Amphetamine/dextroamphetamine

Limits on what this shows

• Key negative/null findings: The human trial (PMID 21309695) does not report a zinc-lowering effect of amphetamine; it evaluates zinc as an add-on treatment, not as an outcome affected by the drug.
• At-risk subgroups: Theoretical, from animal data only. The rat dose (15 mg/kg intraperitoneal) is far above typical human oral therapeutic dosing (roughly 0.15 to 0.5 mg/kg/day), which bounds the applicability of this finding.

Regulatory status

Not addressed in FDA labeling.

Population evidence

Barron JL, "Demonstration of reduced levels of zinc in rat brain after treatment with d-amphetamine, but not after treatment with reserpine," PMID 4044304 (1985): a single 15 mg/kg intraperitoneal d-amphetamine dose significantly decreased neuronal zinc in the hippocampus and parietal cortex at 6 hours. "Zinc for attention-deficit/hyperactivity disorder: placebo-controlled double-blind pilot trial alone and combined with amphetamine," PMID 21309695 (2011, human, amphetamine-specific cohort, but tests zinc supplementation as adjunct treatment, not amphetamine's effect on zinc status).

Mechanism

Named in the animal source only (acute central zinc redistribution following d-amphetamine); not fully characterized in the retrieved snippet.

Limits on what this shows

• Key negative/null findings: None identified. This is a single case report with no replication located in this review, and no study measuring B6 status (blood level or functional marker) before and after amphetamine treatment was found.
• At-risk subgroups: None clinically defined; single-patient finding from 1981.

Regulatory status

Not addressed in FDA labeling. No B6-related warning, monitoring requirement, or interaction is listed for Adderall/Adderall XR.

Population evidence

Frye PE, Arnold LE, "Persistent amphetamine-induced compulsive rituals: response to pyridoxine (B6)," PMID 7260219 (1981). Amphetamine is named specifically in the title and confirmed via the PubMed search-results listing; the individual article page returned a bot-verification challenge and could not be read directly this session, so the pyridoxine dose used and the mechanism proposed in the source's full text are not independently confirmed beyond the indexed title.

Mechanism

Not confirmed in full text; plausible by extension of established biochemistry, pyridoxal-5-phosphate is a required cofactor for aromatic-L-amino-acid decarboxylase (DOPA decarboxylase) in catecholamine synthesis, offering a biochemical link between B6 status and dopaminergic/monoaminergic tone, structurally similar to the iron/tyrosine-hydroxylase mechanism in the Iron entry above.

Counter-evidence held on record

This is a single case report in which pyridoxine was administered to treat an amphetamine-induced side effect, the reverse direction from a depletion claim (Hard Rule 4): the nutrient modulates the drug's adverse effect, not the drug lowering the nutrient. Do not present this as amphetamine depleting or requiring vitamin B6 supplementation; one 41-year-old case report does not establish a treatment protocol.

Limits on what this shows

• Key negative/null findings: No folate-specific finding was located in this review at any tier. No study measuring B12 or folate at labeled therapeutic ADHD dosing, as opposed to a dependence/misuse population, was located.
• At-risk subgroups: Patients with polysubstance misuse involving amphetamine and cocaine together; not established for labeled therapeutic ADHD use.

Regulatory status

Not addressed in FDA labeling.

Population evidence

Malik E, Rozner L, Adelson M, Schreiber S, Peles E, "The Relation between Changes in Vitamin D and Vitamin B12 Levels, Body Mass Index and Outcome in Methadone Maintenance Treatment Patients," PMID 33143561 (2021). Human, observational. Amphetamine is named specifically, alongside cocaine, as a substance of abuse in the studied cohort per the indexed description ("Vitamin B12 was lower in patients abusing cocaine/amphetamine on admission"). Full text was not retrieved this session (opened via PubMed search-results listing only); the magnitude, statistical significance, and whether amphetamine, cocaine, or both drove the association are not independently confirmed beyond the indexed snippet.

Mechanism

Not named for amphetamine specifically in the retrieved material. No amphetamine-specific B12/folate-methylation mechanism was located; the association may reflect the nutritional and lifestyle pattern common to polysubstance misuse rather than a direct pharmacological effect of amphetamine on B12/folate metabolism.

Counter-evidence held on record

This finding is bounded to a dependence/polysubstance-misuse population and confounded by concurrent cocaine abuse and by the nutritional pattern common to substance misuse generally (irregular eating, poor diet), per Hard Rule 6. Do not extrapolate this to patients taking amphetamine/dextroamphetamine at labeled therapeutic ADHD dosing.

Limits on what this shows

• Key negative/null findings: No study located measured serum or whole-body vitamin C/ascorbic acid status after amphetamine treatment in humans or animals; every located study measures acute, local, extracellular brain-tissue ascorbate release, not systemic depletion.
• At-risk subgroups: None clinically defined; a laboratory neurochemistry phenomenon, not a patient-level finding.

Regulatory status

FDA labeling and consumer drug references (WebMD) separately document ascorbic acid as a urinary acidifier that lowers amphetamine blood levels (see Pharmacokinetic basis); that is a labeled timing interaction, not a depletion finding, and is not re-graded here.

Population evidence

Tier B, animal, amphetamine-specific (not methamphetamine or class-extrapolated): Salamone JD, Hamby LS, Neill DB, Justice JB Jr, "Extracellular ascorbic acid increases in striatum following systemic amphetamine," PMID 6728876 (1984). Mueller K, Kunko PM, "The effects of amphetamine and pilocarpine on the release of ascorbic and uric acid in several rat brain areas," PMID 2345762 (1990). Miele M et al., "On the mechanism of d-amphetamine-induced changes in glutamate, ascorbic acid and uric acid release in the striatum of freely moving rats," PMID 10711358 (2000). Desole MS et al., "Neurochemical and behavioural changes induced by ascorbic acid and d-amphetamine in the rat," PMID 3659117 (1987), and "Analysis of the mechanism of d-amphetamine- and apomorphine-induced changes of ascorbic acid catabolism in discrete brain areas of the rat," PMID 2068053 (1991). All opened via PubMed search-results listing; full text not independently retrieved this session.

Mechanism

Named: systemic amphetamine drives dopamine release, which co-releases ascorbic acid from brain tissue via an ascorbate-glutamate heteroexchange mechanism at the cell membrane, detected in vivo by voltammetry. This is a local, acute extracellular efflux used experimentally as an indirect marker of dopamine release, not a description of whole-body vitamin C status or storage depletion.

Counter-evidence held on record

Do not present this as amphetamine depleting vitamin C in patients. This is a local, acute brain-tissue efflux phenomenon used as an experimental proxy for dopamine release, running in the opposite conceptual direction from a depletion claim, release into extracellular fluid, not loss from the body. Separately, reverse-direction studies located here, Kiely ME, Lal S, Nair NP, "Effect of ascorbic acid on brain amphetamine concentrations in the rat," PMID 3628833 (1987), and Gifford JJ, Wagner GC, "The effect of ascorbic acid pretreatment on amphetamine-induced dopamine depletion in male and female mice," PMID 32459674 (2020), test ascorbic acid's effect on amphetamine's brain levels and toxicity, the nutrient affecting the drug (Hard Rule 4), and are noted for completeness but are not counted as support for a depletion claim. Drugs.com and WebMD were checked directly and list no vitamin-C-depletion claim for Adderall beyond the labeled pH/absorption interaction already captured above.

Limits on what this shows

• Key negative/null findings: No amphetamine-specific CoQ10 study, and no study measuring endogenous CoQ10 depletion (as opposed to exogenous CoQ10's protective effect against the drug) after amphetamine or methamphetamine exposure, was located.
• At-risk subgroups: None clinically defined; theoretical class-level extrapolation only.

Regulatory status

Not addressed in FDA labeling.

Population evidence

None with amphetamine/dextroamphetamine specifically in the cohort, at any tier. Tier C, class-level, methamphetamine-specific: Klongpanichapak S et al., "Attenuation of cocaine and methamphetamine neurotoxicity by coenzyme Q10," PMID 16733807 (2006). Jameie SB et al., "Coenzyme Q10 reduces expression of apoptotic markers in adult rat nucleus accumbens dopaminergic neurons treated with methamphetamine," PMID 35034284 (2022). Stephans SE et al., "Substrates of energy metabolism attenuate methamphetamine-induced neurotoxicity in striatum," PMID 9681451 (1998).

Mechanism

Named: CoQ10 supports mitochondrial electron-transport-chain function and antioxidant capacity, mitigating dopamine-oxidation-driven mitochondrial toxicity, the same mechanism already established as amphetamine-specific and Tier B in this dossier's Mitochondrial burden entry (PMID 16638611, PMID 11198300). No study located tested CoQ10 with amphetamine itself, as opposed to methamphetamine.

Counter-evidence held on record

Methamphetamine and amphetamine are related but distinct molecules (methamphetamine is N-methylamphetamine); per this project's cohort test, methamphetamine-only evidence is Tier C for amphetamine/dextroamphetamine, not Tier B. This is also a reverse-direction, protective finding, exogenous CoQ10 defending mitochondria against the drug's toxicity, not evidence that amphetamine depletes endogenous CoQ10 (Hard Rule 4). See Overlap map: this entry's classification leans on the same dopamine-oxidation/mitochondrial mechanism as Mitochondrial burden, ATP production, and Oxidative stress, extrapolated from a different drug's literature; do not count it as a fourth independent redox/mitochondrial confirmation.

Why empty

Ungraded requires both no Tier B/C evidence and no circulating claim to rebut. The four entries previously marked ungraded (vitamin B6, vitamin B12/folate, vitamin C, coenzyme Q10) each turned up at least one real, drug-specific or class-level primary source on a dedicated re-search (see those entries above under Graded entries), so each now carries a yellow grade instead. This revision followed the Step 4 thoroughness requirement: separate queries per nutrient, tried against PubMed search-listing pages and, where reachable, consumer sources (Drugs.com, WebMD), rather than the single combined query run in the prior version of this dossier.

What would refill it

A future nutrient or category for this drug would need a genuine multi-channel search (PubMed, Europe PMC, Semantic Scholar, Crossref, OpenAlex, DailyMed/FDA label, and consumer sources) across more than one phrasing, turning up neither Tier B/C evidence nor a circulating claim, before being marked ungraded again.