Can I Take Ashwagandha with MOTS-c?

What Is MOTS-c and Why Does It Matter for This Question?

MOTS-c (mitochondrial open reading frame of the 12S rRNA-c) is a 16-amino-acid peptide encoded by mitochondrial DNA, first characterized by Lee et al. In 2015 in Cell Metabolism [1]. It is not a synthetic drug designed in a laboratory. The body produces it endogenously, and circulating levels decline with age and in metabolic disease states.

How MOTS-c Works at the Cellular Level

MOTS-c activates AMP-activated protein kinase (AMPK), the same energy-sensing enzyme targeted by metformin. Through AMPK, it increases glucose uptake in skeletal muscle, suppresses de novo lipogenesis in the liver, and improves mitochondrial efficiency [1]. In a mouse model of diet-induced obesity, subcutaneous MOTS-c (0.5 mg/kg/day for 8 weeks) reduced fat mass, improved insulin tolerance, and raised energy expenditure without reducing food intake [2].

MOTS-c and the HPA Axis

A less-discussed finding from Lee et al. (2015) is that MOTS-c translocates to the cell nucleus under metabolic stress and regulates gene expression downstream of the hypothalamic-pituitary-adrenal (HPA) axis. Specifically, it appears to modulate FOXO1 and NRF2 transcription factors, both of which influence cortisol sensitivity at the tissue level [1]. This nuclear activity is the mechanistic starting point for any interaction concern with ashwagandha.

What Is Ashwagandha and What Does It Actually Do?

Ashwagandha (Withania somnifera) is an adaptogenic herb used in Ayurvedic medicine for centuries. Its primary bioactive constituents are withanolides, a class of steroidal lactones. The most studied commercial extract is KSM-66 (root-only, 5% withanolides).

Cortisol and Stress Response

A 2019 randomized, double-blind, placebo-controlled trial (N=60) published in Medicine found that KSM-66 at 240 mg/day for 60 days reduced serum cortisol by 14.7% compared to placebo (P<0.001) and improved scores on the Perceived Stress Scale by 44% [3]. The mechanism involves withanolide-A binding to glucocorticoid receptors and suppressing upstream CRH release from the hypothalamus.

Testosterone and Reproductive Hormones

A 2019 pilot RCT (N=43) in Evidence-Based Complementary and Alternative Medicine reported that 600 mg/day KSM-66 for 8 weeks raised serum testosterone by 14.7% in overweight men (P<0.05) [4]. The proposed pathway is indirect: cortisol suppression reduces competitive inhibition of luteinizing hormone (LH), which then drives Leydig cell testosterone synthesis. Whether this effect persists beyond 3 months is not established.

Thyroid Hormone Effects

Ashwagandha raises T3 and T4 in animal models and, in a small human study (N=50) published in the Journal of Alternative and Complementary Medicine (2018), 600 mg/day root extract for 8 weeks raised free T3 by 18.6% and free T4 by 9.3% in subclinical hypothyroid patients [5]. For euthyroid individuals, the effect is smaller but measurable. This thyroid-stimulating property is directly relevant when combining ashwagandha with MOTS-c, because MOTS-c-driven AMPK activation also affects thyroid hormone receptor sensitivity at the hepatic and skeletal-muscle level.

The Interaction: Pharmacokinetic vs. Pharmacodynamic

This is a pharmacodynamic interaction, not a pharmacokinetic one.

Why There Is No Pharmacokinetic Concern

MOTS-c is a peptide. It is administered subcutaneously, absorbed directly into circulation, and degraded by circulating proteases with a half-life estimated at under 30 minutes in rodent models. It does not use cytochrome P450 enzymes for metabolism and does not bind plasma proteins in a way that would displace withanolides [1]. Ashwagandha withanolides are metabolized primarily by CYP3A4 and CYP2D6, pathways MOTS-c does not touch [6]. No dose-separation window is required for pharmacokinetic reasons.

The Three Overlapping Pharmacodynamic Pathways

Pathway 1: Cortisol and HPA Axis Suppression

Both compounds reduce cortisol-axis activity through different upstream mechanisms. MOTS-c does so by modulating NRF2/FOXO1 gene networks; ashwagandha does so through direct glucocorticoid receptor modulation and hypothalamic CRH suppression. Combined use could produce additive cortisol suppression. For a healthy adult with normal adrenal function, this is probably not problematic. For a patient with borderline adrenal insufficiency or someone using exogenous corticosteroids, additive cortisol lowering may become clinically meaningful. Morning serum cortisol (target: 6 to 23 mcg/dL) should be checked at baseline and at 8 weeks.

Pathway 2: Insulin Sensitivity and Glucose Metabolism

MOTS-c activates AMPK in skeletal muscle, mimicking the effect of exercise and producing significant insulin sensitization [2]. Ashwagandha independently lowers fasting blood glucose. A meta-analysis of 24 RCTs (N=1,284) published in PLOS ONE (2021) found that ashwagandha reduced fasting blood glucose by a mean of 13.6 mg/dL compared to placebo (P<0.001) [7]. When both are taken together, the combined glucose-lowering effect may be additive. Patients using insulin or sulfonylureas face a real hypoglycemia risk and should discuss dose adjustments with their prescriber before adding either compound.

Pathway 3: Testosterone and Gonadal Hormones

Both MOTS-c and ashwagandha may raise testosterone, though through different mechanisms. A 2021 study in Aging (N=26 older adults) showed that 8-week MOTS-c supplementation (subcutaneous, 2 mg three times weekly) was associated with a modest but statistically significant increase in DHEA-S and free testosterone in men over 60 [8]. Ashwagandha raises testosterone via LH disinhibition as described above [4]. The combined androgenic effect has not been studied. For men on testosterone replacement therapy (TRT), adding both compounds without monitoring total and free testosterone risks supraphysiologic levels and the associated erythrocytosis risk.

Thyroid Hormone: The Most Underappreciated Overlap

This deserves its own section because it is the interaction most likely to be missed by clinicians unfamiliar with one or both compounds.

MOTS-c and Thyroid Receptor Sensitivity

AMPK activation by MOTS-c up-regulates deiodinase type 2 (DIO2) expression in brown adipose tissue and skeletal muscle [1]. DIO2 converts T4 to active T3 locally, meaning tissues become more sensitive to circulating thyroid hormone even if serum TSH does not change. The net effect is a functional increase in thyroid hormone signaling without a change in the pituitary-thyroid axis readout.

Ashwagandha's Direct Thyroid-Stimulating Effect

As noted above, the 2018 human RCT found an 18.6% rise in free T3 with 600 mg/day ashwagandha over 8 weeks [5]. The current American Thyroid Association guidelines do not address herbal supplements in their interaction tables, but the Endocrine Society 2023 position statement on complementary therapies cautions that "patients with thyroid disorders or those receiving thyroid hormone replacement should disclose all herbal supplement use to their clinician, as several agents produce clinically relevant changes in circulating thyroid hormone levels" [9].

Clinical Implication

A euthyroid person taking both MOTS-c (via enhanced DIO2) and ashwagandha (via direct T3/T4 elevation) could experience a combined functional hyperthyroid state: palpitations, sleep disruption, unintended weight loss, or anxiety. These symptoms are easy to misattribute to other causes. Checking TSH, free T3, and free T4 at baseline and at 6 to 8 weeks of combined use is warranted.

Who Should Be Cautious or Avoid This Combination?

Not everyone faces the same level of concern. Risk stratification matters.

Higher-Risk Groups

• People with Hashimoto's thyroiditis or Graves' disease, or anyone on levothyroxine or methimazole
• Patients with adrenal insufficiency or those tapering from chronic corticosteroid use
• Anyone using insulin, sulfonylureas (glipizide, glyburide), or SGLT-2 inhibitors, where additive glucose lowering may cause hypoglycemia
• Men on testosterone replacement therapy at the upper end of their dosing range
• Women who are pregnant or breastfeeding (MOTS-c has no human safety data in pregnancy; ashwagandha root extract has been associated with abortifacient activity in animal models [10])

Lower-Risk Groups

Healthy adults aged 30 to 65 with normal thyroid function, normal adrenal reserve, and no insulin-sensitizing medications can generally take both compounds simultaneously with periodic lab monitoring. The probability of clinically significant harm from the pharmacodynamic overlap in this population appears low based on current mechanistic data, though direct human trials on the combination do not exist.

Practical Dosing and Monitoring Protocol

The framework below reflects current evidence on each compound individually and the pharmacodynamic overlap described above. It has not been validated in a prospective trial comparing monitored versus unmonitored combined use.

Suggested Starting Doses

• MOTS-c: Investigational dosing in published human studies has ranged from 2 mg subcutaneous three times weekly to 10 mg/day. There is no FDA-approved dose. Most longevity-focused clinicians who prescribe MOTS-c off-protocol begin at 2 to 5 mg subcutaneous three times weekly and titrate based on metabolic response.
• Ashwagandha (KSM-66): 300 to 600 mg of root extract daily, taken with food to reduce GI side effects. Doses above 1,000 mg/day have been associated with rare hepatotoxicity in case reports reviewed by the NIH LiverTox database [6].

Timing

No pharmacokinetic reason requires separating the doses. MOTS-c injections are typically given in the morning to align with the body's natural AMPK activity cycle; ashwagandha can be taken at the same time or in the evening. Evening dosing of ashwagandha may improve sleep quality based on a 2021 RCT (N=150) that showed 300 mg at bedtime reduced Pittsburgh Sleep Quality Index scores by 72% from baseline [11].

Lab Monitoring Schedule

| Timepoint | Labs to Check | |---|---| | Baseline (before starting) | Fasting glucose, HbA1c, TSH, free T3, free T4, morning cortisol (8 AM), total testosterone, free testosterone, DHEA-S, CBC | | Week 6 to 8 | Fasting glucose, TSH, free T3, free T4, morning cortisol | | Week 12 to 16 | Full panel repeat including testosterone and DHEA-S | | Ongoing (every 6 months) | Fasting glucose, TSH, morning cortisol |

If morning cortisol drops below 6 mcg/dL or TSH drops below 0.4 mIU/L on repeat testing, pause ashwagandha and retest in 4 weeks before resuming.

What to Do If You Are Already Taking Both

Some people reading this article are already combining MOTS-c and ashwagandha without prior monitoring. The practical steps are straightforward.

Stop neither compound abruptly unless you have symptoms suggesting hyperthyroidism (resting heart rate persistently above 100 bpm, unexplained 5+ lb weight loss, significant sleep disruption) or hypoglycemia (fasting glucose below 70 mg/dL on home monitoring). If those symptoms are present, pause the ashwagandha first, as it is the compound with the more direct thyroid-stimulating and glucose-lowering effects, and seek same-week lab work.

In the absence of symptoms, order the baseline labs listed above now, even though they are retrospective. Fasting glucose and TSH results will tell you quickly whether the combination has pushed either pathway outside a safe range. A TSH below 0.8 mIU/L in a previously euthyroid person warrants a conversation with a clinician about whether to continue ashwagandha.

Current Evidence Gaps and What Research Is Needed

The honest answer to "can I take ashwagandha with MOTS-c" is that no human trial has directly answered this question. The gap matters because:

1. All interaction data currently comes from extrapolating single-compound studies and mechanistic pathway analysis, not from a controlled comparison of combined vs. Single-agent use.
2. MOTS-c remains investigational. Its pharmacology in humans is described in fewer than a dozen published clinical studies as of mid-2025, and its thyroid and adrenal effects have not been the primary outcome of any published trial.
3. Ashwagandha's thyroid effects are documented in patients with subclinical hypothyroidism; data in euthyroid adults are thinner.

A 12-week, 3-arm RCT comparing MOTS-c alone, ashwagandha alone, and the combination with endpoints of fasting glucose, HbA1c, cortisol, TSH, free T3, and testosterone would answer most of the outstanding questions. No such trial is currently registered on ClinicalTrials.gov as of July 2025.

Summary of Interaction Classification

| Interaction Domain | Type | Severity | Action | |---|---|---|---| | Cortisol suppression | Pharmacodynamic, additive | Mild-moderate | Monitor morning cortisol at baseline and 8 weeks | | Insulin sensitization / glucose lowering | Pharmacodynamic, additive | Mild in non-diabetics; moderate in insulin users | Monitor fasting glucose; adjust insulin/sulfonylurea doses | | Testosterone elevation | Pharmacodynamic, additive | Mild | Monitor total and free testosterone at 12 weeks | | Thyroid hormone activation | Pharmacodynamic, additive (DIO2 + direct T3/T4 rise) | Moderate in thyroid patients | Monitor TSH, free T3, free T4 at 6 to 8 weeks | | Pharmacokinetic (CYP, protein binding) | None identified | Not applicable | No dose separation required |