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MyDeficiencies

Tizanidine

central alpha-2-adrenergic agonist muscle relaxant

Also sold as Zanaflex, Sirdalud.

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Findings for this medication

Research about this medication, graded for how strongly each finding can be attributed to it. Nothing here describes your own levels.

Tizanidine carries essentially no classical depletion machinery. The current FDA label (ZANAFLEX capsules and tablets, 2025 revision) states that "the primary cytochrome P450 isoenzyme involved in tizanidine metabolism is CYP1A2," that absolute oral bioavailability is about 40% because of extensive first-pass hepatic metabolism, that about 60% and 20% of an oral radiolabeled dose is recovered in urine and feces, and that in vitro "neither tizanidine nor the major metabolites are likely to affect the metabolism of other drugs metabolized by cytochrome P450 isoenzymes." The label describes no chelation, gastric-pH, transporter-competition, enzyme-induction, SIADH or aldosterone-axis mechanism, and the adverse-reaction sections reviewed (Table 1 and the postmarketing list) list no electrolyte, hematologic or weight outcome. Of the nine Step 2 mechanism classes, none is present in the label. Two are weakly and indirectly implicated by non-label sources: renal potassium handling (a single overdose case report) and gut function (a constipation adverse reaction and one small observational serum short-chain-fatty-acid signal). No entry reaches orange or red; the red and orange tiers are printed empty with reasons.

central alpha-2-adrenergic agonist muscle relaxant · ATC M03BX02 · also sold as Zanaflex and Sirdalud and generic tizanidine tablets and capsules · reviewed 2026-10-04. This describes research about the medication. It does not say anything about your own levels or health.

How to read the evidence grades

These colours describe how strongly a finding can be attributed to the medication in the research. They are not a severity score and they say nothing about your own health.

Grades describe how strongly a finding can be attributed to Tizanidine in the research — not how common it is, how serious it would be, and not anything about you personally.

Red — Severe
Two or more independent Tier A sources, this drug in the cohort, the nutrient directly measured, consistent direction, clinically meaningful magnitude, a named mechanism, no substantial contradicting Tier A evidence.
Orange — Moderate
At least one Tier A source with this drug in the cohort showing a real but bounded deficit: an exposure window, a subgroup, low frequency, or a functional rather than circulating deficit.
Yellow — Low
Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction.
Not graded — disclosed evidence gap
Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result.Source definition: Not gradeable under the rules above because nothing has been measured. Published as a documented gap, never as reassurance that there is no effect.

What the research found

Potassium (renal potassium wasting, single overdose case report; retention or dietary-intake framing does not apply)

Yellow — Low

Evidence in: Tier B case report plus labeled Tier C class extrapolation

One documented case of severe, refractory hypokalemia with a urinary pattern of renal potassium wasting followed a tizanidine overdose; the authors judged tizanidine the probable cause, but the case is confounded and no therapeutic-dose, controlled or label-level evidence exists.

Full detail and limits

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. Yellow, Tier B case report plus labeled Tier C class extrapolation

Limits on what this shows

  • Key negative/null findings: No controlled study, registry analysis or therapeutic-dose cohort of serum potassium in tizanidine users was located. The label lists no hypokalemia. The case is confounded by ethanol (acknowledged by the authors as a possible contributor, since alcohol-related hypokalemia involves gastrointestinal loss and kaliuresis with hypomagnesemia), by profuse vomiting, by cocaine screen positivity, by concurrent lisinopril, and by spironolactone started on day 2. The hypomagnesemia (1.4 mg/dL) corrected within hours while potassium wasting persisted for days, which the authors read as magnesium deficiency exacerbating but not fully explaining the loss. Magnesium is not filed as a separate entry because it appears only as a co-finding in this one case.
  • At-risk subgroups: Supratherapeutic or intentional ingestion, particularly with ethanol and vomiting. Patients with markedly raised tizanidine exposure from CYP1A2 inhibitors (fluvoxamine, ciprofloxacin; AUC rises of 33-fold and 10-fold per the label [1]) or with severe renal impairment (clearance reduced by more than 50%) have higher exposure, but whether higher exposure at prescribed doses produces potassium wasting has not been studied and is not asserted here.

Regulatory status

Not in the FDA label. Table 1 and the postmarketing list list no electrolyte or renal tubular outcome [1].

Population evidence

Tier B: Brucculeri MJ, Garcia J. J Med Case Rep 2021 [3], a single 36-year-old man (hypertension, depression, substance abuse, dyslipidemia; home medications atorvastatin, levothyroxine, cetirizine, lisinopril, tizanidine 4 mg every 6 hours as needed) who ingested 80 mg tizanidine with 24 ounces of beer. Ethanol 219 mg/dL; urine drug screen positive for cocaine (use reported nearly a week earlier); profuse vomiting. Serum K 2.7 mmol/L at presentation (2.8 at 24 hours, 4.5 final), Mg 1.4 mg/dL (1.9 at 24 hours), creatinine 1.4 mg/dL (0.81 final), QTc 497 ms (471 ms final). Urine K 38 mEq/L, urine K to creatinine ratio 78 mEq/g, transtubular potassium gradient 5; aldosterone normal (3 ng/dL). Replacement of 100 mEq in the first 24 hours produced minimal improvement and more than 100 mEq daily was needed on days 2 to 4 (nearly 500 mEq total); potassium stabilized on day 5. Spironolactone 25 mg twice daily was started on hospital day 2. Tier C (class extrapolation, labeled): Saad WA, Camargo GMPA, Camargo LAA. Pharmacology 53(5):281-288 [4], conscious rats given clonidine into the ventromedial hypothalamic nucleus after prazosin or yohimbine; the authors report that natriuresis and kaliuresis are mediated through alpha-1 adrenoceptors and require alpha-2A adrenoceptors. A 2012 American Journal of Kidney Diseases abstract titled "Tizanidine: A Cause of Hypokalemia" exists [5]; only its title metadata could be opened, not its content.

Cohort test

The case report [3] names tizanidine directly (cohort of one). The Tier C study [4] studied clonidine, not tizanidine; clonidine is a defensible class member (both are alpha-2 agonists with an imidazoline-type structure), but the model is central hypothalamic microinjection in rats and does not show that oral tizanidine acts on renal potassium handling. It supports plausibility only and is not used to raise the grade above yellow.

Mechanism

Named by the case authors: "a defect in renal potassium handling" demonstrated by inappropriately high urinary potassium excretion during hypokalemia with normal aldosterone. No receptor- or channel-level mechanism for tizanidine was established. Step 2 class C (renal wasting): weakly present.

Counter-evidence held on record

This is a transient renal electrolyte disturbance reported once in an overdose, managed with inpatient monitored replacement. It is not a dietary potassium shortfall, and nothing in it implies that intake should rise at prescribed doses (Hard Rule 5). No potassium or magnesium supplement is recommended by this entry; any electrolyte correction after an overdose or with persistent vomiting is clinical care under a prescriber, guided by measured serum levels.

The five body-system areas

Each finding is counted once, in a single area. Where a study is mentioned in a second area it is context only.

Mitochondrial Burden

Each finding below is counted once, in this area only.

Mitochondrial burden

Not graded — disclosed evidence gap

Evidence: genuine gap with partial tooling limits

No grade assigned: no tizanidine-specific mitochondrial evidence was found at any tier and no circulating claim about tizanidine and mitochondria was found to rebut.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. Ungraded, genuine gap with partial tooling limits

Limits on what this shows

  • Why no grade: Dual condition met. (1) No Tier B or Tier C support: PubMed "tizanidine mitochondria" returned an explicit "No results were found" (clean zero, without automatic term mapping); the variant "tizanidine mitochondrial" returned an empty-metadata page and is treated as inconclusive; Crossref title and bibliographic queries ("tizanidine mitochondrial," "tizanidine antioxidant reactive oxygen species") returned no tizanidine mitochondrial record, and a scan of roughly 300 tizanidine-titled Crossref journal records (three pages) showed no mitochondrial title; the FDA label does not mention mitochondria [1]. A class-level attempt ("alpha-2 agonist, mitochondria, clonidine" in PubMed) was over-specified and returned zero, and no usable class-level source was opened, so no Tier C grade is supported. (2) No circulating claim: none of the eight consumer and practitioner depletion sources audited mentions tizanidine and mitochondria (see Fails verification).

Channels tried

PubMed listing: one clean zero, one inconclusive. Crossref: clean, non-matching. WebSearch: two tizanidine mitochondrial/oxidative/CoQ10 queries returned only generic mitochondrial, drug-induced liver injury or CoQ10 literature before the 200-call session budget was exhausted. Europe PMC REST: HTTP 429 (twice) and one over-length URL rejection. Semantic Scholar Graph API: HTTP 429. OpenAlex works-search: HTTP 429 (single-record lookups worked). DailyMed/FDA: label opened. Unpaywall: not used (no paywalled full text was in question). Because several keyword channels were blocked, this is a genuine-gap finding with a partial tooling limit, and a later revision should re-run Europe PMC, Semantic Scholar and OpenAlex searches. Repair pass, same date: Crossref title and bibliographic queries on alternate phrasings returned clean, non-matching results ("tizanidine mitochondrial respiration membrane potential ATP": 15 records, all generic mitochondrial biochemistry, none naming tizanidine; "tizanidine neuroprotective": 15 records, all titled "Tizanidine" and appearing to be drug monographs or reference chapters, none mitochondrial or neuroprotection-model titles; "tizanidine hepatotoxicity mechanism oxidative metabolite CYP1A2": 15 records, tizanidine CYP1A2 pharmacokinetic and interaction studies plus unrelated oxidative-hepatotoxicity papers on other agents, none linking tizanidine to mitochondria). Surrogate-endpoint and model searches (neuroprotection, rotenone, MPTP, membrane potential, oxidative phosphorylation) were attempted on PubMed listings and a Crossref bibliographic query, but these were refused by the fetch proxy with HTTP 429 (PubMed twice, Crossref twice) with an instruction not to refetch, and WebSearch was at its session cap, so the surrogate-endpoint and class-extrapolation (alpha-2 agonist) channels remain tooling-limited. No class-level source naming tizanidine in its cohort was opened, so the Hard Rule 6 cohort test could not be met for any class extrapolation and no yellow grade is supported. Clonidine and dexmedetomidine literature was not used.

Counter-evidence held on record

This is not a finding of safety and must not be reworded as reassurance. The whole-body oxygen consumption pilot under Oxygen delivery/utilization is not a mitochondrial measurement.

Oxidative Stress

Each finding below is counted once, in this area only.

Oxidative stress

Yellow — Low

Evidence in: Tier B animal study, no pro-oxidant signal

A rat study of tizanidine in ovariectomized animals measured serum total oxidant and antioxidant status and found no rise in oxidant state and no change in antioxidant state attributable to the drug, so the only drug-specific redox measurement located points away from an oxidative burden.

Full detail and limits

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. Yellow, Tier B animal study, no pro-oxidant signal, drug effect not separable

Limits on what this shows

  • Key negative/null findings: The oxidant-state decrease appeared in OVX alone as well, so it cannot be assigned to tizanidine; I could not confirm a direct tizanidine-versus-OVX contrast in the passages read. Total antioxidant status did not differ. Two other drug-specific tizanidine studies surfaced by the PubMed "tizanidine oxidative" listing did not measure redox markers: Pei et al. Int J Mol Med 2018 [8] (spared nerve injury rats; endpoints were mechanical and thermal thresholds, IL-1 beta, IL-6, TNF-alpha, and TLR4/NF-kB signaling, with no ROS, MDA, SOD or GSH) and Berkman et al. Surg Neurol 1998 [9] (focal cerebral ischemia in 48 rats; infarct volume endpoints, glutamate-release rationale, no oxidative markers in the abstract).
  • At-risk subgroups: Not established; findings come from a menopause-model rat and are not human data.

Regulatory status

Not addressed in the FDA label [1].

Population evidence

Tier B: Ince UB, Kilimci FS, Esmerligil T, et al. Rev Osteoporos Metab Miner 2026;18(1):21-27 [7], 50 rats in five groups (Sham, ovariectomy [OVX], OVX plus tizanidine, OVX plus thiocolchicoside, OVX plus cyclobenzaprine); 10-week protocol with drugs given at 2 mg/kg/day for the final 2 weeks. The paper reports significant decreases in serum total oxidant state in the OVX, tizanidine and cyclobenzaprine groups relative to Sham, and no significant between-group differences in total antioxidant status, RANKL or OPG. Bone resistance rose 25% in OVX plus tizanidine, and tizanidine reduced weight gain. Vitamin D, calcium, phosphorus, magnesium, copper and iron were not measured.

Cohort test

Tizanidine is the named test article. Passed as drug-specific preclinical evidence in a rat menopause model; no human redox study of tizanidine was found.

Mechanism

Not established. The paper does not offer a tizanidine-specific redox mechanism in the passages read.

Counter-evidence held on record

The labeled hepatotoxicity of tizanidine is the drug's own toxicity; no source opened links it to an oxidative or glutathione-depleting mechanism (the NCBI Bookshelf LiverTox entry returned a CAPTCHA and could not be read). Class-level redox literature for other alpha-2 agonists such as dexmedetomidine exists in injury models but was not usable here: the one record opened (PMID 37093427) had no accessible abstract, and injury-model protection is not baseline redox status in a tizanidine-treated person. No antioxidant supplement is recommended or implied by this entry.

Copper and Iron Balance

Copper and iron are assessed separately. Nothing here is counted twice.

Copper

Not graded — disclosed evidence gap

Evidence: partly tooling-limited

No grade assigned: no tizanidine-specific copper evidence was found at any tier and no circulating claim about tizanidine and copper was found to rebut.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. Ungraded, partly tooling-limited

Limits on what this shows

  • Why no grade: Dual condition met. (1) No Tier B or Tier C support: the FDA label does not mention copper [1]; Crossref "tizanidine copper" (bibliographic search) returned only tizanidine reference entries with no copper content, and a scan of about 300 tizanidine-titled Crossref records found no copper title. (2) No circulating claim: none of the audited sources links tizanidine to copper (see Fails verification).

Channels tried

PubMed listing for "tizanidine copper," "tizanidine AND (copper OR ceruloplasmin)," and "copper tizanidine": all three returned a page with only metadata and no result content (the same unreliable-render pattern seen elsewhere in this project), so they are inconclusive and not counted as clean zeros. Crossref: clean, non-matching. Europe PMC, Semantic Scholar, OpenAlex works-search: HTTP 429. WebSearch: budget exhausted before a copper-specific query could be run. DailyMed/FDA: label opened. Because PubMed's copper rendering failed on three phrasings, this gap is partly tooling-limited and should be re-checked. Repair pass, same date: Crossref bibliographic query "tizanidine copper ceruloplasmin Wilson" returned 15 records, all copper, ceruloplasmin or Wilson disease literature with none naming tizanidine (clean, non-matching). The PubMed copper re-query was not retried because the fetch proxy returned HTTP 429 with an instruction not to refetch PubMed pages, and the FDA label re-check for copper or ceruloplasmin statements was likewise refused (HTTP 429), so the earlier label reading (no copper statement) stands. The gap remains partly tooling-limited.

Counter-evidence held on record

Copper is kept as its own entry and is not merged with Iron. This is not a finding of safety; no copper or zinc supplement is implied.

Iron

Not graded — disclosed evidence gap

Evidence: genuine gap

No grade assigned: no tizanidine-specific iron evidence was found at any tier and no circulating claim about tizanidine and iron was found to rebut.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. Ungraded, genuine gap

Limits on what this shows

  • Why no grade: Dual condition met. (1) No Tier B or Tier C support: the PubMed listing "tizanidine iron" rendered cleanly with two records, neither a drug-iron study (a GeneReviews chapter on fatty acid hydroxylase-associated neurodegeneration, PMID 21735565, and a chemistry paper that uses iron catalysis in a synthesis of tizanidine, iScience 2020, PMID 32534444). "Tizanidine anemia" and "tizanidine hemoglobin" (see Oxygen delivery/utilization) also found no iron-status study. The label does not mention iron [1]. (2) No circulating claim: none of the audited sources links tizanidine to iron.

Channels tried

PubMed listing: clean, non-relevant results (not blocked). Crossref: clean, non-matching ("tizanidine iron copper anemia hemoglobin" title search returned only unrelated iron-deficiency titles). Europe PMC, Semantic Scholar, OpenAlex works-search: HTTP 429. WebSearch: no iron-specific query was run before the budget was exhausted; one anemia/hemoglobin adverse-event query returned only label and drug-information pages. DailyMed/FDA: label opened. This is a genuine gap on the evidence channels that did respond. Repair pass, same date: Crossref bibliographic query "tizanidine serum iron ferritin" returned 10 records, all general iron-status and ferritin literature with none naming tizanidine; "tizanidine anemia OR hematologic adverse effects blood dyscrasia" returned 15 records, none reporting an anemia, hemoglobin or iron effect of tizanidine (one record titled "Tizanidine", a reference chapter, was seen by title only and not opened, so it is not relied upon). A re-read of the label for hematologic statements was refused by the fetch proxy (HTTP 429), so the earlier reading (no hematologic adverse reaction in Table 1 or the postmarketing list) stands. WebSearch remained at its session cap. Gap status unchanged.

Counter-evidence held on record

Iron is kept as its own entry and is not merged with Copper. This is not a finding of safety; no iron supplement is implied.

Gut Microbiome Risk

Each finding below is counted once, in this area only.

Gut microbiome risk

Yellow — Low

Evidence: hypothesis-generating, metabolite surrogate only

In a small cross-sectional Parkinson's disease cohort, serum propionic acid (a gut-microbial fermentation product) was higher among the 16 patients taking tizanidine than among those not taking it; the microbiome itself was not measured, the p-value was not corrected for multiple comparisons, and disease is a strong confounder.

Full detail and limits

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. Yellow, hypothesis-generating, metabolite surrogate only

Limits on what this shows

  • Key negative/null findings: No stool microbiome sequencing was performed; the reported P values (0.028, 0.032) were not corrected for multiple comparisons; serum propionate is not a measure of microbiome composition or diversity. A PubMed listing for "tizanidine microbiome" returned two records, the study above and a 2026 EBioMedicine repurposing analysis (PMID 42697072) that could not be opened (empty-metadata page), so its relevance is unverified and it is not relied upon.
  • At-risk subgroups: Not defined. Parkinson's disease itself alters gut function and short-chain fatty acids; confounding by indication, disease severity and constipation from the disease is presumed and not excluded (Hard Rule 6).

Regulatory status

The label does not address the microbiome. It lists constipation (4% vs 1% placebo) and vomiting (3% vs 0%) among adverse reactions [1], which are gut-function effects, not microbiome measurements.

Population evidence

Wu G, Jiang Z, Pu Y, et al. BMC Neurol 2022 [6], cross-sectional, 50 Parkinson's disease patients and 50 healthy controls. Tizanidine is named in Table 1 as a drug therapy (n = 16, 32.0%, listed separately from trihexyphenidyl, n = 14, 28.0%). Serum propionic acid (gas chromatography-mass spectrometry) was reported higher in PD patients taking tizanidine (P = 0.032); the same was reported for trihexyphenidyl (P = 0.028). Propionic acid was the only short-chain fatty acid for which a drug association is described in the passages read.

Cohort test

Tizanidine is named in the studied cohort (16 of 50 patients). Passed as drug-specific, but it is a medication-subgroup comparison inside a disease cohort, not a designed drug exposure study.

Mechanism

Not established. The authors state that "the fecal microbiota and SCFAs were not analyzed, which made it unclear how the gut bacteria affect serum SCFAs." A transit-time pathway (Step 2 class A) is a hypothesis consistent with the labeled constipation signal but is not shown by any source opened.

Counter-evidence held on record

The direction of a higher propionate level is not a deficiency and is not interpretable as harm or benefit. Nothing here shows that tizanidine alters microbiome composition or diversity. No probiotic, prebiotic or fiber product is recommended by this entry; a constipation complaint on tizanidine is a matter for the prescriber.

Oxygen and ATP Output

Oxygen delivery and ATP production are assessed separately. Nothing here is counted twice.

Oxygen delivery/utilization (mechanism clarification, not a deficiency)

Yellow — Low

Evidence: context flag, drug's own pharmacology

In a five-volunteer crossover pilot, oral tizanidine lowered whole-body oxygen consumption and energy expenditure; this is the sympatholytic action of an alpha-2 agonist, a reduction in demand, and not a deficiency of oxygen delivery or of any nutrient.

Full detail and limits

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. Yellow, context flag, drug's own pharmacology

Limits on what this shows

  • Key negative/null findings: No study measuring hemoglobin, hematocrit, red-cell mass or arterial oxygenation in tizanidine users was found: PubMed "tizanidine hemoglobin" returned an explicit zero ("No results were found"), and "tizanidine anemia" returned two records (an emergency-department sickle cell order set, PMID 35708651, and a 1997 trigeminal neuralgia drug-choice review, PMID 23338129) that do not measure a hematologic effect of the drug.
  • At-risk subgroups: None established for a deficiency; the labeled hypotension and syncope risk is the drug's own toxicity.

Regulatory status

The label reports no hematologic adverse reaction (no anemia, hemoglobin or hematocrit outcome) in the Table 1 and postmarketing sections reviewed [1]. The label does describe hypotension as a labeled effect of the drug [1].

Population evidence

Taittonen M, Raty H, Kirvela O, Aantaa R, Kanto J. Acta Anaesthesiol Scand 1995;39(5):628-632 [10], randomized, double-blind crossover pilot of placebo, 6 mg and 12 mg oral tizanidine in five healthy volunteers using a portable metabolic monitor. Diastolic pressure fell about 12% (6 mg) and 15% (12 mg) from baseline; oxygen consumption fell 3% (6 mg) and 8% (12 mg); energy expenditure fell 5% (6 mg) and 9% (12 mg); there were no significant differences in subjective tiredness or dry mouth. The authors conclude tizanidine "can be useful for reducing energy expenditure and oxygen consumption without prominent cardiovascular effects."

Cohort test

Tizanidine was the test drug (n = 5, healthy volunteers, not spasticity patients). Passed, but pilot scale.

Mechanism

Central alpha-2 agonism with sympatholysis [1]. Under Hard Rule 2 the drug's intended hemodynamic and metabolic-rate effect is not an oxygen-delivery deficiency and must not be read as one; it is recorded as a mechanism clarification so the finding is not mistaken for a nutrient result.

Counter-evidence held on record

A lower oxygen consumption from reduced sympathetic drive is the opposite of an oxygen-supply shortfall and is not evidence of anemia or tissue hypoxia. This entry is kept separate from ATP production (Hard Rule 7); the same pilot is disclosed in the Overlap map and was not counted toward ATP or mitochondrial entries. No iron, B12, folate or other hematinic is implied or recommended by this entry.

ATP production

Not graded — disclosed evidence gap

Evidence: genuine gap

No grade assigned: no study measured ATP synthesis, cellular energy charge or mitochondrial respiration in the presence of tizanidine, and no circulating claim about tizanidine and ATP or cellular energy was found to rebut.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. Ungraded, genuine gap

Limits on what this shows

  • Why no grade: Dual condition met. (1) No Tier B or Tier C support: PubMed "tizanidine adenosine triphosphate" returned an explicit "No results were found" (clean zero); the label does not mention ATP [1]. The nearest drug-specific data, a five-volunteer pilot in which tizanidine lowered whole-body oxygen consumption and energy expenditure [10], were considered and not used for this entry: they measure demand-side whole-body gas exchange under sympatholysis (the drug's own pharmacology, Hard Rule 2), not ATP production, and treating them as ATP evidence would double-count the Oxygen delivery/utilization source. (2) No circulating claim: no audited source ties tizanidine to ATP or cellular energy; the labeled asthenia (41% vs 16%) is a central adverse reaction listed in the label, not a stated energy-metabolism mechanism.

Channels tried

PubMed listing: "tizanidine adenosine triphosphate" clean zero; "tizanidine ATP" returned HTTP 429 on one attempt and was not repeated. Crossref: no tizanidine ATP record. Europe PMC, Semantic Scholar, OpenAlex works-search: HTTP 429. WebSearch: one tizanidine energy/ATP/CoQ10 depletion-claim query returned only generic CoQ10 and mitochondrial content before the budget was exhausted. DailyMed/FDA: label opened. Repair pass, same date: Crossref title query "tizanidine mitochondrial respiration membrane potential ATP" returned 15 generic mitochondrial biochemistry records, none naming tizanidine; a Crossref bibliographic query on alpha-2 agonist, oxidative phosphorylation and cellular respiration was refused (HTTP 429) and not repeated. The Taittonen whole-body VO2 pilot remains excluded for the reasons above. Gap status unchanged.

Counter-evidence held on record

ATP production is kept independent of Oxygen delivery/utilization and Mitochondrial burden. This is not a finding of safety, and fatigue on tizanidine should not be read as an ATP or nutrient problem on this evidence.

Claims checked and not supported

These circulate online for this medication. They are listed here only so they can be answered, never as findings, and they are not graded.

A claim with no supporting evidence is not necessarily disproven. Where evidence actually argues against a claim, that is stated below.

  • None located (including the seven physiological categories)

    Where it comes from: Eight sources audited for tizanidine, Zanaflex, skeletal muscle relaxant or alpha-2 agonist depletion entries: a pharmacy depletion chart [11], a clinic depletion PDF [12], Life Extension depletion article [13], PBA Health [14], US Pharmacist [15], a consumer interactions blog [16], Drugs.com interaction pages for vitamin D3 [17], and Wikipedia [18].

    Why it fails: None of the eight makes a nutrient, mitochondrial, antioxidant, iron, copper, microbiome, oxygen or energy claim about tizanidine. The one chart that lists skeletal muscle relaxants (baclofen, cyclobenzaprine) states "No Known Significant Depletions"; Drugs.com states "no interactions found between tizanidine and Vitamin D3"; Wikipedia's adverse-effect list names no hypokalemia or nutrient depletion. Limit: the consumer sweep was bounded because the WebSearch budget was exhausted, so a claim elsewhere on the web cannot be excluded, and this row is not a finding that no such claim exists.

How the body handles this medication

Metabolism and CYP enzymes
"The primary cytochrome P450 isoenzyme involved in tizanidine metabolism is CYP1A2." Absolute oral bioavailability is about 40% (CV 24%) "due to extensive first-pass hepatic metabolism." In vitro, "neither tizanidine nor the major metabolites are likely to affect the metabolism of other drugs metabolized by cytochrome P450 isoenzymes" - tizanidine is a CYP1A2 substrate, not an inducer or inhibitor.FDA prescribing information, ZANAFLEX (tizanidine) capsules and tablets, 2025 revision, Section 12.3 [1]
Elimination and renal/hepatic impairment
After oral 14C-tizanidine, "an average of 60% and 20% of total radioactivity was recovered in the urine and feces." Half-life is about 2.5 hours. "Tizanidine clearance is reduced by more than 50% in elderly patients with renal insufficiency (creatinine clearance < 25 mL/min) compared to healthy elderly subjects." Hepatic-impairment pharmacokinetics "has not been evaluated," but because metabolism is extensive the label calls for caution and dosage reduction.FDA label [1], Sections 8.5, 8.6, 8.7, 12.3
Absorption, food effect, protein binding
Food changes tizanidine exposure (drug-side, not nutrient-side): with tablets, fed mean Cmax rose about 30% and extent of absorption rose about 30%; with capsules, fed mean Cmax fell 20% and extent rose about 10%. Volume of distribution is 2.4 L/kg and plasma protein binding is about 30%. No named transporter, chelation or mineral-binding step is described. This is a food-to-drug exposure note (Hard Rule 4), not evidence that tizanidine impairs nutrient absorption.FDA label [1], Section 12.3
Documented drug and substance interactions (magnitude)
Fluvoxamine raised tizanidine Cmax, AUC and half-life by 12-fold, 33-fold and 3-fold; ciprofloxacin raised Cmax and AUC by 7-fold and 10-fold; women taking oral contraceptives had 50% lower tizanidine clearance; alcohol raised AUC and Cmax by about 20% and 15%. No vitamin, mineral or supplement interaction and no separation interval is stated in the label sections reviewed.FDA label [1], Section 12.3 and drug-interaction sections
Renal tubular, electrolyte and hematologic labeling
Label Table 1 (tizanidine tablet vs placebo) lists dry mouth 49% vs 10%, somnolence 48% vs 10%, asthenia 41% vs 16%, dizziness 16% vs 4%, constipation 4% vs 1%, vomiting 3% vs 0%, urinary tract infection 10% vs 7%, liver test abnormality 6% vs 2%. The postmarketing list (ventricular tachycardia, decreased blood pressure, hepatotoxicity, hepatitis, convulsion, hallucinations, depression, Stevens-Johnson syndrome, rash and others) names no electrolyte, renal tubular, hematologic or weight outcome.FDA label [1], Sections 6.1 and 6.2
Mechanism of action
"Tizanidine is a central alpha-2-adrenergic receptor agonist and presumably reduces spasticity by increasing presynaptic inhibition of motor neurons." Class designation in the label: central alpha-2-adrenergic agonist. WHO ATC/DDD index: M03BX02, "Other centrally acting agents" within M03B, DDD 12 mg oral.FDA label [1], Section 12.1; WHO ATC/DDD Index [2]

What the research says is worth watching

General information from the medication label and the studies above. It is not personal medical advice, and any change belongs with your prescriber.

  • Electrolytes, conditional

    Serum potassium and magnesium after overdose or with persistent vomiting

    Not a routine test for therapeutic use. Worth checking after an intentional or accidental overdose, particularly with alcohol or persistent vomiting, because the one documented case showed potassium wasting that outlasted early replacement. Interpretation and any correction belong to the prescriber or treating team.

  • Drug's own toxicity

    Liver tests

    The label calls for aminotransferase monitoring (baseline and one month after reaching the maximum dose) because of hepatotoxicity. This is the drug's own toxicity, not a nutrient finding, and is listed so it is not confused with one.

  • Drug's own toxicity

    Blood pressure, orthostasis, sedation

    Hypotension, syncope and sedation are labeled effects of an alpha-2 agonist. Fatigue and low energy on tizanidine are labeled adverse reactions (asthenia 41% vs 16%) and are not evidence of a nutrient or ATP problem.

  • At-risk group

    Kidney function and CYP1A2 inhibitors

    Clearance is reduced by more than 50% when creatinine clearance is below 25 mL/min in the elderly, and fluvoxamine or ciprofloxacin can raise exposure 33-fold and 10-fold. Higher exposure raises the drug's own risks; whether it raises electrolyte risk is untested.

  • Gut function

    Bowel habit

    Constipation (4% vs 1%) and vomiting (3% vs 0%) are labeled. A bowel-habit review is reasonable; no microbiome or stool test is supported by this evidence.

  • Supplement separation

    No interval documented

    The label sections reviewed state no vitamin, mineral or supplement interaction and no separation interval. Food changes tizanidine exposure (tablets about 30% higher Cmax and extent when fed; capsules about 20% lower Cmax), so tablets and capsules should be taken consistently with respect to meals as the prescriber directs. No hematologic, copper or iron testing is indicated by tizanidine on this evidence.

Overlap map, to prevent double counting

Entries that rest on the same underlying source or mechanism. Copper and Iron share no positive evidence.

  • Oxygen delivery/utilization (yellow)

    Shares evidence with: ATP production (ungraded); Mitochondrial burden (ungraded)

    Note: The Taittonen five-volunteer VO2 and energy-expenditure pilot [10] is the only drug-specific energy-metabolism dataset and sits in the Oxygen entry only. It was considered for ATP production and Mitochondrial burden and excluded because it measured whole-body gas exchange under alpha-2 sympatholysis, not ATP or mitochondrial function. It is not independent confirmation of either ungraded entry.

  • Oxidative stress (yellow)

    Shares evidence with: Mitochondrial burden; ATP production

    Note: The Ince rat study [7] supports the Oxidative stress entry only. Serum total oxidant and antioxidant status is not a mitochondrial or ATP measure and was not carried into either ungraded entry. The same study also reports bone strength, which is not a nutrient finding and is not filed.

  • Gut microbiome risk (yellow)

    Shares evidence with: FDA label constipation and vomiting rows [1]

    Note: The label gut-function adverse reactions and the Wu serum propionate observation [6] are two different kinds of evidence for the same loosely related question and neither measures the microbiome; they must not be counted as two confirmations. The Wu cohort is also a Parkinson's disease population, so disease-intrinsic gut and SCFA change overlaps with any drug signal.

  • Potassium (yellow)

    Shares evidence with: Magnesium co-finding (not a separate entry); alpha-2 agonist class dossiers (clonidine, guanfacine; earlier batches, files not available)

    Note: The single case report [3] supplies both the potassium and the magnesium observations, so they are one source. The Tier C clonidine rat study [4] shares the alpha-2 mechanism. If the clonidine or guanfacine dossiers carry an electrolyte or renal-handling entry, it would rest on the same pharmacologic class and must not be counted as independent confirmation for tizanidine; their contents were not available to this review. The 2012 AJKD abstract [5] may describe the same or a different case and could not be read, so it is not counted. Siblings in this batch folder (baclofen, meclizine) are not the same class.

  • Copper; Iron

    Shares evidence with: FDA label silence [1]; shared search channels

    Note: Independent entries. Both are ungraded on the same pattern of silent label and empty literature searches; that shared absence is not two independent null studies.

  • All entries

    Shares evidence with: FDA label [1]

    Note: The label underlies the pharmacokinetic basis and is cited in several entries as a null or context source; it is one document, not several lines of evidence.

All references used above
  1. ZANAFLEX (tizanidine hydrochloride) capsules and tablets, FDA prescribing information — Tier A regulatory label, 2025 revision (NDA 020397 and 021447); Sections 5, 6, 8, 12 read via fetch tool.Direct shell access to accessdata.fda.gov and dailymed.nlm.nih.gov returned proxy 403; the label PDF and a DailyMed search listing opened through the fetch tool. DailyMed search listing: https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=tizanidine
  2. WHO Collaborating Centre for Drug Statistics Methodology, ATC/DDD Index, code M03BX02 (tizanidine) — Classification reference; DDD 12 mg oral; parent M03BX "Other centrally acting agents."
  3. Brucculeri MJ, Garcia J. Potassium wasting nephropathy in the setting of tizanidine overdose: a case report. J Med Case Rep 2021 — Case report, n = 1; tizanidine is the named drug; confounded by ethanol, vomiting, cocaine screen, lisinopril, spironolactone. PMID 33931107, DOI 10.1186/s13256-021-02811-8. Tier B.
  4. Saad WA, Camargo GMPA, Camargo LAA. On a dual role for clonidine stimulation of the ventromedial nucleus of the hypothalamus in sodium and potassium renal excretions of rats. Pharmacology 53(5):281-288 — Rat study, clonidine (not tizanidine); abstract read via OpenAlex single-record lookup (PMID 8990486, DOI 10.1159/000139440; OpenAlex lists year 2008). Tier C, labeled class extrapolation.Cohort excluded tizanidine (clonidine only); central microinjection model; supports plausibility only.
  5. "Tizanidine: A Cause of Hypokalemia." Am J Kidney Dis 2012;59(4):B60 (abstract) — DOI 10.1053/j.ajkd.2012.02.187. Title and venue confirmed through OpenAlex single-record lookup; no abstract text in the record.Content could not be opened (publisher page 403, linking hub returned empty, ResearchGate HTTP 429). Cited as existence only; not relied upon for any claim.
  6. Wu G, Jiang Z, Pu Y, Chen S, Wang T, Wang Y, Xu X, Wang S, Jin M, Yao Y, Liu Y, Ke S, Liu S. Serum short-chain fatty acids and its correlation with motor and non-motor symptoms in Parkinson's disease patients. BMC Neurol 2022 — Cross-sectional, 50 PD patients and 50 controls; tizanidine in cohort (n = 16). PMID 34996385, DOI 10.1186/s12883-021-02544-7.
  7. Ince UB, Kilimci FS, Esmerligil T, Gursoy SN, Demirci B, Dost T. Comparison of tizanidine, thiocolchicoside and cyclobenzaprine on bone metabolism in ovariectomized rats. Rev Osteoporos Metab Miner 2026;18(1):21-27 — Rat study, 50 animals, 2 mg/kg/day for 2 weeks; serum total oxidant and antioxidant status. DOI 10.20960/revosteoporosmetabminer.00095. Tier B.
  8. Pei W, Zou Y, Wang W, Wei L, Zhao Y, Li L. Tizanidine exerts anti-nociceptive effects in spared nerve injury model of neuropathic pain through inhibition of TLR4/NF-kB pathway. Int J Mol Med 2018 — Rat study, intrathecal tizanidine 2.5 microgram; cytokine and TLR4/NF-kB endpoints; no redox, mitochondrial or ATP endpoints. DOI 10.3892/ijmm.2018.3878. Tier B, cited as counter-context.
  9. Berkman MZ, Zirh AT, Berkman K, Pamir MN. Tizanidine is an effective agent in the prevention of focal cerebral ischemia in rats: an experimental study. Surg Neurol 1998;50(3):264-271 — Rat study, n = 48; infarct volume endpoints; abstract mentions glutamate and aspartate release, no oxidative or mitochondrial markers. PMID 9736090, DOI 10.1016/S0090-3019(97)00500-4. Tier B, cited as counter-context.
  10. Taittonen M, Raty H, Kirvela O, Aantaa R, Kanto J. The metabolic effects of oral tizanidine in healthy volunteers. Acta Anaesthesiol Scand 1995;39(5):628-632 — Randomized double-blind crossover pilot, n = 5; 6 mg and 12 mg; oxygen consumption and energy expenditure. PMID 7572012, DOI 10.1111/j.1399-6576.1995.tb04139.x. Abstract read via OpenAlex single-record lookup. Tier A for its own endpoint; interpreted as the drug's own pharmacology.Publisher page (Wiley) returned 403; only the abstract was read.
  11. Drug-Induced Nutrient Depletions chart (Coastal Pharmacy and Wellness) — Tier D, used only for the circulating-claim audit; lists skeletal muscle relaxants (baclofen, cyclobenzaprine) as "No Known Significant Depletions."Tier D; no tizanidine entry; not used as evidence.
  12. Nutrient depletion that arises from using prescribed medication (chiropractic clinic PDF) — Tier D, audit only; no mention of tizanidine, muscle relaxants or alpha-2 agonists.Tier D; audit only.
  13. Drug-induced nutrient depletion (Life Extension) — Tier D, audit only; no mention of tizanidine or muscle relaxants.Tier D; audit only.
  14. Drug-induced nutrient deficiencies (PBA Health) — Tier D, audit only; ten medication categories, none muscle relaxants.Tier D; audit only.
  15. Drug-induced nutrient depletions: what pharmacists need to know (US Pharmacist) — Tier D, audit only; no mention of tizanidine or muscle relaxants.Tier D; audit only.
  16. Zanaflex (tizanidine) interactions: what to avoid (Doctronic blog) — Tier D, audit only; discusses drug, alcohol, food-timing and smoking interactions, no supplement or nutrient-depletion claims.Tier D; audit only.
  17. Tizanidine and Vitamin D3 interaction (Drugs.com) — Tier D, audit only; states no interactions found.Tier D; audit only.
  18. Tizanidine (Wikipedia) — Tier D, audit only; confirms ATC M03BX02, brands Zanaflex and Sirdalud, class alpha-2 agonist muscle relaxant, and an adverse-effect list with no nutrient depletion or hypokalemia.Tier D; audit only.
  19. PubMed search-listing pages and Crossref works queries (access record) — PubMed: "tizanidine mitochondria" (clean zero), "tizanidine iron" (2 records), "tizanidine microbiome" (2), "tizanidine oxidative" (13 results, 10 rendered), "tizanidine anemia" (2), "tizanidine hemoglobin" (clean zero), "tizanidine adenosine triphosphate" (clean zero), "dexmedetomidine oxidative stress meta-analysis" (4); copper and mitochondrial-adjective queries returned empty-metadata pages. Crossref: tizanidine title scan (three pages) and four bibliographic queries. Repair pass (same date) Crossref queries: "tizanidine serum iron ferritin", "tizanidine mitochondrial respiration membrane potential ATP", "tizanidine neuroprotective", "tizanidine copper ceruloplasmin Wilson", "tizanidine hepatotoxicity mechanism oxidative metabolite CYP1A2", "tizanidine anemia OR hematologic adverse effects blood dyscrasia": all returned no tizanidine record relevant to the four ungraded categories. Refused with HTTP 429 in the repair pass: PubMed listings ("tizanidine neuroprotection"; tizanidine with rotenone, MPTP, respiratory chain or membrane potential), FDA label PDF re-read, DailyMed search, and three further Crossref queries.Not evidence in themselves. Could not be opened or read: NCBI Bookshelf LiverTox tizanidine entry (CAPTCHA), livertox.nlm.nih.gov (robots check failed), PubMed record 42697072 (empty-metadata page), Emre M. 1998 "The gastroprotective effects of tizanidine: an overview" (no abstract in OpenAlex record), and Gatica et al. 2023 dexmedetomidine meta-analysis (no abstract in OpenAlex record).