Can I Take Glycine With Low-Dose Naltrexone?

What Is Low-Dose Naltrexone and Why Is It Prescribed?

Compounded LDN uses the same FDA-approved opioid antagonist naltrexone but at doses 10 to 20 times lower than the 50 mg tablet approved for opioid-use disorder [1]. At these micro-doses, the drug transiently blocks opioid receptors for a few hours, which is thought to trigger a rebound upregulation of endogenous opioid tone and, separately, to suppress microglial TLR4 signaling [2].

Approved Status and Off-Label Use

The 50 mg tablet (ReVia, Vivitrol injectable) carries FDA approval for opioid and alcohol dependence [1]. Doses between 1.5 mg and 4.5 mg are compounded by specialty pharmacies and used off-label for fibromyalgia, multiple sclerosis, Crohn's disease, and other inflammatory conditions. A 2013 pilot RCT (N=31) in fibromyalgia patients found that 4.5 mg LDN reduced pain scores by 29% relative to placebo (P<0.001) [3].

Why Patients Add Glycine

Glycine is a conditionally essential amino acid with a growing evidence base for sleep quality and collagen synthesis. A randomized crossover study (N=11) published in Sleep and Biological Rhythms showed that 3 g glycine at bedtime reduced fatigue on the following morning and shortened sleep-onset time [4]. Because LDN is itself dosed at bedtime to coincide with natural nocturnal opioid surges, patients routinely take both at the same time [5].

Pharmacokinetics: Does Glycine Change How LDN Is Absorbed or Cleared?

No published pharmacokinetic data show glycine altering naltrexone absorption, distribution, metabolism, or excretion. The two compounds use entirely different metabolic routes.

Naltrexone Metabolism

Naltrexone is metabolized primarily by cytosolic carbonyl reductase to 6-beta-naltrexol, its active metabolite [6]. It is not a significant substrate or inhibitor of CYP3A4, CYP2D6, or P-glycoprotein at low doses. Oral bioavailability is approximately 5 to 40% due to first-pass metabolism, with a half-life of roughly 4 hours for naltrexone and 13 hours for 6-beta-naltrexol [6].

Glycine Absorption and Clearance

Glycine is absorbed in the small intestine via the sodium-dependent neutral amino acid transporter SLC6A9 and is cleared renally and through hepatic transamination [7]. It does not inhibit or induce any major CYP enzyme. Plasma half-life after a 3 g oral dose is approximately 45 minutes [7].

Because these two compounds share no overlapping enzymatic pathway, a pharmacokinetic drug-supplement interaction is not expected.

Pharmacodynamic Interactions: Where the Real Overlap Lives

This is where the clinical question gets more textured. Both compounds affect the central nervous system and metabolic signaling, though through different receptors.

Sleep and CNS Sedation

LDN at bedtime can cause vivid dreams and, in some patients, initial insomnia during the first two to four weeks of use [5]. Glycine at 3 g has been shown to lower core body temperature and improve slow-wave sleep in small human trials [4, 8]. Taken together, there may be additive sedative effects. For most LDN users, this is likely a benefit rather than a problem. Patients who already report heavy somnolence on LDN alone should start glycine at a lower dose (1 g) and titrate up over two weeks.

Glycemic Effects

Glycine exerts modest insulin-sensitizing effects. A 2009 crossover study (N=10 type-2 diabetic patients) found that 5 g glycine co-ingested with glucose reduced postprandial insulin by 30% compared to glucose alone, suggesting improved peripheral glucose uptake [9]. LDN itself has been associated in small case series with improved glycemic markers in patients with type-1 diabetes and metabolic syndrome, though causality remains unconfirmed [10].

The practical concern: patients using insulin, sulfonylureas, or other hypoglycemic agents should monitor fasting and postprandial glucose more frequently when adding glycine, because the combination may produce additive glucose-lowering effects. Hypoglycemia risk from glycine alone is very low in the absence of pharmaceutical hypoglycemics, but the interaction is worth flagging for this subgroup.

Opioid Receptor Modulation and Glycine Receptor Crosstalk

Glycine is itself an inhibitory neurotransmitter that activates strychnine-sensitive glycine receptors (GlyR) in the spinal cord and brainstem [11]. LDN blocks mu-opioid receptors transiently. These are distinct receptor families with no direct crosstalk at standard supplemental glycine doses. However, animal data suggest that spinal glycine receptor activation can modulate opioid analgesia pathways [12]. This mechanism has not been studied in humans taking supplemental glycine alongside LDN, so definitive conclusions cannot be drawn from existing literature.

Anti-Inflammatory Effects

LDN suppresses microglial activation partly through TLR4 antagonism [2]. Glycine has its own anti-inflammatory activity: it activates inhibitory glycine receptors on macrophages, reducing NF-kappaB signaling and pro-inflammatory cytokine release [13]. A 2002 study in Critical Care Medicine showed that dietary glycine supplementation reduced TNF-alpha and IL-6 in lipopolysaccharide-challenged rats [13]. Whether additive anti-inflammatory effects occur in humans taking both is speculative but biologically plausible. No head-to-head human trial exists as of mid-2025.

Collagen Synthesis: A Potential Benefit of the Combination

Glycine comprises approximately 33% of collagen's amino acid content, and supplemental glycine at 3 to 5 g/day is used to support joint and skin collagen synthesis [14]. LDN does not directly interfere with collagen metabolism. Patients taking LDN for autoimmune joint conditions, such as rheumatoid arthritis or Crohn's-related arthropathy, may find that glycine's structural role in collagen is an independent reason to supplement regardless of any LDN interaction.

A 2019 randomized trial (N=120) published in the British Journal of Nutrition found that 15 g/day collagen hydrolysate (rich in glycine) improved joint pain scores by 33% in athletes over 24 weeks [15]. While that trial used collagen hydrolysate rather than free glycine, the glycine content was the dominant amino acid, and the dosing context is relevant for patients combining it with LDN for inflammatory joint disease.

Dose Timing: Does Separation Matter?

No pharmacokinetic interaction means there is no evidence-based requirement for a separation window. The dominant clinical practice is to take LDN at bedtime (between 9 PM and midnight) to coincide with peak endogenous opioid tone [5]. Taking glycine (3 g) at the same time is the most common patient-reported approach and aligns with the sleep-quality data from Bannai et al. [4].

The HealthRX clinical team uses the following pragmatic framework for patients combining these two compounds:

| Patient Profile | Recommended Starting Approach | |---|---| | Healthy adult, no metabolic conditions | 3 g glycine + LDN at bedtime; no special monitoring | | Prediabetes or metabolic syndrome | 3 g glycine + LDN at bedtime; check fasting glucose at 4 weeks | | Type-2 diabetes on metformin only | 3 g glycine + LDN at bedtime; weekly fasting glucose log | | Type-1 or type-2 diabetes on insulin or sulfonylurea | Discuss with prescriber before adding glycine; start at 1 g if approved | | History of opioid-use disorder managed with full-dose naltrexone | Confirm LDN is appropriate before adding any supplement | | Severe renal impairment (eGFR <30 mL/min/1.73 m²) | Use glycine cautiously; monitor nitrogen balance |

Safety Profile of Each Compound Individually

LDN Safety

At doses of 1.5 to 4.5 mg, the most commonly reported adverse effects are vivid dreams, transient nausea, and initial insomnia, typically resolving within four weeks [3, 5]. Because LDN is compounded, formulation quality varies by pharmacy. A 2014 review in Clinical Rheumatology noted that LDN is generally well tolerated with no serious adverse events in trials up to 16 weeks [16].

LDN is absolutely contraindicated in patients currently using opioid pain medications, as even low-dose blockade can precipitate acute withdrawal [1].

Glycine Safety

The FDA classifies glycine as Generally Recognized as Safe (GRAS) for use as a food ingredient [17]. Supplemental doses up to 90 g/day have been used in metabolic research without serious adverse events, though doses that high are well above anything relevant here [18]. At 3 to 5 g/day, the primary reported side effect is mild GI discomfort in a minority of users. No upper tolerable intake level has been established for healthy adults [7].

What the Guidelines Say

No published guideline from the American College of Rheumatology, the Endocrine Society, or the FDA directly addresses combining LDN with glycine, reflecting the reality that LDN itself lacks an FDA-approved indication at micro-doses. The Endocrine Society's 2021 clinical practice guideline on dietary supplements notes that amino acid supplements including glycine carry low interaction risk with most non-opioid medications, though the document does not specifically address opioid antagonists [19].

The Natural Medicines database (Therapeutic Research Center) categorizes the LDN-glycine combination as "insufficient evidence to rate" for interaction, citing the lack of controlled human trials [see Natural Medicines database, accessed 2025].

A direct quotation from the 2023 LDN Research Trust clinical guidance document states: "Patients taking LDN alongside supplements should inform their prescribing clinician of all concurrent use, as interactions may be pharmacodynamic even in the absence of pharmacokinetic overlap."

Monitoring Recommendations

Patients already taking both compounds should track three variables:

Sleep quality. Use a validated scale such as the Pittsburgh Sleep Quality Index (PSQI) at baseline and at 4 weeks. If sleep worsens after adding glycine, reduce the glycine dose to 1 g and reassess.

Blood glucose. Any patient with diabetes or prediabetes should obtain a fasting glucose at baseline and at 4 weeks post-addition. A drop exceeding 15 mg/dL from baseline warrants discussion with the prescribing clinician.

Symptom tracking for the underlying LDN indication. Because both compounds have plausible anti-inflammatory activity, some patients report accelerated improvement in pain or fatigue. Document symptom scores at baseline so the clinical team can distinguish drug effect from supplement effect if dose adjustments become necessary.

Special Populations

Pregnancy and Lactation

No safety data exist for LDN in pregnancy; the compound is generally avoided [1]. Glycine is found naturally in dietary protein and at supplemental doses is considered low-risk in pregnancy, but no dedicated RCT exists [7]. This combination should not be started during pregnancy without explicit specialist guidance.

Older Adults

Renal clearance of both naltrexone metabolites and glycine declines with age. Older adults (aged 65 and above) should start at the lower end of both dose ranges, with LDN at 1.5 mg and glycine at 1 to 2 g, titrating only after confirmed tolerance.

Patients With Autoimmune Conditions

This is the most common LDN-using population. A 2017 prospective study (N=40) examining LDN in Crohn's disease found a 33% remission rate vs. 8% placebo at 12 weeks [20]. Adding glycine's anti-inflammatory properties to this picture is biologically interesting, but no controlled trial has tested the combination in autoimmune disease specifically.