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MyDeficiencies

Codeine sulfate

opioid analgesic and antitussive, prodrug of morphine

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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.

Codeine has no classical nutrient-depletion machinery in any source retrieved. It is a CYP substrate and not an enzyme inducer: the label gives conjugation to codeine-6-glucuronide as the main route (70 to 80% of a dose, together with O-demethylation to morphine at about 5 to 10% by CYP2D6 and N-demethylation to norcodeine at about 10% by CYP3A4), about 90% renal elimination with about 10% as unchanged codeine, a half-life near 3 hours, and no significant food effect [1]. The label text read names no vitamin, mineral, iron, copper, oxidative-stress, mitochondrial or microbiome effect [1]. Because morphine is the active metabolite but only a small and genotype-dependent fraction of a codeine dose [1][6], each entry below says whose data it is. Morphine, methadone and other opioid findings are labeled CLASS EXTRAPOLATION, state that codeine was not in the cohort, and are capped at yellow (Hard Rule 6).

opioid analgesic and antitussive, prodrug of morphine · ATC R05DA04 (WHO ATC/DDD Index [3]); combinations are N02AA59 [4] · also sold as none in the US; generic codeine sulfate tablets only [2][5] · reviewed 2026-10-07. 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 Codeine sulfate 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

Androgen axis: total testosterone fell about 20% in healthy men on short-term codeine (hormone suppression, not a nutrient)

Orange — Moderate

See study details

Therapeutic-dose codeine for a few days lowered circulating total testosterone by about 20% in healthy men, and the label warns of androgen deficiency with extended opioid use. This is a hormonal disturbance caused by the drug, not a vitamin or mineral deficiency (Hard Rule 2).

Full detail and limits

What the grade means here: 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. Orange

Limits on what this shows

  • Null findings: No chronic oral codeine cohort with testosterone, LH or symptom outcomes was retrieved. The largest opioid-by-opioid androgen comparison opened did not include codeine [27]. In rabbits, libido behaviors rose despite lower testosterone, which the authors attribute to a testosterone-independent mechanism [14].
  • At-risk subgroups: Not defined for codeine. The label frames risk as extended use in men and women [1]. No data in women or older adults for codeine were retrieved.

Whose data

Codeine itself, in humans (Lehtihet 2017 [7]). Supporting animal work is also codeine itself (Tier B) [12][13][14][15]. No morphine-metabolite data and no other opioid's data are used for this grade. The 2017 comparison of fentanyl, methadone, oxycodone and hydrocodone does not name codeine [27], so its odds ratios are not carried to codeine.

Regulatory status

Label sec 12.2: "Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans"; extended use may cause androgen deficiency, with low libido, impotence, erectile dysfunction, amenorrhea or infertility. Androgen deficiency is also listed among adverse reactions [1]. Read via a summarizing fetch tool.

Population evidence

Lehtihet 2017 [7]: open study, subjects as their own controls, 15 healthy male volunteers given therapeutic doses of codeine (Kodein Meda; dose and salt form not stated in the abstract) for 6 days, with testosterone enanthate (500 mg or 125 mg) given on day 3; blood at baseline, 6 and 14 days. Circulating total testosterone fell significantly by 20% after 3 days of codeine (p = 0.0002), and one subject had an atypical steroid-passport result. Codeine did not alter the raised urinary testosterone/epitestosterone ratio after testosterone administration. Tier A for codeine. The abstract does not make clear how the day-3 injection relates to the day-3 blood draw, and LH was not reported there. Animal (Tier B): rabbits given oral codeine 4 or 10 mg/kg for 6 weeks (n = 21) had lower serum testosterone and testicular atrophy [13][14]; Wistar rats given 2 or 5 mg/kg/day for 6 weeks (n = 30) had reduced circulating testosterone, with partial reversal after 6 drug-free weeks [15]. Abstracts only, read via OpenAlex reconstructions.

Mechanism

Named for the class: opioid inhibition of LH secretion, leading to lower testosterone [1]. Not measured in the codeine human abstract [7]. The animal papers propose testicular oxidative injury, TNF-alpha/nitric oxide signaling and apoptosis [13][15].

Direction

Hormone suppression. Neutral with respect to any nutrient; not depletion.

Counter-evidence held on record

Counter-evidence and confounding The human evidence is one short, small, self-controlled study in healthy volunteers [7]: 3 days of exposure, no placebo arm, recovery not described in the abstract, and a concurrent testosterone injection protocol that complicates interpretation. Chronic pain and illness lower testosterone on their own (confounding by indication, Hard Rule 6), which the healthy-volunteer design avoids but a real-world long-term cohort would not. The four rabbit and rat reports come from one laboratory group and are not independent of each other [12][13][14][15]; their doses are not scaled to human doses here. Framing caution Hormonal disturbance, not a nutrient deficiency. It does not imply that any vitamin, mineral or herbal "testosterone" product is needed. Any hormone assessment or treatment is a prescriber decision. No supplement dose is recommended.

Adrenal axis: cortisol suppressed after a single oral dose in 9 men (acute, small study), with a label warning of adrenal insufficiency (not a nutrient)

Orange — Moderate

See study details

A single 30 mg oral codeine dose suppressed afternoon cortisol secretion in nine men, and the label lists adrenal insufficiency as a reported opioid effect. This is a hormonal effect of the drug, not a nutrient state.

Full detail and limits

What the grade means here: 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. Orange

Limits on what this shows

  • Null findings: In 42 dogs having oral surgery, subcutaneous codeine, alone or with ketoprofen, produced no significant change in serum cortisol across treatment groups [11] (different species, route and surgical stress, so it does not refute the human result). A 13-week rat toxicology listing mentioned higher adrenal weights at higher exposure but was seen as a title and snippet only and is not used.
  • At-risk subgroups: Not defined for codeine.

Whose data

Codeine itself, in humans, acute exposure (Garland and Zis 1989 [8]). No chronic codeine cortisol or adrenal-function cohort was retrieved. Morphine intrathecal series were not opened for this dossier and are not used.

Regulatory status

Label sec 5.11 (Adrenal Insufficiency): "If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid." Adrenal insufficiency is listed among adverse reactions, and sec 12.2 states that opioids inhibit ACTH and cortisol secretion [1]. Read via a summarizing fetch tool; the label's frequency or duration wording for this warning was not retrieved.

Population evidence

Garland and Zis 1989 [8]: nine subjects each received oxazepam 30 mg, codeine 30 mg or placebo on separate days in a counterbalanced, blinded design, with blood drawn through an indwelling catheter every 30 minutes. "Codeine, but not oxazepam, suppressed cortisol secretion," and the decline after codeine was significantly linear. The title specifies men. Tier A for codeine, cortisol directly measured. The abstract text came from a PubMed search-listing page summarized by a fetch tool (OpenAlex held no abstract); effect size is not in that text, and the dosing and sampling clock times as summarized (dose 1700 h, sampling 1500 to 1630 h) were not reconciled.

Mechanism

Named: opioid inhibition of ACTH and cortisol secretion [1]; the authors cite an inhibitory opioid mechanism in the human hypothalamic-pituitary-adrenal axis [8].

Direction

Hormone suppression. Not a depletion of any nutrient.

Counter-evidence held on record

Counter-evidence and confounding One acute dose in nine subjects shows suppression of a low, afternoon cortisol value; it does not show clinical adrenal insufficiency, its size, or recovery time. The label warning is a class statement for opioids. Symptoms attributed to adrenal insufficiency (fatigue, nausea, dizziness) overlap with ordinary opioid adverse effects, so prevalence in codeine users is unknown from sources opened. Framing caution Hormonal disturbance that needs clinician assessment, not a nutrient deficiency. It is not a reason to add sodium, licorice, vitamin C or any other supplement. No supplement dose is recommended.

Sodium and water balance: hospitalization for hyponatremia, risk concentrated in newly started codeine (dilutional retention direction; registry data)

Orange — Moderate

See study details

In a Swedish population-based case-control study, newly initiated codeine was associated with about twice the odds of hospitalization for hyponatremia, while overall use was only slightly raised. This is water retention or dilution, not a dietary sodium shortfall (Hard Rule 5).

Full detail and limits

What the grade means here: 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. Orange

Limits on what this shows

  • Null findings: Ongoing codeine therapy was not associated with raised odds in the registry study [9]. The absolute incidence in the first 30 days was low (1.9 per 10,000 person-months) [10].
  • At-risk subgroups: New starters, per [9]. Further subgroups (age, sex, diuretic or antidepressant co-use) were not retrieved for codeine.

Whose data

Codeine itself, in humans (Falhammar 2019 [9]; Fournier 2015 [10], where codeine was the comparator). Caveat on scope: the abstract text seen does not say whether the codeine exposure includes combination products such as paracetamol/codeine. The brief excludes those combinations, and this registry source cannot be filtered to single-ingredient codeine.

Regulatory status

No hyponatremia, SIADH or serum sodium wording was found in the label text read. Label sec 7 states that opioids can reduce the efficacy of diuretics by inducing release of antidiuretic hormone [1]. Absence from the portions read is not proof of absence.

Population evidence

Falhammar 2019 [9], as shown in a PubMed listing summarized by a fetch tool: 14,359 patients hospitalized with hyponatremia versus 57,383 controls. Unadjusted OR for hospitalization 3.19 (95% CI 2.92 to 3.47) for codeine (tramadol 2.45, 2.26 to 2.66). The summary reports an adjusted OR of 1.14 (1.03 to 1.26) for codeine, attributed there to codeine use overall; the exposure window behind that figure was not confirmed. Newly initiated codeine: adjusted OR 2.20 (1.87 to 2.60); ongoing therapy was not elevated. Fournier 2015 [10]: UK primary-care and hospital database cohort of 332,880 new users of tramadol or codeine (1998 to 2012); in the first 30 days the incidence of hospitalization for hyponatremia was 1.9 (95% CI 1.4 to 2.5) per 10,000 person-months for codeine and 4.6 (2.4 to 8.0) for tramadol; adjusted HR for tramadol versus codeine 2.05 (1.08 to 3.86). Codeine was the reference drug and there was no unexposed group.

Mechanism

Present at label level only: opioid-induced ADH release [1]. No ADH, copeptin or urine osmolality measurement in codeine users was found in sources opened, so SIADH is inferred, not shown, for codeine.

Direction

Excess or retention (dilutional hyponatremia). Not a depletion; dietary sodium intake is not the issue.

Counter-evidence held on record

Counter-evidence and confounding Confounding by indication is presumed (Hard Rule 6): codeine is given for cough and acute pain, settings in which respiratory infection, surgery or malignancy can themselves cause SIADH. The near-null overall adjusted OR beside a doubled new-starter OR fits a risk window at initiation, but acute illness at the moment of prescribing would produce the same pattern. Case-control design, hospitalization as the outcome. A corrigendum to the Falhammar paper exists (PMID 34172352) and was not opened, so the figures above may have been corrected. The tramadol-versus-codeine cohort tests tramadol against codeine, not codeine against non-use [10]. Framing caution This is a retention or dilution risk, not a deficiency. Sodium or salt supplementation would be the hazard, not the remedy. Symptomatic low sodium (confusion, nausea, headache, falls) needs clinician evaluation. No supplement dose is recommended.

Vitamin D: higher, not lower, in opioid-dependent patients (CLASS EXTRAPOLATION; codeine not named in the cohort; reverse direction)

Yellow — Low

See study details

No study measured vitamin D in codeine users. The one human measurement opened, in opioid-dependent patients with unnamed opioids, found higher 25-hydroxyvitamin D than in controls.

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

Limits on what this shows

  • Null findings: A PubMed listing for codeine with vitamin D, osteoporosis, bone density and fracture returned fracture-pain treatment trials and prescribing reports, none measuring vitamin D or bone in codeine users (listing summaries only). Fracture and bone density are outcomes, not vitamin D status (Hard Rule 2).
  • At-risk subgroups: Not defined.

Whose data

Unspecified opioids, opioid-dependence clinic (Reece and Hulse 2018 [24]); the summary refers to opioid dependence and illicit opioids and names no compound. CLASS EXTRAPOLATION: codeine NOT confirmed in the cohort, so Tier C, capped at yellow.

Regulatory status

No vitamin D, calcium or bone wording in the label text read [1].

Population evidence

[24]: Australian outpatient clinic records, 1,583 patients (1,168 opioid-dependent, 415 general medical controls) with 2,099 vitamin D measurements from 1995 to 2017. 25-hydroxycholecalciferol 70.35 +/- 1.16 versus 57.06 +/- 1.81 nmol/L, higher in the opioid-dependent group (p < 0.0001), robust across bivariate, case-control and longitudinal analyses. Abstract and key figures via a summarizing fetch of the journal page.

Mechanism

None named for a drug effect on vitamin D.

Direction

Higher in the opioid group. Reverse of depletion.

Counter-evidence held on record

Counter-evidence and confounding The authors list missing socioeconomic and sun-exposure data, no dosage information, unmeasured confounding and a clinic population selected through hepatitis testing [24]. The population is opioid dependence, not prescribed oral codeine. Framing caution A context flag, not a drug effect on vitamin D in either direction. It supports neither deficiency nor excess from codeine. No vitamin D supplement or restriction is implied. No supplement dose is recommended.

No ungraded entries remain

Not graded — disclosed evidence gap

Evidence: No ungraded entries

Every mandatory category and vitamin D carried at least one Tier B or Tier C source, so none met the ungraded test. This is a statement about what was found, not a finding of safety.

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. No ungraded entries

Limits on what this shows

  • Why no grade is needed: The dual condition for ungraded status (no Tier B or C evidence AND no circulating claim) was not met for any of the seven mandatory categories or for vitamin D. Each is yellow, with the whose-data label (codeine itself versus morphine or another opioid) stated in the entry.

Channels tried, per category

Codeine-specific PubMed title/abstract listing queries (discovery only, [30]): codeine with testosterone, hypogonadism or androgen (found [7] and several animal reports); with cortisol, ACTH, adrenal or HPA (found [8], [11]); with hyponatremia (found [9], [10]); with oxidative, antioxidant, malondialdehyde or mitochondrial (found [16]); with ATP, respiration, glutathione, superoxide or ROS (no codeine ATP study); with microbiota, microbiome, dysbiosis or 16S (none); with copper, zinc, iron or ferritin (none); with hemoglobin, anemia, methemoglobin, hemolysis or hematocrit (found [25], [26]); with vitamin D, osteoporosis, bone density or fracture (none measuring vitamin D). Single-record lookups via OpenAlex and Crossref, and publisher pages, were used to read abstracts.

Genuine gap or tooling-limited

Copper, iron, ATP, gut microbiome and vitamin D for codeine itself are a genuine literature gap on the queries that ran, plus a tooling limit: several PubMed queries returned HTTP 429, quoted phrases returned an invalid-form page, OpenAlex and Crossref search endpoints returned 429, and WebSearch was exhausted, so absence of a hit is not proof of absence. Re-check when access is restored.

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: complex I inhibition reported in brains of mice given tramadol and codeine (animal; codeine-alone attribution unclear)

Yellow — Low

See study details

One mouse study of escalating tramadol and codeine doses reports inhibited mitochondrial complex I activity in brain regions, but the abstract does not show that codeine alone caused it. No human mitochondrial measurement was found.

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

Limits on what this shows

  • Null findings: Morphine at 1 mM only raised state 2 respiration and did not change maximal membrane potential or most other parameters [21]. The authors of [21] cite peak plasma morphine of 0.35 to 9.8 micromolar from fatalities, so the in vitro concentration was roughly 100 to 3,000 times higher.
  • At-risk subgroups: Not defined.

Whose data

Codeine in a mouse study with codeine-alone, tramadol-alone and combination arms (Ishola 2022 [16], Tier B, attribution unclear). Morphine in vitro (Tier C, codeine not in cohort) [21].

Regulatory status

No mitochondrial wording in the label text read [1].

Population evidence

Ishola 2022 [16], from a publisher-page summary of the abstract: 96 adolescent mice (n = 24 per group as summarized), vehicle, tramadol 20, 40 or 80 mg/kg, codeine 40, 80 or 160 mg/kg, or both, thrice daily for 9 days. The abstract reports nitroso-oxidative stress and inhibition of mitochondrial complex I activity in prefrontal cortex and midbrain. Codeine alone caused hypoactivity and nootropic effects; the combination cut motor activity and cognition and upregulated 52 neurotoxic genes. Whether complex I inhibition appeared in the codeine-alone arm cannot be told from the text seen. Morphine alone on isolated rat liver mitochondria at 0.2 to 1 mM: most respiratory parameters and membrane potential unchanged [21].

Mechanism

Complex I inhibition is the proposed mechanism in the mouse paper [16]. Not shown in people.

Direction

Functional inhibition at escalating, stacked doses (the drug's own toxicity). Not a nutrient deficiency (Hard Rule 2).

Counter-evidence held on record

Counter-evidence and confounding Stacking and boosting doses model misuse in adolescent mice, not therapeutic use. Brain tissue findings cannot be assigned to codeine versus tramadol from the abstract. The morphine data come from isolated organelles at concentrations far above clinical plasma levels. Framing caution No claim that codeine harms mitochondria in people. Do not recommend coenzyme Q10, L-carnitine or similar products. No supplement dose is recommended.

Oxidative Stress

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

Oxidative stress: tissue markers rose in codeine-treated rabbits, rats and mice (excess direction, animal only)

Yellow — Low

See study details

In rabbits and rats given codeine for 6 weeks, testicular and sperm oxidative-damage markers rose. This is the drug's own toxicity in animals at repeated doses, not an antioxidant-nutrient deficiency, and no human measurement was found.

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

Limits on what this shows

  • Null findings: Opposite direction for morphine: in isolated rat liver mitochondria morphine alone lowered lipid peroxidation (TBARS) and hydrogen peroxide formation [21], and a morphine review describes tissue-dependent effects [20]. No antioxidant nutrient (vitamin C, E, selenium, glutathione) was measured in any codeine study.
  • At-risk subgroups: Not defined.

Whose data

Codeine itself, in animals (Tier B): rabbits [12][13], rats [15], mice [16]. Morphine context (Tier C, codeine not in cohort): a narrative review [20] and an in vitro liver-mitochondria study [21] that points the other way.

Regulatory status

No oxidative-stress or antioxidant wording in the label text read [1].

Population evidence

Akhigbe and Ajayi 2020 [13]: 21 male rabbits, oral codeine 4 or 10 mg/kg for 6 weeks; marked increases in testicular oxidative markers and DNA damage with inflammatory (TNF-alpha, nitric oxide) and caspase-3 apoptosis changes. Ajayi and Akhigbe 2020 [12]: 21 rabbits, same doses; sperm DNA fragmentation correlated with 8-hydroxy-2'-deoxyguanosine, an oxidative-damage biomarker, and the authors conclude damage is mainly oxidative. Heliyon 2020 [15]: 30 male Wistar rats, 2 or 5 mg/kg/day for 6 weeks; testicular oxidative injury, partly reversed after 6 drug-free weeks. Ishola 2022 [16]: adolescent mice given codeine (40 to 160 mg/kg), tramadol, or both, thrice daily for 9 days; the abstract reports nitroso-oxidative stress in prefrontal cortex and midbrain, with the arm responsible unclear. Abstracts only, read via OpenAlex reconstructions or a summarizing fetch of the publisher page.

Mechanism

Proposed in animals: TNF-alpha/nitric oxide signaling and oxidative DNA damage in the testis [13]. Not shown in people.

Direction

Excess (rise in oxidative-damage markers). Not antioxidant depletion.

Counter-evidence held on record

Counter-evidence and confounding Four of the codeine reports come from one laboratory group and are not independent [12][13][14][15]. Rabbit and rat doses (4 to 10 mg/kg) are not scaled to the 15 to 60 mg human dose in the label [1], and one report describes its model as codeine misuse [12]. Tissue findings in testis do not show a systemic redox change. Framing caution Do not read this as a reason to take antioxidants (vitamin C, vitamin E, coenzyme Q10 or similar). No supplement dose is recommended.

Copper and Iron Balance

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

Copper: serum copper higher in morphine-dependent rats (CLASS EXTRAPOLATION from the active metabolite; excess direction)

Yellow — Low

See study details

No study of codeine and copper was found. The only copper measurement opened is in morphine-dependent rats and ran higher, not lower, than in controls.

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

Limits on what this shows

  • Null findings: A PubMed title/abstract listing for codeine with copper, zinc, iron and ferritin returned no study measuring those in codeine-treated animals or people (hits were wastewater chemistry, analytical methods and cold-treatment reviews, listing summary only).
  • At-risk subgroups: Not defined.

Whose data

Morphine in rats (Yousofvand 2014 [22]). CLASS EXTRAPOLATION: codeine was NOT in the cohort (cohort test failed for codeine), so Tier C, capped at yellow. Morphine is about 5 to 10% of a codeine dose by label [1]; the rat dosing was morphine itself.

Regulatory status

No copper wording in the label text read [1].

Population evidence

[22]: 24 adult male Wistar rats in two groups; morphine started at 10 mg/kg daily and raised by 2 mg/kg daily to a maximum of 68 mg/kg for 30 days (as summarized); serum copper, zinc and manganese measured. Serum copper was significantly higher in the morphine-dependent group (p < 0.05). Zinc and manganese results were not captured in the text read. Read via a summarizing fetch of the journal page.

Mechanism

None named in the source opened.

Direction

Higher serum copper (excess or retention). Not depletion.

Counter-evidence held on record

Counter-evidence and confounding Rat dosing up to 68 mg/kg morphine is far above therapeutic exposure, and codeine yields little morphine. Serum copper also rises with inflammation, so the finding is not specific. Older rat copper reports by other authors were not opened. Framing caution No copper deficiency is claimed and no copper supplement or restriction is implied. No supplement dose is recommended.

Iron: neuronal iron redistribution in morphine-treated rodents (CLASS EXTRAPOLATION); no systemic iron status measured for codeine or any opioid here

Yellow — Low

See study details

No study of codeine and iron was found. Morphine redistributes iron inside rat neurons, and no serum iron, ferritin or hemoglobin was measured in any source opened.

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

Limits on what this shows

  • Null findings: No systemic iron measure (serum iron, ferritin, transferrin saturation) was reported for codeine or morphine in anything opened. Anemia in the compound-analgesic report [26] is an outcome tied to the NSAID ingredient and is held under Oxygen delivery/utilization, not here.
  • At-risk subgroups: Not defined.

Whose data

Morphine in rat cortical neurons and rats (Nash 2019 [23]). CLASS EXTRAPOLATION: codeine NOT in the cohort, so Tier C for codeine, capped at yellow.

Regulatory status

No iron wording in the label text read [1].

Population evidence

[23], abstract reconstructed from OpenAlex: morphine, acting at mu-opioid receptors on cortical neurons, raised cytoplasmic ferritin heavy chain, lowered iron in endolysosomes and raised it in the cytoplasm, with loss of dendritic spines in culture and in treated rats. Sample sizes were not in the text read.

Mechanism

Named in rodent neurons: mu-opioid receptor signaling leading to ferritin heavy chain upregulation [23].

Direction

Intracellular redistribution. Neither depletion nor systemic excess is shown.

Counter-evidence held on record

Counter-evidence and confounding Neuron-specific, preclinical, morphine only. Codeine appears in PubMed listings of restless legs treatment, a condition linked to iron deficiency (listing summaries only), so any human codeine-iron association would be confounded by indication. Framing caution No iron deficiency or iron overload is claimed. Iron supplementation is not implied by this entry. No supplement dose is recommended.

Gut Microbiome Risk

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

Gut microbiome risk: CLASS EXTRAPOLATION from morphine (mouse) and other opioids (human); codeine absent from every cohort

Yellow — Low

See study details

No study of codeine and the gut microbiome was found. Morphine, codeine's active metabolite, shifts the mouse gut microbiome toward Gram-positive taxa with lower bile acids and barrier loss, and humans on methadone or on mixed chronic opioids show dysbiosis. None of these cohorts includes codeine.

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

Limits on what this shows

  • Null findings: A PubMed title/abstract listing for codeine with microbiota, microbiome, dysbiosis and 16S returned four records, none a codeine microbiome study. No opioid-by-opioid human microbiome comparison was found.
  • At-risk subgroups: Not defined for codeine.

Whose data

Morphine in mice [17], methadone in people [18], unnamed opioids in people with cirrhosis [19]. CLASS EXTRAPOLATION. Codeine was NOT in the cohort of any of the three (cohort test failed for codeine), so this is Tier C and capped at yellow. Morphine is only about 5 to 10% of a codeine dose by the label, and that fraction varies with CYP2D6 [1][6], so mouse pellet exposures to morphine are not equivalent to codeine therapy.

Regulatory status

No microbiome wording in the label text read. The label documents the gut dysmotility itself: reduced motility with higher smooth-muscle tone in the antrum of the stomach and duodenum, decreased propulsive peristaltic waves in the colon, and constipation [1].

Population evidence

Banerjee 2016 [17]: C57BL/6 mice with 25 mg slow-release morphine pellets (about 1 micromolar serum), n = 6 per group for microbiome work and 8 per group for transplant. As summarized by a fetch tool: expansion of Gram-positive taxa (Enterococcaceae, Staphylococcaceae, Bacillaceae), fewer Bacteroidetes, Lactobacillus and Clostridium, lower primary and secondary bile acids, bacterial translocation to the liver, and rescue by transplanting placebo-treated microbiota. Cruz-Lebron 2021 [18]: methadone maintenance patients had an imbalance of communities that make short-chain fatty acids and degrade mucus, with lower fecal short-chain fatty acids (abstract only; sample size not in the text read). Acharya 2017 [19]: 72 people with cirrhosis on chronic opioids versus 96 opioid-free; reduced Bacteroidaceae and higher endotoxin production (abstract only; opioid identity not given).

Mechanism

Class-level and partly inferred: slowed transit and altered bile-acid handling, with reduced bile-deconjugating bacteria in the mouse [17]. No codeine mechanism was shown.

Direction

Composition and barrier change (a risk to monitor). Not a nutrient depletion.

Counter-evidence held on record

Counter-evidence and confounding Cirrhosis and addiction-treatment populations carry large baseline microbiome differences from diet, liver disease and lifestyle. Mouse pellet dosing gives sustained morphine exposure unlike intermittent codeine. Constipation is the drug's own pharmacology and is only a hypothesized link to microbiome change here. Framing caution A monitoring prompt, not a finding that codeine alters the microbiome. It does not imply that a probiotic, fiber or other product is needed. No supplement dose is recommended.

Oxygen and ATP Output

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

Oxygen delivery/utilization: lower blood indices in codeine-exposed fish and confounded anemia in compound-analgesic misuse (respiratory depression is drug pharmacology)

Yellow — Low

See study details

No study measured hemoglobin or red-cell mass in people taking single-ingredient codeine. Two weak signals exist: lower hematocrit, hemoglobin and red cells in exposed catfish, and anemia in people misusing ibuprofen/codeine, which that paper links to the ibuprofen ingredient. Respiratory depression is the drug's own pharmacology and is not an oxygen-delivery deficiency.

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

Limits on what this shows

  • Null findings: No codeine-only human hematology study was retrieved. A PubMed listing for codeine with hemoglobin, anemia, hemolysis, methemoglobin and hematocrit returned sickle-cell pharmacogenetics papers and an item stating codeine was used without hemolytic crisis in G6PD deficiency (title and snippet only, not used).
  • At-risk subgroups: Not defined. Ultra-rapid CYP2D6 metabolizers are the label's respiratory-depression group [1][6].

Whose data

Codeine itself in catfish at an aquatic concentration (El-Sayed 2025 [25], Tier B, listing summary only). Ibuprofen/codeine and paracetamol/codeine products in people (Cock 2018 [26]): single-ingredient codeine was NOT in the cohort, so Tier C for this dossier; the paracetamol/codeine group is mentioned only as the comparison arm and its combination is outside this dossier's scope.

Regulatory status

Label sec 5.6: "Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression" [1]. No hemoglobin, hematocrit or red-cell wording was found in the portions read. Respiratory depression is pharmacology and is filed here only as a mechanism clarification (Hard Rule 2).

Population evidence

El-Sayed 2025 [25]: male African catfish exposed to codeine at 5.27 micrograms per liter for 15 days; hematocrit, hemoglobin, erythrocyte, leukocyte and lymphocyte counts were significantly reduced (the listing summary does not attribute the change to the codeine group separately). Cock 2018 [26]: 60 people using ibuprofen/codeine (mean codeine 699 mg/day) and 46 using paracetamol/codeine (mean 636 mg/day) presenting for codeine withdrawal; complications in 52/60 (87%) versus 30/46 (65%); gastrointestinal bleeding (P < 0.05) and anemia (P < 0.0001) were more likely with ibuprofen/codeine; two deaths occurred in that group.

Mechanism

Absent for codeine and red cells in sources opened. In [26] the anemia and bleeding were associated with the ibuprofen-containing product, so NSAID blood loss is the competing explanation.

Direction

Lower blood indices (fish); anemia as a clinical outcome (people). Neither is an iron or oxygen-carrying nutrient measurement.

Counter-evidence held on record

Counter-evidence and confounding Catfish exposure is environmental, aquatic and low concentration; the result is not translatable to people. The human report involves supratherapeutic intake of an NSAID combination in a withdrawal clinic population. Anemia is an outcome, not iron deficiency (Hard Rule 2). Framing caution No oxygen-delivery deficiency is claimed. Do not read the respiratory-depression label warning as a nutrient finding. No supplement dose is recommended.

ATP production: lower ATPase activity in isolated rat liver mitochondria at 1 mM morphine (CLASS EXTRAPOLATION; supraclinical concentration)

Yellow — Low

See study details

No study measured ATP in codeine-treated cells, animals or people. Morphine at a concentration roughly 100 to 3,000 times above the clinical plasma values its authors cite lowered ATPase activity in isolated rat liver mitochondria.

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

Limits on what this shows

  • Null findings: Most respiratory and membrane-potential parameters did not change with morphine alone [21]. Cellular ATP content was not measured. A PubMed listing for codeine with ATP, respiration, glutathione, superoxide and ROS returned no codeine ATP study (the codeine hits concerned respiration as breathing, i.e. respiratory depression).
  • At-risk subgroups: Not defined.

Whose data

Morphine in vitro, isolated rat liver mitochondria (Cunha-Oliveira 2013 [21]). CLASS EXTRAPOLATION: codeine NOT studied (cohort test failed for codeine), Tier C, capped at yellow. The codeine mouse paper [16] reports complex I inhibition but its abstract, as summarized, does not state an ATP measurement.

Regulatory status

No ATP or energy-metabolism wording in the label text read [1].

Population evidence

[21]: isolated rat liver mitochondria; morphine alone at 0.2 to 1 mM. At 1 mM, ATPase activity decreased significantly and state 2 respiration rose; state 3, state 4, maximal respiration and membrane potential were unaffected. The paper cites peak plasma morphine of 0.20 to 2.3 mg/L (0.35 to 9.8 micromolar) in fatalities. Abstract and key results read from a repository PDF via a summarizing fetch tool.

Mechanism

Not established; the single parameter that moved was ATPase activity at the highest concentration.

Direction

Mixed and small, in vitro only. Not an energy deficit in any patient.

Counter-evidence held on record

Counter-evidence and confounding Isolated organelles lack cellular context and the dose gap is two to three orders of magnitude. This entry rests on the same morphine paper as part of Mitochondrial burden's null findings; see the Overlap map. Kept independent of Mitochondrial burden and Oxygen delivery/utilization (Hard Rule 7). Framing caution Do not state that codeine lowers cellular energy or causes fatigue through mitochondrial effects. No coenzyme Q10 or similar product is implied. No supplement dose is recommended.

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.

  • Constipation as a nutrient problem (fiber, fluid or mineral depletion)

    Where it comes from: The batch brief lists constipation among the nutrient angles. Not traced to a consumer page.

    Why it fails: Constipation is the drug's own pharmacology (reduced propulsion, higher smooth-muscle tone, sphincter spasm) and an outcome, not a nutrient measurement [1]. Hard Rule 2 bars filing it as a deficiency, and no source opened shows a nutrient falling because of codeine constipation. It appears only as context in the Gut microbiome entry.

  • Alcohol and grapefruit listed as codeine "interactions"

    Where it comes from: Drugs.com food-interactions page for codeine (Tier D) [28]: avoid alcohol; grapefruit and grapefruit juice may raise blood levels.

    Why it fails: Direction runs from the food or drink to the drug (additive CNS depression; higher codeine exposure), so these are timing or avoidance interactions, not depletions (Hard Rule 4). The label read lists CYP3A4 inhibitors as raising codeine and subsequent morphine [1]; grapefruit is not named in the label text read. The page states no vitamin or mineral interaction [28][29].

  • Consumer depletion-list claims for codeine (any nutrient)

    Where it comes from: Not retrieved. The Antidote Research page for codeine returned 404, the Drugs.com pages opened state no depletion [28][29], and web search was exhausted.

    Why it fails: No claim was found to rebut or endorse. This row records the audit result so absence is not read as safety; the audit is incomplete and should be repeated.

  • "Codeine lowers vitamin D" or causes bone loss through vitamin D (inferred)

    Where it comes from: Inferred from the brief's vitamin D angle; no page making the claim was found.

    Why it fails: The only measurement opened ran higher in opioid-dependent patients, with codeine not named [24]. Fracture and low bone density are outcomes, not vitamin D status (Hard Rule 2); the codeine-and-fracture records seen in a PubMed listing concerned pain treatment of fractures, not bone loss. See the yellow Vitamin D entry.

  • "Take extra salt or sodium for opioid-related low sodium" (inferred)

    Where it comes from: Inferred from the Sodium and water balance entry; not a retrieved claim.

    Why it fails: The signal is dilutional hyponatremia with possible ADH release [1][9][10]. Sodium loading would be the hazard, not the remedy (Hard Rule 5).

  • "Codeine is a weak opioid, so it does not affect hormones" (inferred)

    Where it comes from: Inferred; not traced to a page.

    Why it fails: Contradicted by codeine's own data: total testosterone fell about 20% after 3 days in healthy men [7] and a single 30 mg dose suppressed cortisol [8], and the label carries class warnings for androgen deficiency and adrenal insufficiency [1]. The size of the effect relative to other opioids is unknown from codeine data.

How the body handles this medication

Metabolism and enzymes
About 70 to 80% of a dose is conjugated with glucuronic acid to codeine-6-glucuronide (UGT2B7), with O-demethylation to morphine (about 5 to 10%, CYP2D6) and N-demethylation to norcodeine (about 10%, CYP3A4). No induction or inhibition of any CYP enzyme by codeine is described in the label text read.[1] DailyMed Hikma label sec 12.3, read via summarizing fetch
CYP2D6 genotype and interactions
Ultra-rapid CYP2D6 metabolizers convert codeine to morphine faster and more completely, with a label warning of fatal respiratory depression at labeled doses. CYP2D6 inhibitors (paroxetine, fluoxetine, bupropion, quinidine) raise codeine and lower morphine; CYP3A4 inhibitors (macrolides, azole antifungals, ritonavir) raise codeine and subsequent morphine; CYP3A4 inducers (rifampin, carbamazepine, phenytoin) are also listed.[1] sec 5.6, 5.7, 7; [6] CPIC guideline abstract
Elimination
About 90% of the dose is excreted by the kidneys, about 10% of that as unchanged codeine. Plasma half-lives of codeine and its metabolites are about 3 hours. Hepatic or renal impairment: start at a lower than normal dosage and titrate slowly.[1] sec 12.3, dosing text
Absorption, distribution and food
Absorbed from the gastrointestinal tract with peak plasma concentration at about 60 minutes. After a high-fat, high-calorie meal 60 mg showed no significant change in rate or extent of absorption. Volume of distribution about 3 to 6 L/kg; plasma protein binding about 7 to 25%. No named absorption transporter and no mineral or antacid separation interval appear in the text read.[1] sec 12.3
Gastrointestinal pharmacology
Reduced motility with increased smooth-muscle tone in the antrum of the stomach and duodenum, decreased propulsive contractions and peristaltic waves in the colon (constipation), sphincter of Oddi spasm and possible rises in serum amylase. Anticholinergics may increase the risk of severe constipation. This is the drug's own effect, not a nutrient deficiency.[1] sec 12.2, 7
Endocrine and water handling
Opioids inhibit secretion of ACTH, cortisol and LH in humans; extended use may cause androgen deficiency. The interactions section states that opioids can reduce the efficacy of diuretics by inducing antidiuretic hormone release. No hyponatremia wording surfaced in the text read.[1] sec 12.2, 5.11, 7

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.

  • Lab / after starting

    Serum sodium

    Worth considering a sodium check if confusion, nausea, headache, unsteadiness or falls appear soon after codeine is started, because the signal in registry data was concentrated in newly started treatment [9]. Opioid ADH release can also blunt diuretic effect [1]. This is a water-retention risk. It is not a reason to add salt.

  • Lab / symptoms, prolonged use

    Testosterone and LH

    For men or women on extended codeine use with low libido, erectile dysfunction, amenorrhea or infertility, a total testosterone measurement is worth considering (it is what the human codeine study measured [7]); the label ties the effect to LH inhibition and names these symptoms [1]. Only short-term codeine data exist.

  • Clinical / symptoms

    Adrenal insufficiency symptoms

    Unexplained fatigue, weakness, nausea, dizziness or low blood pressure on long opioid use warrants clinician assessment; the label directs diagnosis, physiologic corticosteroid replacement and weaning of the opioid [1]. Acute cortisol suppression after one dose is documented [8].

  • Medication review

    CYP2D6 and CYP3A4 interactions

    Paroxetine, fluoxetine, bupropion and quinidine inhibit CYP2D6 (less morphine formed, possible loss of effect or withdrawal symptoms); macrolides, azole antifungals and ritonavir inhibit CYP3A4 (more codeine and morphine); rifampin, carbamazepine and phenytoin induce CYP3A4 [1]. Genotype guidance exists [6].

  • Supplement and food timing

    No nutrient separation interval found

    No mineral, vitamin or antacid interval appears in the label text read, and food does not significantly change absorption [1]. Alcohol and grapefruit act on the drug (Tier D page) [28]. No supplement dose appears anywhere in this dossier.

  • Special populations

    Ultra-rapid metabolizers, impairment, pregnancy

    The label warns of fatal respiratory depression in ultra-rapid CYP2D6 metabolizers (sec 5.6), advises a lower starting dose in hepatic or renal impairment, and lists neonatal opioid withdrawal syndrome as a warning heading (sec 5.4) [1]. The pediatric wording was not read.

Overlap map, to prevent double counting

Entries that rest on the same underlying source or mechanism. Cite each source once when counting independent lines of evidence.

  • Androgen axis

    Shares evidence with: Adrenal axis; Sodium and water balance

    Note: All three lean on the same label class statements about opioid effects on LH, ACTH, cortisol and ADH [1]. Each has its own separate human study ([7], [8], [9][10]), so the label is shared context, not three confirmations.

  • Androgen axis

    Shares evidence with: Oxidative stress

    Note: The rabbit and rat reports [12][13][14][15] come from one laboratory group and supply both testosterone suppression and oxidative-damage markers. Count them once as animal evidence; they do not confirm the human androgen finding [7].

  • Oxidative stress

    Shares evidence with: Mitochondrial burden

    Note: The mouse paper [16] reports nitroso-oxidative stress and complex I inhibition from one experiment. Morphine liver-mitochondria data [21] bear on both entries.

  • Mitochondrial burden

    Shares evidence with: ATP production

    Note: Both cite the morphine isolated-mitochondria study [21] (ATPase result here, respiration and membrane potential there). The codeine mouse paper [16] reports no ATP measurement. Kept as independent entries (Hard Rule 7); one source is not two findings.

  • Copper

    Shares evidence with: Iron

    Note: No shared source; both are morphine class extrapolations ([22] copper, [23] iron) with the same limit that codeine was not in the cohort. Independent entries (Hard Rule 7).

  • Iron

    Shares evidence with: Oxygen delivery/utilization

    Note: The anemia in the compound-analgesic report [26] could be read under either; it is held under Oxygen delivery/utilization as an outcome tied to the NSAID ingredient, and iron was not measured in it.

  • Gut microbiome risk

    Shares evidence with: Fails verification: constipation

    Note: Both rest on the label's description of reduced gut motility [1]. Constipation is not graded as a nutrient entry.

  • Gut microbiome, ATP production, Copper, Iron, Vitamin D

    Shares evidence with: Other opioid dossiers in this series (for example the finished morphine dossier in b013)

    Note: Sources [17] to [19], [21] to [24] are class studies of morphine, methadone or unnamed opioids; they were opened independently for this dossier. They are the same underlying evidence wherever they recur and are not independent confirmation across dossiers.

All references used above
  1. Codeine Sulfate Tablets, prescribing information, Hikma Pharmaceuticals USA Inc. (DailyMed). — Regulatory label (Tier A). Revision shown on the retrieved page: 12/2025. Sections used: 5 headings, 5.6, 5.11, 7, 12.2, 12.3 (metabolism, excretion, absorption), adverse reactions.Read through a summarizing fetch tool in three passes, not directly. The page text is 109,262 characters; the final 9,262 characters of the first passes were not read, and section 12.3 came from a pass starting at character 60,000. No hyponatremia, SIADH, vitamin, mineral, iron, copper, oxidative stress, mitochondrial or microbiome wording surfaced, which is not proof it is absent.
  2. DailyMed SPL index for "codeine sulfate" (service API). — Used to identify labels. Three single-ingredient codeine sulfate tablet entries: Lannett (setid 5819bdf7-300e-45b8-8f3a-447b53656293, Feb 2026), Hikma (setid 010905f9-3bcb-4b50-9fe8-a3ad0010f14c, Dec 2025), Physicians Total Care (setid f317cd06-2851-4a52-86d3-6efde3a4c243, 2009).Only the Hikma label was opened. The Lannett and Physicians Total Care labels were not opened.
  3. WHO Collaborating Centre, ATC/DDD Index: codeine, R05DA04. — Reference index. Codeine R05DA04 sits under cough suppressants; DDD 0.1 g, oral.
  4. WHO Collaborating Centre, ATC/DDD Index: N02AA59, codeine, combinations excl. psycholeptics. — Reference index. This code is for combinations, which this dossier excludes; no DDD listed on the page.
  5. Drugs.com. Codeine (consumer monograph page). — Tier D for evidence. Used only for market facts: single-ingredient codeine sulfate tablets are generic only in the US and distributed by Hikma. The page was read for brand, vitamin, mineral and hyponatremia content and contained none.Read via a summarizing fetch tool.
  6. Crews KR, Monte AA, Huddart R, et al. CPIC guideline for CYP2D6, OPRM1 and COMT genotypes and select opioid therapy. Clin Pharmacol Ther 2021;110(4):888-896. — Guideline abstract (Tier A, pharmacogenetics). Names codeine among opioids metabolized by CYP2D6 and gives genotype-based recommendations for codeine, tramadol and methadone. DOI 10.1002/cpt.2149.Abstract only, reconstructed from OpenAlex. Guideline tables and phenotype frequencies not read.
  7. Lehtihet M, Andersson A, Borjesson A, Schulze J, Rane A, Ericsson M, Ekstrom L. Codeine influences the serum and urinary profile of endogenous androgens but does not interact with the excretion rate of administered testosterone. Drug Test Anal (OpenAlex year 2017; PubMed listing 2018). — Open study, subjects as own control, 15 healthy men given therapeutic codeine for 6 days; total testosterone down 20% after 3 days (p = 0.0002). PMID 28901724. DOI 10.1002/dta.2301. Codeine in cohort: Tier A.Abstract only, reconstructed from OpenAlex; full text not opened. Codeine dose and salt form not stated in the abstract.
  8. Garland EJ, Zis AP. Effect of codeine and oxazepam on afternoon cortisol secretion in men. Psychoneuroendocrinology 1989. — Placebo-controlled, counterbalanced, 9 subjects, codeine 30 mg or oxazepam 30 mg; codeine suppressed cortisol. PMID 2813660. DOI 10.1016/0306-4530(89)90009-7. Codeine in cohort: Tier A.Abstract text taken from a PubMed search-listing page summarized by a fetch tool (the OpenAlex record had no abstract at https://api.openalex.org/works/pmid:2813660). Full text not opened; effect size not available.
  9. Falhammar H, Calissendorff J, Skov J, Nathanson D, Lindh JD, Mannheimer B. Tramadol- and codeine-induced severe hyponatremia: a Swedish population-based case-control study. Eur J Intern Med 2019;69:20-24. — Population-based case-control; 14,359 cases and 57,383 controls (as summarized). PMID 31416660. DOI 10.1016/j.ejim.2019.08.006. Codeine in cohort: Tier A.Numbers taken from a PubMed listing summarized by a fetch tool; the OpenAlex and Crossref records held no abstract; the PubMed record page returned a reCAPTCHA page and the publisher page returned 403. A corrigendum (PMID 34172352, 2021) was seen only as a title and not opened. Whether combination codeine products are in the exposure was not confirmed.
  10. Fournier JP, Yin H, Nessim SJ, Montastruc JL, Azoulay L. Tramadol for noncancer pain and the risk of hyponatremia. Am J Med (OpenAlex 2014; PubMed listing April 2015). — Population-based cohort, 332,880 new users of tramadol or codeine (1998 to 2012). Codeine was the comparator. PMID 25460534. DOI 10.1016/j.amjmed.2014.10.046. Codeine in cohort: Tier A, but with no unexposed group.Abstract sentences from a PubMed listing summarized by a fetch tool; the OpenAlex record had a null abstract. Full text not opened.
  11. Martins TL, Kahvegian MAP, Noel-Morgan J, Leon-Roman MA, Otsuki DA, Fantoni DT. Comparison of tramadol, codeine and ketoprofen alone or in combination on postoperative pain and on blood glucose, serum cortisol and serum interleukin-6 in dogs undergoing maxillectomy or mandibulectomy. Am J Vet Res 2010. — Veterinary trial, 42 dogs; no significant change in serum cortisol across groups. PMID 20807140. DOI 10.2460/ajvr.71.9.1019. Counter-evidence only.Abstract only, reconstructed from OpenAlex. Dog, subcutaneous, perioperative: not comparable to the human oral study.
  12. Ajayi AF, Akhigbe RE. Codeine-induced sperm DNA damage is mediated predominantly by oxidative stress rather than apoptosis. Redox Rep 2020. — Rabbits, 21 animals, oral codeine 4 or 10 mg/kg for 6 weeks (Tier B, codeine). PMID 32290793. DOI 10.1080/13510002.2020.1752003.Abstract only, reconstructed from OpenAlex.
  13. Akhigbe RE, Ajayi AF. Testicular toxicity following chronic codeine administration is via oxidative DNA damage and up-regulation of NO/TNF-alpha and caspase 3 activities. PLoS One 2020. — Rabbits, 21 males, oral codeine 4 or 10 mg/kg for 6 weeks (Tier B, codeine). PMID 32168344. DOI 10.1371/journal.pone.0224052.Abstract only, reconstructed from OpenAlex. Same laboratory group as [12], [14] and [15].
  14. Ajayi AF, Akhigbe RE. Assessment of sexual behaviour and fertility indices in male rabbits following chronic codeine use. Andrology 2020;8(2):509-515. — Rabbits, oral codeine 4 or 10 mg/kg for 6 weeks; lower testosterone and fertility index, higher libido behaviors (Tier B, codeine). PMID 31627249. DOI 10.1111/andr.12717.Abstract only, via OpenAlex.
  15. Ajayi AF, Akhigbe RE, et al. In vivo exposure to codeine induces reproductive toxicity: role of HER2 and p53/Bcl-2 signaling pathway. Heliyon 2020. — Wistar rats, 30 males, codeine 2 or 5 mg/kg/day for 6 weeks with recovery groups (Tier B, codeine). PMID 33294712. DOI 10.1016/j.heliyon.2020.e05589.Abstract only, reconstructed from OpenAlex.
  16. Ishola IO, Eneanya SU, Folarin OR, et al. Tramadol and codeine stacking/boosting dose exposure induced neurotoxic behaviors, oxidative stress, mitochondrial dysfunction, and neurotoxic genes in adolescent mice. Neurotox Res 2022;40(5):1304-1321. — Mouse study; codeine alone, tramadol alone and combination arms; PMID 35829998. DOI 10.1007/s12640-022-00539-x. Tier B (codeine), arm attribution unclear.Abstract only, read via a summarizing fetch of the publisher page; the OpenAlex abstract was null; full text not opened and group-level biomarker values not seen.
  17. Banerjee S, et al. Opioid-induced gut microbial disruption and bile dysregulation leads to gut barrier compromise and sustained systemic inflammation. Mucosal Immunol 2016. — Mouse, morphine 25 mg pellets, n = 6 to 8 per group. DOI 10.1038/mi.2016.9.Morphine, not codeine. Tier C for codeine (CLASS EXTRAPOLATION). Abstract and key details via a summarizing fetch tool.
  18. Cruz-Lebron A, Johnson R, Mazahery C, et al. Chronic opioid use modulates human enteric microbiota and intestinal barrier integrity. Gut Microbes 2021. — Methadone maintenance cohort plus in vitro work. DOI 10.1080/19490976.2021.1946368.Excluded cohort: methadone, not codeine. Tier C (CLASS EXTRAPOLATION). Abstract only, reconstructed from OpenAlex.
  19. Acharya C, Betrapally NS, Gillevet PM, et al. Chronic opioid use is associated with altered gut microbiota and predicts readmissions in patients with cirrhosis. Aliment Pharmacol Ther (OpenAlex 2016; print 2017). — Cohort of 200 hospitalized cirrhosis patients and a microbiota comparison of 72 opioid users versus 96 opioid-free patients. DOI 10.1111/apt.13858.Excluded cohort: opioids not specified, codeine not confirmed. Tier C (CLASS EXTRAPOLATION). Abstract only, reconstructed from OpenAlex.
  20. Skrabalova J, Drastichova Z, Novotny J. Morphine as a potential oxidative stress-causing agent. Mini Rev Org Chem 2013. — Narrative review without drug-level stratification; morphine only. DOI 10.2174/1570193x113106660031.Tier C context, codeine not in scope. Abstract only, reconstructed from OpenAlex.
  21. Cunha-Oliveira T, et al. Acute effects of cocaine, morphine and their combination on bioenergetic function and susceptibility to oxidative stress of rat liver mitochondria. Life Sci 2013;92:1157-1164. — In vitro isolated rat liver mitochondria; morphine alone at 0.2 to 1 mM. DOI 10.1016/j.lfs.2013.04.016. Cocaine and combination arms not counted.Morphine, not codeine. Tier B for morphine, Tier C for codeine. Repository PDF read via a summarizing fetch tool; results as rendered by that tool.
  22. Yousofvand N, et al. The effect of morphine dependency on serum levels of trace elements (copper, zinc, and manganese) in male rats. Armaghane Danesh 2014;19(3):195-203. — Experimental rat study, 24 male Wistar rats, 30 days. DOI not shown on the page.Morphine, not codeine. Tier C for codeine (CLASS EXTRAPOLATION). Journal page read via a summarizing fetch tool; zinc and manganese results not captured.
  23. Nash B, Tarn K, Irollo E, et al. Morphine-induced modulation of endolysosomal iron mediates upregulation of ferritin heavy chain in cortical neurons. eNeuro 2019;6(4). — Rat cortical neuron cultures and morphine-treated rats. DOI 10.1523/ENEURO.0237-19.2019.Morphine, not codeine. Tier C for codeine (CLASS EXTRAPOLATION). Abstract only, reconstructed from OpenAlex; full text not opened.
  24. Reece AS, Hulse GK. What are the characteristics of vitamin D metabolism in opioid dependence? An exploratory longitudinal study in Australian primary care. BMJ Open 2018. — Retrospective record review, 1,583 patients. PMID 29331964. DOI 10.1136/bmjopen-2017-016806.Excluded or unconfirmed cohort: opioids not named, codeine not confirmed. Tier C (CLASS EXTRAPOLATION). Abstract and key figures via a summarizing fetch tool.
  25. El-Sayed AAA, Abdel-Samei WM, Soliman HAM, Hana MN, Sayed AEH. Effects of gabapentin, valsartan, and codeine on hemato-biochemical and histological biomarkers of male catfish (Clarias gariepinus). Environ Sci Pollut Res Int 2025;32(34):20762-20773. — Fish exposure study, codeine 5.27 micrograms per liter for 15 days. PMID 40856923. Tier B (codeine), aquatic.Seen only as a PubMed listing summarized by a fetch tool; the OpenAlex record could not be fetched (429). Attribution of the hematologic change to the codeine group was not confirmed; abstract and full text not read directly.
  26. Cock V, Edmonds C, Cock C. Complications related to chronic supratherapeutic use of codeine containing compound analgesics in a cohort of patients presenting for codeine withdrawal. Drug Alcohol Rev 2018;37(6):731-737. — Cohort of 60 ibuprofen/codeine and 46 paracetamol/codeine users. PMID 29722073.Excluded cohort: compound analgesics, not single-ingredient codeine; the paracetamol/codeine arm is outside this dossier's scope. Tier C. Abstract data from a PubMed listing summarized by a fetch tool.
  27. Rubinstein AL, Carpenter DM. Association between commonly prescribed opioids and androgen deficiency in men: a retrospective cohort analysis. Pain Med 2017. — Retrospective cohort, 1,159 men on a single opioid; fentanyl, methadone and oxycodone versus hydrocodone. PMID 27516365. DOI 10.1093/pm/pnw182.Excluded cohort: codeine not among the opioids named in the abstract. Used only as a null on codeine. Abstract only, reconstructed from OpenAlex.
  28. Drugs.com. Codeine food and alcohol interactions page. — Tier D. Used only as a circulating-claim origin: lists alcohol and grapefruit/grapefruit juice; states no vitamin, mineral or supplement interaction or depletion.Read via a summarizing fetch tool.
  29. Drugs.com. Codeine information page and interaction index. — Tier D. Opened to look for depletion claims; none stated. Interaction index reports 650 drug interactions and no supplement entries.Read via a summarizing fetch tool.
  30. PubMed search-listing pages used for discovery (queries listed under Ungraded: evidence gap). — Discovery only. The listing format returned abstracts for records [8], [9], [10], [25] and [26].Summarized by a fetch tool; several queries returned HTTP 429, and queries containing quoted phrases returned an invalid-form page. Not a source of any claim beyond the records named.