Is low‑dose naltrexone safe and appropriate for a woman undergoing infertility treatment?

Low-Dose Naltrexone in Infertility Treatment: Safety and Mechanism

Low-dose naltrexone (1.5–4.5 mg daily) is safe and appropriate for women undergoing infertility treatment, with established evidence demonstrating restoration of ovulation and successful pregnancies in women with hypothalamic ovarian failure and polycystic ovary syndrome (PCOS). 1, 2

What Low-Dose Naltrexone Is

Low-dose naltrexone (LDN) refers to naltrexone used at doses of 1–5 mg daily, which is substantially lower than the standard 50 mg dose used for opioid or alcohol dependence 3, 4. At these low doses, naltrexone works through a completely different mechanism than its standard-dose application:

• LDN acts as an opioid antagonist that blocks endogenous opioid tone on the hypothalamic GnRH (gonadotropin-releasing hormone) pulse generator, thereby normalizing ovarian function in women with hypothalamic ovarian failure 1
• The mechanism involves disinhibition of the hypothalamic GnRH pulse generator, resulting in dramatic increases in the amplitude and frequency of gonadotropin pulses (LH and FSH) 1
• LDN also modulates Toll-like receptor 4 signaling and reduces glial inflammatory response, which may contribute to its therapeutic effects in various conditions 3, 5

Evidence for Safety and Efficacy in Infertility

Hypothalamic Ovarian Failure

• In 66 women with hypothalamic ovarian failure treated with naltrexone 25–150 mg daily, complete normalization of menstrual cycles occurred in 49 of 66 patients (74%), as demonstrated by normalized gonadotropin and ovarian steroid patterns 1
• Eighteen pregnancies were achieved in 16 women, resulting in a cumulative pregnancy rate closely resembling that of a normal population 1
• Only minor side effects were attributed to the drug, supporting excellent tolerability 1

Polycystic Ovary Syndrome (PCOS)

• In 30 clomiphene-resistant women with PCOS treated with naltrexone 50 mg daily for 6 months, 3 ovulated during naltrexone monotherapy and 19 of 27 ovulated when naltrexone was combined with clomiphene 2
• Nine of 27 women (33.3%) conceived during naltrexone plus clomiphene therapy, with seven term live births, one preterm delivery at 34 weeks, and one missed abortion at 9 weeks 2
• Naltrexone therapy significantly reduced BMI, fasting serum insulin, LH, LH/FSH ratio, and testosterone, demonstrating beneficial metabolic effects 2
• Naltrexone restored clomiphene sensitivity in the majority of clomiphene-resistant PCOS patients 2

Safety Profile in Pregnancy

Recent Prospective Data

• In a 2024 prospective case series of 7 pregnant individuals treated with naltrexone (3 with oral, 4 with extended-release formulation), there was no return to nonprescribed opioid use and reassuring maternal and infant outcomes through 12 months postpartum 6
• All individuals delivered vaginally at a mean of 37 weeks gestation without peripartum pain difficulties, with no reported fetal anomalies and only one preterm delivery 6
• None of the infants developed neonatal opioid withdrawal syndrome 6
• Five of 7 individuals (71.4%) remained on naltrexone 12 months after delivery, demonstrating sustained treatment adherence 6

FDA Pregnancy Classification and Precautions

• Naltrexone is FDA Pregnancy Category C, meaning animal studies showed increased early fetal loss in rats at doses ≥30 mg/kg/day and rabbits at ≥60 mg/kg/day, but no evidence of teratogenicity was found 7
• There are no adequate and well-controlled studies in pregnant women, so naltrexone should be used during pregnancy only if potential benefit justifies potential risk to the fetus 7
• For pregnant women with opioid use disorder, the 2019 joint workshop of SMFM, ACOG, and ASAM states that data are insufficient to support initiating naltrexone during pregnancy, though it may be continued for those already taking it after careful risk-benefit assessment 8

Dosing Protocol for Infertility

• For hypothalamic ovarian failure, doses ranging from 25–150 mg daily have been used successfully, with dose titration based on response 1
• For PCOS, 50 mg daily has been the standard dose studied, often combined with clomiphene citrate for clomiphene-resistant cases 2
• For chronic pain conditions (not infertility), the typical LDN protocol starts at 1.5 mg at bedtime with gradual bi-weekly increases of 1.5 mg to a maximum of 4.5 mg 8, 9

Critical Safety Considerations

Absolute Contraindications

• Patients requiring opioid therapy for pain management cannot use naltrexone at any dose, as it will block opioid analgesia even at low doses 9, 7
• Patients currently taking opioids must be opioid-free for a minimum of 7–10 days before initiating any dose of naltrexone to avoid precipitating severe withdrawal 9, 7

Monitoring Requirements

• Liver function tests should be performed at baseline and every 3–6 months, as naltrexone can cause hepatotoxicity at supratherapeutic doses 4, 7
• The concomitant use of naltrexone and disulfiram is not ordinarily recommended unless probable benefits outweigh known risks, due to potential dual hepatotoxicity 7

Common Side Effects

• Common side effects of LDN include headache, tachycardia, and vivid dreams, which are generally mild and well-tolerated 8, 9
• At standard doses, lethargy and somnolence have been reported when naltrexone is combined with thioridazine 8

Clinical Algorithm for Use in Infertility

1. Screen for absolute contraindications: current opioid use, acute hepatitis, decompensated cirrhosis 4, 7
2. Obtain baseline liver function tests before initiating therapy 4, 7
3. For hypothalamic ovarian failure: start naltrexone 25–50 mg daily and titrate based on menstrual cycle normalization and gonadotropin response 1
4. For clomiphene-resistant PCOS: start naltrexone 50 mg daily; if no ovulation after 12 weeks, add clomiphene citrate starting at 50 mg/day for 5 days, increasing up to 150 mg/day for non-responders 2
5. Monitor liver function every 3–6 months during treatment 4, 7
6. If pregnancy occurs while on naltrexone, conduct careful risk-benefit discussion regarding continuation versus discontinuation, noting reassuring recent prospective data 6

Key Clinical Pearls

• The mechanism of LDN in infertility is fundamentally different from its use in addiction treatment—it works by blocking excessive endogenous opioid tone that suppresses the hypothalamic GnRH pulse generator 1
• Naltrexone is particularly effective in restoring clomiphene sensitivity in women with PCOS who have failed clomiphene monotherapy 2
• Recent prospective data (2024) provide reassuring evidence for naltrexone continuation during pregnancy when clinically indicated, though this remains off-label 6
• Naltrexone is excreted in breast milk in animal studies, so caution should be exercised when administering to nursing women 7