What are the recommended dosages and timing for mood‑modulating supplements such as ashwagandha root extract, L‑theanine, magnesium glycinate, 5‑hydroxy‑tryptophan (5‑HTP), and L‑tryptophan?

Mood-Modulating Supplements: Evidence-Based Dosing and Timing

Overview and Critical Safety Considerations

The supplements you mention have varying levels of evidence, but none should replace standard psychiatric care for diagnosed mood disorders—they function best as adjunctive therapy or for mild symptoms. 1, 2

Key Safety Warning: Perioperative Management

• 5-HTP and L-tryptophan must be held 24 hours before any surgery due to rapid metabolism and risk of serotonin syndrome when combined with anesthetic agents like meperidine or tramadol 1
• L-theanine should be held 24 hours before surgery due to dose-dependent blood pressure effects 1
• Magnesium glycinate has no specific perioperative restrictions but monitor for interactions with neuromuscular blocking agents

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Ashwagandha (Withania somnifera)

Evidence Base

• Provisionally recommended (++) by the World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) for anxiety disorders 2
• A 2024 randomized controlled trial demonstrated significant improvement in both Hamilton Depression Rating Scale (HDRS) and Hamilton Anxiety Rating Scale (HARS) scores compared to placebo, with increased serum serotonin levels 3

Dosing Protocol

• Dose: 500 mg once daily of root extract standardized to 2.5% withanolides (per USP protocol) 3
• Timing: Take at night to optimize tolerability and leverage potential sedative effects 3
• Duration: Minimum 30 days for initial response; optimal benefits seen at 60-90 days 3
• Consider formulations with 5 mg piperine (95% standardized) to enhance bioavailability 3

Clinical Considerations

• Most effective for mild-to-moderate anxiety and depression, not severe disorders 3
• Well-tolerated with minimal adverse effects in clinical trials 3
• Quality matters: Use USP-standardized preparations to ensure consistent withanolide content 2

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L-Theanine

Evidence Base

• Limited high-quality evidence for mood disorders specifically
• Primarily studied for anxiety reduction and stress management 1

Dosing Protocol

• Dose: 200-400 mg daily (based on general clinical use; no Grade A evidence available)
• Timing: Can be taken with or without food; consider morning or early afternoon dosing to avoid potential interference with sleep architecture
• Derivative of glutamate with dose-dependent blood pressure lowering effects 1

Clinical Considerations

• Hold 24 hours before surgery due to cardiovascular effects 1
• Generally well-tolerated with minimal drug interactions
• May be useful for situational anxiety but lacks robust evidence for clinical mood disorders

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Magnesium Glycinate

Evidence Base

• Not currently recommended (+/-) for depression based on WFSBP/CANMAT guidelines due to mixed study findings 2
• Magnesium in general showed insufficient evidence in meta-analyses for mood disorders 2

Dosing Protocol (If Used)

• Dose: 200-400 mg elemental magnesium daily (glycinate form preferred for better absorption and GI tolerability)
• Timing: Take at bedtime to leverage potential muscle relaxation and sleep-promoting effects
• Divide doses if using higher amounts to minimize GI side effects

Clinical Considerations

• Despite lack of strong evidence for mood, may be beneficial for comorbid conditions (muscle tension, sleep disturbances, migraine prophylaxis)
• Glycinate form has fewer laxative effects than other magnesium salts
• Monitor for diarrhea as dose-limiting side effect

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5-HTP (5-Hydroxytryptophan)

Evidence Base

• Weakly recommended (+) as adjunctive therapy for unipolar depression by WFSBP/CANMAT 2
• A Cochrane review found 5-HTP better than placebo (Peto OR 4.10; 95% CI 1.28-13.15; NNT 2.78), but evidence quality was insufficient for conclusive recommendations 4
• Bypasses rate-limiting tryptophan hydroxylase enzyme, with ~70% oral bioavailability and effective CNS penetration 5

Dosing Protocol

• Dose: 50-100 mg three times daily, titrated up to 300 mg daily maximum 5
• Timing: Take with meals (absorption not affected by other amino acids, unlike L-tryptophan) 5
• Start low (50 mg once or twice daily) and increase gradually over 1-2 weeks to minimize GI side effects

Critical Safety Warnings

• Hold 24 hours before surgery due to serotonin syndrome risk with anesthetic agents 1
• Do not combine with SSRIs, SNRIs, MAOIs, or other serotonergic medications without close medical supervision due to serotonin syndrome risk 1
• Historical association with Eosinophilia-Myalgia Syndrome (EMS) from contaminated batches—use only pharmaceutical-grade products from reputable manufacturers 4
• Not recommended as monotherapy for clinical depression; use only adjunctively 2, 4

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L-Tryptophan

Evidence Base

• Not currently recommended (+/-) for depression monotherapy by WFSBP/CANMAT 2
• Cochrane review showed potential benefit but insufficient quality evidence 4
• Less efficient than 5-HTP because it requires conversion by tryptophan hydroxylase (rate-limiting step) and competes with other amino acids for absorption 5

Dosing Protocol (If Used)

• Dose: 1-3 grams daily in divided doses (typically 500-1000 mg three times daily)
• Timing: Take on empty stomach, 30-60 minutes before meals or at bedtime to avoid competition with dietary amino acids for absorption
• Bedtime dosing may enhance sleep quality due to serotonin-to-melatonin conversion

Critical Safety Warnings

• Hold 24 hours before surgery 1
• Same serotonin syndrome risks as 5-HTP when combined with serotonergic medications 1
• Same EMS contamination concerns—use pharmaceutical-grade only 4
• Less clinically useful than 5-HTP due to absorption limitations 5

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Algorithmic Approach to Supplement Selection

Step 1: Assess Clinical Context

• Diagnosed major depressive disorder or anxiety disorder: Prioritize evidence-based pharmacotherapy (SSRIs, SNRIs) or psychotherapy (CBT) first 1
• Mild-to-moderate symptoms or adjunctive therapy: Consider supplements with strongest evidence (ashwagandha for anxiety, omega-3 fatty acids for depression) 6, 2, 3
• Subclinical symptoms or wellness optimization: Broader range of options acceptable with informed consent

Step 2: Screen for Contraindications

• Upcoming surgery within 24 hours: Avoid 5-HTP, L-tryptophan, L-theanine 1
• Current serotonergic medications: Avoid 5-HTP and L-tryptophan entirely 1
• Pregnancy/breastfeeding: Insufficient safety data for most supplements; omega-3 fatty acids are safest option 6

Step 3: Select Based on Primary Symptom

• Anxiety predominant: Ashwagandha 500 mg at night (first-line supplement choice) 2, 3
• Depression predominant: Consider omega-3 fatty acids (1-2 g EPA daily) as adjunct to standard treatment 6, 2
• Mixed anxiety/depression: Ashwagandha or omega-3 fatty acids 2, 3
• Sleep disturbance with mood symptoms: Magnesium glycinate 200-400 mg at bedtime (for sleep, not mood per se)

Step 4: Initiate and Monitor

• Start single supplement at lowest effective dose
• Assess response at 2-4 weeks; full benefits may require 8-12 weeks 6, 3
• If partial response, optimize dose before adding second agent
• Do not use supplements as monotherapy for moderate-to-severe mood disorders 2, 4

Step 5: Quality Assurance

• Use USP-verified or pharmaceutical-grade products when available 2, 3
• For omega-3 fatty acids, prescription formulations (RxOM3FAs) preferred if unfamiliar with OTC quality 6
• Avoid products with proprietary blends that don't disclose exact ingredient amounts

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Common Pitfalls to Avoid

Polypharmacy Without Evidence

• Do not combine multiple serotonergic supplements (5-HTP + L-tryptophan, or either with St. John's wort) due to additive serotonin syndrome risk 1
• Avoid "kitchen sink" approach—use targeted, evidence-based interventions

Unrealistic Expectations

• Supplements work more slowly than prescription medications; expect 4-8 weeks for meaningful benefit 6, 3
• Effect sizes are generally modest compared to standard antidepressants 2, 4

Neglecting Underlying Pathology

• Supplements are not appropriate monotherapy for major depressive disorder, bipolar disorder, or severe anxiety disorders 1, 2, 4
• Screen for suicidality, psychosis, and severe functional impairment that require immediate psychiatric intervention

Drug Interactions

• St. John's wort (not requested but commonly used) induces CYP3A4 and should be avoided due to multiple drug interactions 1
• 5-HTP and L-tryptophan interact dangerously with all serotonergic medications 1

Quality Control Issues

• Phytoceuticals lack FDA regulation and standardization is inconsistent 1, 2
• Historical contamination events (EMS with L-tryptophan/5-HTP) underscore importance of pharmaceutical-grade products 4

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Summary of Recommendations by Supplement

Supplement	Evidence Grade	Recommended Dose	Timing	Primary Indication
Ashwagandha	++ (Provisional) [2]	500 mg (2.5% withanolides)	Nightly [3]	Anxiety, mild-moderate depression
L-theanine	Insufficient	200-400 mg	Morning/afternoon	Situational anxiety
Magnesium glycinate	+/- (Not recommended for mood) [2]	200-400 mg elemental	Bedtime	Sleep support, not mood
5-HTP	+ (Weak) [2]	50-100 mg TID (max 300 mg/day)	With meals [5]	Adjunctive depression only
L-tryptophan	+/- (Not recommended) [2]	1-3 g divided	Empty stomach or bedtime	Limited clinical utility

The strongest evidence supports ashwagandha for anxiety and omega-3 fatty acids (not requested but mentioned in guidelines) for depression as adjunctive therapies. 6, 2, 3 All other supplements have weaker or insufficient evidence and should be used cautiously with informed consent about limited data quality.