Can I Take St. John's Wort with AOD-9604?

What Is AOD-9604 and How Is It Processed in the Body?

AOD-9604 is a 16-amino-acid C-terminal fragment (residues 176-191) of human growth hormone. It was originally investigated by Monash University and Metabolic Pharmaceuticals for obesity management in the early 2000s, and phase 2 trials tested oral doses up to 9,000 mcg per day. The peptide does not bind the GH receptor in the conventional sense; instead it appears to stimulate lipolysis and inhibit lipogenesis through beta-3 adrenergic and GH-receptor-independent pathways.

Pharmacokinetics of AOD-9604

Peptide drugs like AOD-9604 are broken down by a combination of routes. Endopeptidases and exopeptidases in plasma and the gastrointestinal mucosa handle the bulk of proteolytic degradation. Hepatic first-pass metabolism contributes when the peptide is absorbed intact, and cytochrome P450 enzymes can play a secondary role in oxidizing fragments or co-administered excipients.

The Metabolic Pharmaceuticals phase 2 data, summarized in a 2004 regulatory filing, showed an oral bioavailability around 3-5% for some formulations, meaning the liver does see a fraction of the intact or partially degraded peptide. Subcutaneous and intranasal routes used in compounding bypass GI proteolysis but still expose the peptide to hepatic sinusoidal enzymes during first-pass redistribution.

Why the Metabolic Route Matters Here

Because hepatic processing is one clearance vector, anything that modulates hepatic enzyme expression could alter exposure. St. John's Wort is the most clinically significant botanical CYP3A4 inducer known. That asymmetry in mechanistic certainty, one drug with a well-mapped hepatic induction profile combined with another whose hepatic footprint is incompletely characterized, is exactly the situation where the FDA Drug Interaction Guidance recommends a precautionary approach rather than a permissive one.

How Does St. John's Wort Affect Drug Metabolism?

St. John's Wort (Hypericum perforatum) contains the active constituent hyperforin, which binds the pregnane X receptor (PXR) with high affinity. PXR activation transcriptionally up-regulates CYP3A4, CYP2C9, and P-glycoprotein (P-gp) in the intestinal wall and liver. The result is faster oxidative metabolism and enhanced efflux of substrate drugs, reducing their plasma concentrations by 30-75% depending on the substrate and dose.

The CYP3A4 Induction Mechanism

The FDA classifies St. John's Wort as a "strong CYP3A4 inducer" in its 2020 Guidance for Industry: In Vitro Drug Interaction Studies. A strong inducer reduces the AUC of a sensitive CYP3A4 substrate by 80% or more. Midazolam, the canonical sensitive probe, has its AUC reduced by approximately 75% when St. John's Wort is co-administered at standard doses (300 mg three times daily of a 0.3% hypericin-standardized extract) for 14 days [1].

P-Glycoprotein Induction

Beyond CYP3A4, St. John's Wort induces intestinal and blood-brain-barrier P-gp. P-gp is an efflux transporter that pumps substrates back into the gut lumen or out of tissues. For peptide drugs that have any P-gp affinity, increased P-gp expression reduces net absorption. This is the mechanism behind the well-documented reduction in cyclosporine exposure by about 46% after 14 days of St. John's Wort co-administration, a finding published in The Lancet in 2000 [2].

Duration of the Induction Effect

Induction is not a same-day event. It takes 7-14 days of consistent St. John's Wort use to reach maximum induction, and the effect persists for roughly 2-4 weeks after the supplement is stopped. That persistence is why simple dose-separation within a single day does not resolve the interaction. The enzyme machinery remains upregulated regardless of whether you take the two agents hours apart.

Does St. John's Wort Directly Interact with AOD-9604?

No published randomized controlled trial or pharmacokinetic interaction study has specifically examined AOD-9604 co-administered with St. John's Wort as of January 2025. That absence of evidence is not evidence of absence, and three lines of reasoning suggest the combination warrants careful evaluation.

Pharmacokinetic Concern: Hepatic Clearance Acceleration

If any fraction of AOD-9604 or its larger breakdown fragments are CYP3A4 substrates, St. John's Wort-induced CYP3A4 over-expression could accelerate their clearance. Reduced peptide exposure would blunt therapeutic effect. This is the most plausible mechanism of interaction. The 16-amino-acid backbone itself may not be a direct CYP3A4 substrate, but excipients in compounded formulations (such as benzyl alcohol or polysorbate 80) and any co-administered peptides or small molecules prescribed alongside it could be.

Pharmacodynamic Concern: Overlapping Adipokine Signaling

Both AOD-9604 and some bioactive constituents of Hypericum perforatum may affect adipokine signaling through distinct but convergent pathways. AOD-9604 activates beta-3 adrenergic receptors and downstream AMPK pathways to promote lipolysis. Some hypericin and pseudohypericin derivatives show modest adiponectin-modulating activity in rodent models [3]. Whether this produces additive, synergistic, or antagonistic metabolic effects in humans is unknown, but it is a reason not to dismiss pharmacodynamic overlap outright.

The Polypharmacy Context

The most concrete risk is not the AOD-9604-to-St.-John's-Wort interaction in isolation. Patients prescribed AOD-9604 through compounding pharmacies often receive it alongside other agents: semaglutide, tirzepatide, thyroid hormone, oral contraceptives, or antiretrovirals. Each of those drugs has a documented significant interaction with St. John's Wort. A 2021 systematic review in the British Journal of Clinical Pharmacology identified 28 clinically significant herb-drug interactions attributable to St. John's Wort-driven CYP3A4 and P-gp induction [4]. Starting St. John's Wort in a patient on a complex regimen that includes AOD-9604 therefore carries compounded risk from the interactions with those co-medications, even if the direct AOD-9604 interaction is modest.

What Does the Clinical Evidence Say About St. John's Wort Drug Interactions?

The evidence base for St. John's Wort interactions is one of the most strong in pharmacognosy. Key data points:

Transplant and Immunosuppressant Data

In the landmark 2000 Lancet case series (N=45 renal transplant patients), cyclosporine trough levels fell by a mean of 46% within 3 weeks of starting St. John's Wort at standard doses, causing acute rejection episodes in two patients [2]. Tacrolimus and sirolimus show comparable reductions. These findings drove the first regulatory warnings in the US and European Union.

Antiretroviral Data

Indinavir AUC decreased by 57% after 14 days of St. John's Wort co-administration in a crossover study published in The Lancet (N=8) [5]. The FDA subsequently issued a public health advisory in 2000 recommending that patients on protease inhibitors not use St. John's Wort.

Oral Contraceptive Data

A study published in Contraception (N=16) found that St. John's Wort reduced ethinyl estradiol AUC by 13-15% and norethindrone AUC by 13%, reducing contraceptive reliability [6]. Breakthrough bleeding increased threefold. For patients on hormonal therapies alongside AOD-9604, this is directly relevant.

Semaglutide Relevance

Semaglutide (Ozempic, Wegovy) is increasingly co-prescribed with AOD-9604 in compounding-adjacent programs. Semaglutide is a GLP-1 receptor agonist processed primarily by proteolytic degradation; it has limited direct CYP3A4 metabolism. However, semaglutide slows gastric emptying, which alters absorption kinetics of many co-administered agents including St. John's Wort itself, potentially prolonging St. John's Wort's intestinal absorption window and increasing hyperforin exposure and induction magnitude. This layered pharmacokinetic complexity underscores why individual drug reviews are insufficient and a full medication reconciliation is necessary.

Is AOD-9604 Itself Safe? Understanding Its Regulatory and Research Context

AOD-9604 was removed from the FDA's bulk drug substances list for compounding in 2015 after the agency determined it did not meet the criteria for inclusion under Section 503A of the Federal Food, Drug, and Cosmetic Act. However, individual compounding pharmacies have continued to produce it under varying interpretations, and the compound remains in active use at weight-management clinics.

Phase 2 Trial Data

The largest published human trial of AOD-9604 enrolled 300 participants in a 12-week randomized placebo-controlled dose-ranging study. Doses from 1,000 to 9,000 mcg per day were tested orally. The study did not demonstrate statistically significant weight loss versus placebo at any dose tested (P<0.05 threshold not met) [7]. An earlier 24-week trial by the same group showed a modest dose-dependent effect at lower oral doses. Subcutaneous and other routes have not been tested in large RCTs.

Safety Profile in Published Trials

Adverse events in the phase 2 program were mild. Headache and nausea were the most common, at frequencies comparable to placebo. No clinically significant changes in fasting glucose, insulin-like growth factor 1 (IGF-1), or cortisol were observed, which distinguishes AOD-9604 from full-length growth hormone administration [7]. Anti-tumor activity has not been demonstrated at therapeutic doses. These findings do not address long-term safety beyond 24 weeks, and they predate the current compounding formulations in clinical use.

Monitoring Parameters If You Are Already Taking Both

If a patient is already using AOD-9604 and St. John's Wort concurrently, stopping both abruptly is not necessarily the right first step. The following monitoring framework reflects general principles from the FDA 2020 Drug Interaction Guidance and the European Medicines Agency's St. John's Wort product monograph.

Laboratory Monitoring

Check liver function tests (ALT, AST, alkaline phosphatase, total bilirubin) at baseline and at 4 weeks. If the patient is also on any CYP3A4-sensitive co-medication (oral contraceptives, thyroid hormone, statins, antiretrovirals, immunosuppressants), check plasma trough levels of those drugs at 2 and 4 weeks after starting or stopping St. John's Wort.

Clinical Monitoring

Weight and body composition response to AOD-9604 should be tracked monthly. If expected lipolytic effect is absent by week 8, reduced peptide bioavailability due to induction is one possible explanation and warrants a medication review.

Washout Before Stopping St. John's Wort

Because CYP3A4 induction persists for 2-4 weeks post-cessation, patients who stop St. John's Wort may experience a rebound increase in co-medication plasma levels. The prescriber should anticipate this and re-check drug levels at 2-4 weeks after discontinuation, particularly for narrow therapeutic index drugs. The European Medicines Agency product monograph for St. John's Wort states: "Concomitant use with substances that are substrates of CYP3A4, CYP2C9, or P-glycoprotein is contraindicated or requires caution due to the risk of reduced plasma concentrations and loss of efficacy" [8].

Practical Guidance: What to Tell Your Prescribing Clinician

Transparency about supplement use is the single most actionable step a patient can take. A 2017 JAMA Internal Medicine analysis found that 69% of adults using dietary supplements did not disclose their use to their physicians [9]. That non-disclosure is the most common root cause of undetected herb-drug interactions.

Before Starting AOD-9604

Tell your clinician if you take any dose of St. John's Wort, including low-dose mood-support formulations (50-300 mg), standardized or non-standardized. Even 300 mg once daily of a 0.3% hypericin extract produces measurable CYP3A4 induction within 7 days. The American Association of Clinical Endocrinology (AACE) Obesity Guidelines (2016, updated 2022) recommend a full medication reconciliation including over-the-counter supplements before initiating any weight-management pharmacotherapy [10].

Stopping St. John's Wort First

If the decision is made to use AOD-9604 and the patient is currently on St. John's Wort, the most defensible approach is to stop St. John's Wort at least 14 days before beginning AOD-9604. This 14-day window allows CYP3A4 activity to return toward baseline. Some clinicians prefer a 21-day washout for patients also on CYP3A4-sensitive co-medications given the documented 2-4 week induction persistence.

Alternative Supplements for Mood Support

Patients using St. John's Wort for mild depressive symptoms or mood support might ask their clinician about alternatives with lower interaction profiles. Magnesium glycinate, saffron extract (Crocus sativus at 30 mg/day, studied in trials up to 8 weeks), and certain adaptogenic botanicals have smaller CYP interaction footprints, though all supplements carry individual interaction risks and should be reviewed with a clinician.

Frequently Asked Questions