What is the evidence for using glycine (amino acid) supplements as a sleep aid?

Glycine Supplements for Sleep: Evidence Assessment

Primary Recommendation

Glycine is not recommended by major sleep medicine guidelines for treating insomnia, as it lacks the rigorous clinical trial evidence required for formal endorsement, though emerging research suggests potential benefit for subjective sleep quality in individuals with mild sleep difficulties. 1

Guideline Position

• The American Academy of Sleep Medicine (AASM) 2017 clinical practice guideline does not include glycine among recommended treatments for chronic insomnia 1
• The AASM explicitly recommends against herbal/nutritional supplements for chronic insomnia due to lack of demonstrated efficacy and safety concerns 2
• Over-the-counter and nutritional substances are generally not recommended due to insufficient evidence, similar to the weak recommendation against melatonin, valerian, and L-tryptophan 2, 1

Research Evidence for Glycine

Mechanism of Action:

• Glycine appears to promote sleep through peripheral vasodilation and core body temperature reduction via NMDA receptor activation in the suprachiasmatic nucleus (SCN) 3
• Animal studies demonstrate that glycine increases cutaneous blood flow at the plantar surface, facilitating heat loss and temperature decline associated with sleep onset 3, 4
• The hypothermic effect is blocked by NMDA receptor antagonists but not by glycine receptor antagonists, indicating NMDA-mediated mechanisms 3

Human Clinical Data:

• A 2012 study found that 3 grams of glycine before bedtime significantly reduced subjective daytime fatigue and sleepiness in sleep-restricted healthy volunteers 5
• Glycine improved psychomotor vigilance test performance following acute sleep restriction 5
• Subjective sleep quality improvements have been reported in individuals with "insomniac tendencies," though objective polysomnographic data are limited 4

Important Limitations:

• No large-scale randomized controlled trials meeting AASM inclusion criteria exist for glycine 1
• Studies lack the rigorous methodology (adequate sample sizes, objective sleep measures, clinically significant thresholds) required for guideline-level recommendations 2
• Glycine did not significantly alter circadian clock genes or plasma melatonin concentrations, though it modulated certain neuropeptides in the SCN 5

Clinical Application Framework

When Glycine May Be Considered:

• Patients seeking non-pharmaceutical sleep aids who understand the limited formal evidence base 1
• Individuals with mild sleep onset difficulties or occasional sleep restriction rather than chronic insomnia disorder 1, 5
• As a potential adjunct (not replacement) to cognitive-behavioral therapy for insomnia (CBT-I), which remains first-line treatment 2, 1

Dosing from Available Research:

• 3 grams orally before bedtime was the dose used in human studies showing benefit 5, 4

Critical Pitfalls to Avoid:

• Do not use glycine as a substitute for CBT-I, which has strong evidence for improving sleep outcomes and quality of life 2, 1
• Do not delay evaluation for underlying sleep disorders (sleep apnea, restless legs syndrome, circadian rhythm disorders) by relying on unproven supplements 2
• Recognize that glycine occupies a similar evidence tier to melatonin and valerian—not formally recommended but potentially used by informed patients given perceived safety 1

Evidence-Based Treatment Hierarchy

First-Line Treatment:

• Cognitive-behavioral therapy for insomnia (CBT-I) is the standard of care with strong evidence for chronic insomnia disorder 2, 1

Pharmacotherapy (After CBT-I Failure or as Temporary Adjunct):

• FDA-approved options with stronger evidence include eszopiclone, zolpidem, suvorexant, and doxepin for sleep onset and maintenance 2, 1
• Short-term use only (4-5 weeks) is recommended due to tolerance, dependence, and serious adverse effects including falls, cognitive impairment, and mortality risk 2, 1
• Benzodiazepine receptor agonists or ramelteon are recommended as first-line pharmacotherapy when medication is necessary 2

Supplements Position:

• Melatonin 2 mg has weak evidence and is suggested against for primary insomnia, though it may benefit delayed sleep-wake phase disorder 2, 6
• Diphenhydramine and other antihistamines are not recommended due to lack of efficacy data and safety concerns, particularly anticholinergic effects in older adults 2, 7
• Glycine has insufficient evidence for formal recommendation but may be reasonable for informed patients seeking alternatives 1

Comparative Context

Glycine occupies a unique position: it has more mechanistic research than many supplements but lacks the clinical trial infrastructure required for guideline inclusion 1, 3, 4. Unlike prescription hypnotics with established efficacy but significant adverse effect profiles 2, 1, glycine appears to have minimal safety concerns but unproven clinical benefit in rigorous trials 1.