofenadine 60 mg, alcohol at about 0.1% blood alcohol, or placebo. Diphenhydramine gave the poorest overall driving performance of the four treatments, lane keeping was impaired after both alcohol and diphenhydramine, and self-reported drowsiness did not predict impairment [8].

Older adults

The 2023 Beers Criteria advise adults 65 and older to avoid first-generation antihistamines, including oral diphenhydramine, because of their anticholinergic effects; they note that diphenhydramine may be appropriate for acute treatment of a severe allergic reaction [6][7]. The criteria also advise avoiding anticholinergic drugs in people with dementia or cognitive impairment, in delirium or at high risk of delirium, and with a history of falls or fractures, unless safer alternatives are unavailable [7].

The drug-drug interaction table in the same criteria says that using more than one anticholinergic drug increases the risk of cognitive decline and that the number of anticholinergic drugs should be minimized [6]. It separately advises avoiding any combination of three or more CNS-active drugs in older adults because of falls and fracture risk [6].

Does diphenhydramine's CYP2D6 inhibition matter here?

Diphenhydramine is a potent competitive CYP2D6 inhibitor in vitro, with an inhibitory constant of 2 micromol/L [5]. The controlled human study of that effect randomized 16 healthy men with genetically high or low CYP2D6 activity to metoprolol 100 mg taken with steady-state diphenhydramine or with placebo. In extensive metabolizers, diphenhydramine cut metoprolol oral and nonrenal clearance about twofold and metoprolol alpha-hydroxylation clearance 2.5-fold, with stronger and longer-lasting heart-rate and blood-pressure effects from metoprolol; poor metabolizers showed no such change [5].

Metoprolol was the test drug, not naltrexone, so this study does not show whether diphenhydramine changes naltrexone levels.

Using diphenhydramine as a sleep aid while on LDN

Diphenhydramine is also sold over the counter as a nighttime sleep aid. Beers states that tolerance develops when first-generation antihistamines are used as a hypnotic [6][7]. Insomnia is among the effects LDN trials commonly report [4].

Dose matters for this drug in general. FDA warned in 2020 that taking more than the recommended dose of over-the-counter diphenhydramine can cause serious heart problems, seizures, coma or death, citing teenagers who ended up in emergency rooms or died after the social media Benadryl Challenge [10]. The Benadryl Allergy tablet label directs adults and children 12 and older to take 1 to 2 tablets every 4 to 6 hours, no more than 6 times in 24 hours [2].