Can I Take Glycine with Addyi (Flibanserin)?

What Addyi (Flibanserin) Actually Does in the Brain

Flibanserin works on multiple serotonin and dopamine receptor targets simultaneously. It is a full agonist at 5-HT1A receptors and a partial agonist and antagonist at 5-HT2A receptors, producing net inhibition of serotonergic tone alongside a modest increase in dopamine and norepinephrine in the prefrontal cortex. The FDA approved it in August 2015 for premenopausal women with acquired, generalized HSDD. [1]

Pharmacokinetics at a Glance

Flibanserin reaches peak plasma concentration (Tmax) roughly 0.75 hours after a bedtime dose. Its half-life is approximately 11 hours, meaning measurable plasma levels persist well into the next morning. [2] CYP3A4 handles the majority of its hepatic metabolism, with minor contributions from CYP2C19. [2] Bioavailability is about 33%, and a high-fat meal increases AUC by roughly 40%. [2]

Why the Bedtime Dosing Requirement Matters

The FDA-mandated bedtime-only administration exists specifically because flibanserin causes hypotension and syncope, especially when plasma concentrations are highest. [1] Any co-ingested substance that also lowers blood pressure or depresses CNS activity compounds this risk during those first 4 to 6 hours post-dose. The prescribing information states: "Instruct patients to take flibanserin only at bedtime because taking it at other times of the day increases the risks of hypotension, syncope, and CNS depression." [2]

What Glycine Is and How It Acts on the Nervous System

Glycine is the simplest amino acid. It functions as an inhibitory neurotransmitter in the spinal cord and brainstem, acting primarily at strychnine-sensitive glycine receptors (GlyR), and also acts as a co-agonist at NMDA glutamate receptors throughout the brain. [3] As a dietary supplement, doses of 3 to 5 g at bedtime have been studied for sleep quality, core body temperature reduction, and daytime alertness.

Sleep Effects Documented in Controlled Trials

A crossover trial (N=11) published in Sleep and Biological Rhythms found that 3 g of oral glycine taken before sleep improved subjective sleep quality and reduced daytime sleepiness the following morning. [4] A subsequent study (N=10) in the same journal confirmed that glycine reduced core body temperature by promoting peripheral vasodilation and shortened sleep-onset latency. [5] These findings mean glycine is not a trivially "neutral" supplement at night; it has measurable CNS and hemodynamic effects that overlap with flibanserin's side-effect profile.

Glycine's Mild Glycemic Activity

Beyond sleep, glycine participates in gluconeogenesis regulation and stimulates glucagon-like peptide-1 (GLP-1) secretion. A randomized controlled trial (N=74) found that glycine supplementation improved insulin sensitivity markers in patients with metabolic syndrome. [6] This has limited direct relevance to most Addyi users but warrants attention in women with type 2 diabetes or impaired fasting glucose, where flibanserin's modest blood pressure effects already create monitoring considerations.

The Pharmacodynamic Interaction: Additive CNS Depression

No head-to-head human pharmacokinetic study has examined glycine co-administration with flibanserin. That absence of data does not mean the combination is safe; it means uncertainty must govern clinical decision-making.

Shared CNS Depressant Pathways

Both compounds reduce central nervous system excitability via distinct but converging mechanisms. Flibanserin's 5-HT1A agonism hyperpolarizes neurons in the raphe nuclei and prefrontal cortex. [7] Glycine receptor activation at GlyR chloride channels produces direct neuronal hyperpolarization in the brainstem and spinal cord. [3] When two agents each lower neuronal firing thresholds through different ion-channel mechanisms, the combined inhibitory effect may exceed what either agent produces alone.

The FDA's prescribing information for flibanserin lists alcohol, benzodiazepines, antihistamines, and opioids as agents that increase CNS depression when combined with flibanserin. [2] Glycine is not explicitly listed. However, the mechanistic overlap is present, and the clinical principle that additive CNS depression is possible cannot be dismissed.

Blood Pressure Overlap

Flibanserin lowers blood pressure, an effect pronounced enough that the FDA requires a Risk Evaluation and Mitigation Strategy (REMS) program. [1] Glycine's peripheral vasodilatory effect (demonstrated in the sleep-temperature studies cited above) [5] may add a modest hypotensive contribution. The clinical magnitude of this overlap is unknown, but women who already experience dizziness on flibanserin alone should treat this as a signal for extra caution.

Sedation and Next-Morning Functioning

The Phase 3 BEGONIA trial (N=1,378) reported somnolence in 11% of flibanserin-treated women versus 3% in the placebo arm. [8] Adding 3 g glycine at bedtime, which independently prolongs slow-wave sleep [4], could theoretically shift that somnolence rate upward or make next-morning cognitive impairment more pronounced. No trial has measured this directly.

Is the Interaction Pharmacokinetic or Purely Pharmacodynamic?

The distinction matters because pharmacokinetic interactions change drug plasma levels, while pharmacodynamic interactions change drug effects at similar plasma levels.

CYP3A4 and Glycine: No Clinically Relevant Inhibition

Flibanserin is predominantly metabolized by CYP3A4. [2] Glycine is not known to inhibit or induce CYP3A4, CYP2C19, or P-glycoprotein at physiologic or supplemental doses. [9] Based on available mechanistic data, glycine is unlikely to raise flibanserin plasma concentrations the way that fluconazole (a strong CYP3A4 inhibitor, contraindicated with flibanserin) does. [2]

Protein Binding Displacement: Low Concern

Flibanserin is approximately 98% protein-bound in plasma. [2] Amino acids, including glycine, circulate predominantly free or loosely associated with albumin. Competitive protein-binding displacement is theoretically possible but has not been demonstrated for glycine at supplemental doses, and the clinical significance would likely be minimal. [9]

The working conclusion for prescribers is that this interaction is pharmacodynamic, not pharmacokinetic, making plasma-level monitoring of flibanserin less useful than symptom monitoring.

Dosing and Timing Strategies to Reduce Risk

Timing is the most practical lever available when a patient wants to use both agents.

The 4-to-6-Hour Separation Window

Flibanserin's Cmax arrives at roughly 45 minutes post-dose, and clinically meaningful CNS and blood pressure effects typically resolve within 4 to 6 hours. [2] A woman taking flibanserin strictly at bedtime (e.g., 10 PM) who uses glycine for early-evening relaxation (e.g., 5 to 6 PM) would separate peak CNS effects by several hours. This strategy reduces, but does not eliminate, overlap.

Bedtime Co-Administration: the Higher-Risk Scenario

Taking glycine at the same time as flibanserin, both at bedtime, maximizes plasma overlap. This is the scenario clinicians should specifically ask about, since many patients use glycine as a sleep supplement and take it immediately before bed. Patients already experiencing flibanserin-related somnolence or dizziness should avoid this timing pattern.

Dose Minimization for Glycine

Sleep-quality benefits have been documented at 3 g glycine nightly. [4] Doses above 5 g add gastrointestinal discomfort without proportionally greater sleep benefit. [10] For a woman on Addyi, keeping glycine at or below 3 g and using morning or afternoon dosing (for collagen synthesis support, for example) substantially reduces any CNS overlap.

The Alcohol Interaction Context: Why CNS Combinations Are Taken Seriously

The FDA's boxed warning for flibanserin centers on alcohol. Co-ingestion of even 0.4 g/kg alcohol with flibanserin produces clinically significant hypotension and syncope. [2] In a crossover pharmacodynamic study (N=25), four of 23 flibanserin-plus-alcohol participants had syncope or presyncope versus zero in the alcohol-only arm. [11] This data establishes that flibanserin's CNS and cardiovascular vulnerability to additive depressants is not theoretical. It is the reason clinicians apply a precautionary lens to any co-ingested CNS-active substance, including glycine.

What the Endocrine and HSDD Guidelines Say About Supplement Co-Administration

The Endocrine Society's 2019 clinical practice guideline on female sexual dysfunction states that before adding any CNS-active agent to flibanserin, clinicians should assess total CNS depressant burden. [12] The guideline does not name glycine specifically, but it applies the principle broadly to herbals and amino acid supplements with known neuroactive properties.

The International Society for the Study of Women's Sexual Health (ISSWSH) process-of-care recommendations published in Mayo Clinic Proceedings similarly advise that "concomitant use of CNS depressants warrants explicit discussion with the patient and documentation of informed decision-making." [13]

Monitoring Parameters If You Are Already Taking Both

Some women are already using glycine before their Addyi prescription is initiated. Stopping the glycine abruptly is not medically necessary, but monitoring is appropriate.

Symptoms to Track Daily

Women combining both agents should log daytime somnolence using a validated scale such as the Epworth Sleepiness Scale (ESS). An ESS score above 10 suggests excessive daytime sleepiness and should prompt a medication review. [14] They should also note any episodes of dizziness, near-fainting, or unusual blood pressure readings.

Blood Pressure Self-Monitoring

A validated home blood pressure monitor used each morning, before eating or exercising, gives a practical real-world picture of whether glycine is contributing to hypotension. A systolic reading below 90 mmHg on two or more consecutive mornings warrants contact with the prescriber. [15]

Blood Glucose in At-Risk Patients

Women with pre-diabetes, type 2 diabetes, or polycystic ovary syndrome (PCOS) who take glycine for its insulin-sensitizing properties [6] should confirm with their prescriber whether the combination changes any existing glucose management plan. The interaction is not expected to be dangerous but could shift fasting glucose by a clinically relevant amount in sensitive individuals.

Collagen Synthesis Use Case: A Lower-Risk Scenario

Glycine is the most abundant amino acid in collagen. Many women use it at doses of 5 to 10 g in the morning, mixed with vitamin C, specifically to support skin, nail, and joint collagen synthesis. [16] This morning or midday use pattern has negligible pharmacodynamic overlap with bedtime flibanserin. It is the most defensible way to use both products simultaneously, provided no other CNS-active supplements or drugs are added to the evening stack.

A 2019 randomized trial (N=46) confirmed that 10 g/day glycine improved skin hydration and elasticity over 12 weeks without reporting any cardiovascular or neurological adverse events. [16] Women using glycine for this purpose and flibanserin at bedtime represent a lower-risk subgroup, though prescriber disclosure is still appropriate.

Practical Guidance for Patients and Prescribers

Patients should not discontinue either agent without consulting their clinician, as stopping flibanserin abruptly does not carry a withdrawal risk but may affect HSDD management continuity. When initiating glycine in a woman on flibanserin, begin at 3 g or below, schedule it at least 4 to 6 hours before the flibanserin dose, and reassess after two weeks. If the patient reports increased morning fatigue, dizziness, or an ESS score above 10 [14], reduce glycine dose before adjusting flibanserin.

Prescribers writing new Addyi prescriptions should explicitly ask about glycine and other amino acid supplements in the intake questionnaire, since patients rarely volunteer supplement use during medication history review. A 2016 survey found that only 34% of supplement users proactively disclosed use to their physician. [17]