What are 5‑hydroxytryptophan (5‑HTP) and melatonin, and what are the recommended dosages, safety profile, and contraindications for using them together?

What are 5-HTP and Melatonin?

5-Hydroxytryptophan (5-HTP) is the direct metabolic precursor to serotonin that bypasses rate-limiting enzymatic steps and crosses the blood-brain barrier to increase central nervous system serotonin synthesis, while melatonin is a hormone that regulates circadian rhythms and sleep-wake cycles by binding to M1 and M2 receptors. 1, 2

5-Hydroxytryptophan (5-HTP)

Biochemistry and Mechanism

• 5-HTP is the intermediate metabolite between L-tryptophan and serotonin, produced by the enzyme tryptophan hydroxylase (TPH), which represents the rate-limiting step in serotonin biosynthesis 1, 3
• Unlike L-tryptophan, 5-HTP does not require a transport molecule for intestinal absorption and is not affected by the presence of other amino acids, meaning it can be taken with meals without reducing effectiveness 1
• Approximately 70% of an oral 5-HTP dose reaches the bloodstream, and it readily crosses the blood-brain barrier to increase CNS serotonin synthesis 1
• 5-HTP cannot be diverted into niacin or protein production, unlike L-tryptophan, making it a more direct serotonin precursor 1

Physiological Effects

• In the CNS, serotonin derived from 5-HTP regulates sleep, mood, anxiety, appetite, temperature, sexual behavior, and pain sensation 1
• 5-HTP is further metabolized to serotonin, which is then converted to melatonin (N-acetyl-5-methoxytryptamine) 3, 4

Clinical Applications (Research Evidence)

• Therapeutic administration of 5-HTP has shown effectiveness in treating depression, fibromyalgia, binge eating associated with obesity, chronic headaches, and insomnia in research studies 1
• 5-HTP plays a major role in both neurologic and metabolic diseases, with its synthesis from tryptophan representing the limiting step in both serotonin and melatonin biosynthesis 3

Melatonin

Mechanism of Action

• Melatonin works primarily by binding to M1 and M2 receptors, suppressing REM sleep motor tone and renormalizing circadian features of sleep 2
• Melatonin exhibits a phase response curve approximately 180 degrees out of phase with light, such that dosing in the afternoon/evening shifts rhythms earlier and morning dosing shifts rhythms later 5
• The Dim Light Melatonin Onset (DLMO) serves as the approximate inflection point for advancing and delaying effects of melatonin 5

Dosing Recommendations (Guideline-Based)

For Adults:

• Start with 3 mg of immediate-release melatonin taken 1.5-2 hours before desired bedtime 2, 5
• If ineffective after 1-2 weeks, increase by 3 mg increments up to a maximum of 15 mg 2
• Lower doses (0.3-1 mg) may be more effective than higher doses due to receptor desensitization at higher doses 6
• For elderly patients (65-80 years), start with 1-2 mg immediate-release melatonin, as lower doses mimic normal physiological circadian rhythm 7

For Children:

• For children 6-12 years without comorbidities: 0.15 mg/kg (approximately 1.6-4.4 mg) 2
• For children with psychiatric comorbidities: 3 mg if <40 kg, 5 mg if >40 kg 2
• For children with autism spectrum disorder or ADHD: start with 1-3 mg, 30-60 minutes before bedtime 2

Safety Profile

Adverse Effects:

• The most frequently reported adverse effect is daytime sleepiness/somnolence, occurring in 1.66% of participants, with headache (0.74%) and dizziness (0.74%) also reported 2, 5
• No clinically significant differences in adverse events between melatonin and placebo have been observed across various dosages and durations 5, 6, 7
• Higher doses (10 mg) are associated with more frequent adverse effects like morning headache and morning sleepiness due to melatonin's half-life extending into morning hours 2
• Gastrointestinal upset has been reported more frequently at higher melatonin doses 2, 5

Special Populations:

• No serious adverse reactions have been documented in children using melatonin at appropriate doses 2
• In elderly patients, melatonin has a favorable safety profile and is not listed on the American Geriatrics Society Beers Criteria of potentially inappropriate medications 7
• The American Academy of Sleep Medicine recommends avoiding melatonin for irregular sleep-wake rhythm disorder in older adults with dementia due to lack of benefit and potential harm 2

Duration of Use

• For chronic insomnia, melatonin use should be limited to a maximum of 3-4 months due to insufficient long-term safety data beyond several months 2, 5
• For circadian rhythm disorders (Delayed Sleep-Wake Phase Disorder, Non-24-Hour Sleep-Wake Rhythm Disorder), long-term continuous melatonin therapy may be appropriate 2, 5
• In pediatric populations with autism spectrum disorder, safe use has been documented for up to 24 months with continued efficacy 2

Contraindications and Drug Interactions

Caution Required:

• Use with caution in patients taking warfarin due to potential interactions reported to the World Health Organization 2, 6
• Exercise caution in patients with epilepsy based on case reports 2, 6
• Fluvoxamine markedly increases the risk of drug-drug interactions when combined with melatonin because it inhibits CYP1A2, the primary pathway for melatonin metabolism 2
• Concurrent use with CNS depressants (benzodiazepines, sedative-hypnotics, antipsychotics) or alcohol can produce additive sedation and impair psychomotor performance 2

Metabolic Considerations:

• Melatonin has been associated with impaired glucose tolerance in healthy individuals after acute administration, warranting monitoring of fasting glucose if metabolic concerns exist 2

Product Quality Concerns

• Melatonin is regulated as a dietary supplement in the U.S., raising significant concerns about purity and reliability of stated doses 2, 5
• Choose United States Pharmacopeial Convention (USP) Verified formulations for more reliable dosing and purity 2, 5

Combined Use of 5-HTP and Melatonin

Biochemical Rationale

• 5-HTP serves as the precursor to serotonin, which is then converted to melatonin, creating a direct metabolic pathway linking these compounds 3, 4
• A 2026 exploratory pilot study in children with neurodevelopmental disorders found that melatonin combined with 5-HTP (1 mg melatonin + 10 mg 5-HTP) resulted in significant reduction in the Sleep Movement Index (nocturnal motor activity) from baseline (6.55) to follow-up (1.25, p=0.006) 8

Safety Considerations for Combined Use

• When melatonin is used together with several serotonergic agents, clinicians should start at low doses, titrate slowly, and monitor closely for signs of serotonin syndrome 2
• No documented interactions between melatonin and SSRIs exist, and melatonin has been used safely with sertraline 2

Important Caveats

• The American Academy of Sleep Medicine suggests clinicians not use melatonin as first-line treatment for chronic insomnia based on weak evidence showing benefits approximately equal to harms 2, 5
• The American Academy of Sleep Medicine recommends against using tryptophan (5-HTP's precursor) as a treatment for sleep onset or sleep maintenance insomnia in adults 5
• Evidence for combined 5-HTP and melatonin use is limited to small exploratory studies with high attrition rates, and findings should be considered hypothesis-generating 8