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A prodrug and its active product can produce different pharmacokinetic findings in the same study. Analytical interference can complicate the comparison further. A historical 2016 lisdexamfetamine experiment shows why both analytes and the specimen’s characteristics belong in the interpretation.

What was the study design?

Forty adults, eight in each of five renal-function groups, received a single oral 30-mg dose of lisdexamfetamine dimesylate. Groups ranged from normal renal function to end-stage renal disease requiring hemodialysis. This was an open-label pharmacokinetic study, not a trial of treatment effectiveness or overdose management.

For participants not requiring dialysis, blood sampling continued for 96 hours. The dialysis group received separate predialysis and postdialysis doses with a 7–14-day washout. Investigators measured plasma lisdexamfetamine, the prodrug, and d-amphetamine, the active product, and examined dialysate recovery.

What happened to active d-amphetamine?

Overall d-amphetamine exposure increased and its half-life lengthened as renal impairment increased, while mean peak concentration decreased. Weight-adjusted apparent clearance in end-stage disease was approximately 50% lower than in normal renal function. These findings concern the tested single-dose conditions.

A lower peak and greater overall exposure are compatible because they summarize different parts of the concentration–time profile. A single plasma value cannot substitute for the serial sampling used to estimate area under the curve or elimination.

Why were prodrug results less straightforward?

Mean lisdexamfetamine peak and exposure measures in mild to severe impairment were not substantially different from normal renal function. In the dialysis group, however, unexpectedly variable lisdexamfetamine results led investigators to identify a sample-related matrix effect.

The assay had been validated using plasma from people whose renal impairment was less severe. Validation had not revealed the interference later encountered in end-stage-disease samples. The authors therefore cautioned that the apparent magnitude of higher prodrug exposure in that group could not be determined accurately.

What does that analytical limitation mean?

Validation is evidence for the matrices actually tested. A specimen can differ from ordinary plasma in ways that alter measurement, even when it has the same general specimen label. An unexpected result may require investigation of the assay as well as the patient’s physiology.

The limitation was analyte-specific in the report. It should not be silently transferred to every d-amphetamine measurement, nor ignored when interpreting lisdexamfetamine. Keeping the two analytical records separate prevents a prodrug finding from being mistaken for active-drug exposure.

Did dialysis remove substantial drug?

Little d-amphetamine was recovered: a mean of 2.63%, with a reported range of 2.18%–3.30%. Lisdexamfetamine recovery was almost absent. “Little” is more precise than claiming that exactly zero active drug was recovered.

These observations came from a small renal-impairment study after the specified dose and dialysis sessions. They do not establish outcomes in overdose, compare every dialysis technique or reconstruct an individual’s exposure history. The paper’s dosing recommendations are historical and are not reproduced here as current prescribing guidance.

What should a forensic interpretation preserve?

Preserve the dose as lisdexamfetamine dimesylate, rather than relabeling 30 mg as 30 mg of d-amphetamine. Identify the measured analyte, plasma or dialysate, sampling interval and renal group. The study illustrates distinct physiological and analytical uncertainties; it does not convert a blood concentration into functional impairment.

Source

A Single-Dose, Open-Label Study of the Pharmacokinetics, Safety, and Tolerability of Lisdexamfetamine Dimesylate in Individuals With Normal and Impaired Renal Function. Therapeutic Drug Monitoring. 2016;38(4):546–555. DOI: 10.1097/FTD.0000000000000296. Full text; bibliographic record.

A clinical syndrome score and a positive drug screen answer different questions. One summarizes signs and symptoms; the other supplies exposure-related information. A 2017 case involving untreated hyperthyroidism and methamphetamine illustrates why neither measurement independently proves what triggered the illness.

What was documented at presentation?

Viswanath and colleagues described a 47-year-old woman with palpitations, shortness of breath and vomiting for approximately 24 hours after reported first-time methamphetamine use. She had untreated hyperthyroidism. Her pulse was 123 beats/minute, blood pressure 120/67 mmHg and temperature 36.4°C. A urine screen was positive for methamphetamine.

Thyroid-stimulating hormone was below 0.004 microunits/mL, and free thyroxine was 4.47 ng/dL against the report’s reference range of 0.70–1.48 ng/dL. The Burch–Wartofsky score was 35. The clinicians treated suspected thyroid storm.

What did the score establish?

The paper described scores of 25–44 as suggestive, rather than using 35 as definitive laboratory proof. The score incorporates clinical features and contains subjective elements. It does not measure methamphetamine concentration or determine whether a particular exposure caused the thyroid disturbance.

The actual observations also deserve precedence over a generic description of thyroid storm. This patient was not febrile at presentation. Omitting the measured temperature and substituting a stereotypical hyperthermic presentation would alter the case.

Why is the pre-existing thyroid disease central?

Untreated hyperthyroidism preceded the reported stimulant exposure. The authors proposed that catecholamine sensitivity and methamphetamine’s stimulant effects could have interacted. That is a plausible interpretation of the sequence, but the patient’s pre-exposure hormone trajectory and the proposed mechanism were not experimentally measured.

A positive urine screen does not fill those gaps. The report supplies no quantified absorbed dose, blood concentration or controlled comparison with an otherwise similar patient who did not use methamphetamine. Temporal coincidence supports considering a contribution; it cannot isolate the contribution.

What happened during treatment?

The patient received several therapies, including propylthiouracil. By day three, clinicians documented a sharp fall in the white-cell count and attributed agranulocytosis to that treatment. Propylthiouracil was stopped. Modified thyroidectomy occurred on day eight, followed by discharge on day ten.

This sequence separates a suspected precipitating exposure from a complication attributed to treatment. Collapsing both into “methamphetamine toxicity” would conceal an important intervening event and change the authors’ account.

Can the surgical outcome establish a general management rule?

No. One patient’s postoperative course cannot compare surgical techniques, quantify their complication rates or establish that a particular sequence prevented intraoperative thyroid storm. The article reports an approach used under unusual constraints; its therapeutic discussion is historical evidence, not a contemporary treatment protocol.

For scientific review, retain three separate levels: the thyroid abnormalities and clinical score, the reported methamphetamine exposure, and the proposed trigger mechanism. The case documents their coexistence and chronology. It does not validate a drug-specific diagnostic test or assign causation from a screen alone.

Source

Viswanath O, Menapace DC, Headley DB. Methamphetamine Use With Subsequent Thyrotoxicosis/Thyroid Storm, Agranulocytosis, and Modified Total Thyroidectomy: A Case Report. Clinical Medicine Insights: Ear, Nose and Throat. 2017;10:1179550617741293. DOI: 10.1177/1179550617741293. Full report; bibliographic record.

Severe muscle injury after methamphetamine use does not establish that methamphetamine was the only cause. A historical 2022 case brought together rapid water intake, a thiazide-containing medicine, seizures, antiretroviral therapy and profound hyponatraemia. Preserving that combination is more informative than reducing the case to a drug-positive label.

What sequence was reported?

A 52-year-old man with HIV and hypertension reported inhaling approximately 0.1 g of methamphetamine. After developing neck discomfort, he drank 6 L of water over about 30 minutes and took three tablets of his usual irbesartan/hydrochlorothiazide medicine. Seizures followed.

Initial serum sodium was 113 mmol/L, creatine kinase 1,979 U/L and creatinine 107 micromol/L. After two days, muscle pain, weakness, dark urine and reduced urine output accompanied a reported creatine kinase of 150,324 U/L. Creatinine subsequently peaked at 632 micromol/L on day four. The patient improved without renal replacement therapy.

Why preserve the serial measurements?

The first creatine-kinase value and the later markedly elevated value describe different times in an evolving illness. An initial result cannot substitute for the later course. Conversely, a later peak should not be presented as though it was measured immediately after the reported inhalation.

Sodium, creatine kinase and creatinine also answer different questions: electrolyte concentration, a marker of muscle injury and a marker used in assessing kidney function. Their parallel trajectories do not make them interchangeable measurements or establish which process started every subsequent change.

Which alternative contributors were present?

The authors considered severe hyponatraemia, methamphetamine exposure, seizure activity and the patient’s antiretroviral regimen. Rapid water intake and thiazide exposure were important parts of the preceding history. These factors were not assigned independently or removed one at a time in an experiment.

The reported methamphetamine amount was a history estimate, not an analytically verified absorbed dose. It provides no blood concentration, product purity or individual susceptibility measurement. Describing it as a small amount cannot by itself exclude a contribution from the drug.

Did the treatment course identify the cause?

No. Management changed as electrolyte disturbance and muscle and kidney injury evolved. Clinical improvement under a sequence of interventions does not quantify each contributor’s causal share. The report is a record of care in one complex presentation, not a comparative test of fluid strategies.

Its title appropriately uses “suspected.” A scientific summary should retain that uncertainty. It should also avoid converting the reported management into a contemporary treatment protocol, because the paper did not compare alternatives or establish a generally applicable regimen.

How should inconsistent units be handled?

The narrative contains some creatinine values labeled in mmol/L, whereas the serial table uses micromol/L. Those units differ by a factor of 1,000. The peak value above follows the table and the accompanying peak description; an apparent unit error should not be reproduced as a plausible physiological measurement.

More broadly, a case report should be checked across its text and tables before using a number in an opinion. Here, the defensible conclusion is that severe hyponatraemia and major muscle injury occurred within a multifactorial exposure and clinical sequence. One patient supplies no incidence estimate, dose threshold or isolated methamphetamine-causation test.

Source

A suspected case of hyponatraemia induced rhabdomyolysis: a case report. BMC Nephrology. 2022;23:180. DOI: 10.1186/s12882-022-02787-7. Full report; bibliographic record.

When an association remains after accounting for a proposed mediator, it is tempting to declare a direct biological effect. A historical HIV cohort shows why that step requires restraint. Measuring medication adherence imperfectly is different from experimentally excluding adherence as an explanation.

Who was studied?

Feelemyer and colleagues analyzed 645 HIV-positive people who injected drugs in Hai Phong, Vietnam, with follow-up over 24 months. Approximately 95% were men. Nearly the entire population injected heroin; fewer than 1% reported injecting methamphetamine. Methamphetamine use was predominantly through smoking, so the cohort label must not be mistaken for its methamphetamine route.

Analysis required reported antiretroviral therapy, adherence data and laboratory viral-load measurements. Recent methamphetamine exposure was self-reported days of use during the preceding 30 days: none, 1–19 days, or at least 20 days. It was not a controlled-dose exposure.

What did viral suppression mean here?

The investigators defined suppression as HIV viral load below 1,000 copies/mL, measured from banked blood samples. About 76% were suppressed at baseline. The threshold is essential: this study’s definition should not be silently replaced with an undetectable result or another clinical cutoff.

During follow-up, recent methamphetamine use was associated with lack of suppression in the adjusted random-effects analysis: odds ratio 1.84, 95% confidence interval 1.06–3.17. That is an odds ratio for the specified outcome, not a direct multiplication of every participant’s probability.

How was adherence measured?

Participants rated adherence over the preceding six months on a 1–10 visual scale. Scores 9–10 were classified as high or complete adherence; 1–8 formed the lower category. This was self-report, rather than continuous observation of ingestion or a drug-concentration measure.

The adherence and exposure windows also differed: six months for adherence versus 30 days for recent methamphetamine use. Their relationship therefore cannot be interpreted as a precisely synchronized day-by-day experiment.

What did the mediation analysis establish?

In this 2020 analysis, self-reported adherence did not statistically explain the methamphetamine–viral-load association. The association remained after the adherence measure was included. That result is specific to the variables, measurement windows and model used.

It does not prove that adherence played no role. A broad self-rating may miss interruptions, timing differences or other medication-taking patterns. Residual association could also reflect unmeasured factors or other pathways. Naming a direct effect in a statistical model does not, by itself, identify a molecular mechanism.

What limits the interpretation?

The authors identified possible underreporting of drug use and adherence difficulties, uncertainty about generalizability, and approximately 16% loss to follow-up. Losses may matter when retention relates to exposure or health outcomes. This selected cohort does not represent every person with HIV or every pattern of methamphetamine use.

The paper discussed biological hypotheses, but did not experimentally test methamphetamine’s effect on antiretroviral metabolism in these participants. It supplies a historical clinical association and a constrained mediation result, not a current treatment recommendation or proof that an individual patient’s virological result was drug-caused.

Source

Feelemyer J and colleagues, DRIVE Study Team. Associations between methamphetamine use and lack of viral suppression among a cohort of HIV-positive persons who inject drugs in Hai Phong, Vietnam. AIDS. 2020;34(13):1875–1882. DOI: 10.1097/QAD.0000000000002680. Full text; bibliographic record.

A large dataset can estimate an association precisely while leaving important exposure details unknown. In a 2024 California pregnancy study, the key measurement was a delivery-record diagnosis code. It was not a standardized methamphetamine dose or a quantitative toxicology result.

What population was examined?

The retrospective cohort linked California vital statistics and hospital discharge records from 2008–2019. It included 4,775,463 singleton pregnancies at 23–42 weeks, of which 18,473 had the selected psychostimulant-use codes. The comparison group contained 4,756,990 pregnancies.

The authors used the label methamphetamine use for ICD-9 codes 304.4 and 305.7 and ICD-10 F15 diagnoses recorded at delivery. Those administrative categories do not provide quantity, route, exact timing or a distinction between episodic use and dependence. Recorded concurrent opioid, cocaine, alcohol or nicotine use was excluded, along with other eligibility restrictions.

What did severe maternal morbidity mean?

It was a composite defined by at least one of a set of serious conditions or procedures. Indicators included acute renal failure, eclampsia, sepsis, ventilation, hysterectomy and blood-product transfusion, among others. It was not a synonym for maternal death, and it did not require every listed complication to occur.

The composite occurred in 858/18,473 coded-exposure pregnancies, or 4.6%, versus 56,172/4,756,990 comparison pregnancies, or 1.2%. The adjusted risk ratio was 3.53, with a 95% confidence interval of 3.29–3.77.

How should the ratio and percentages be read together?

The percentages describe observed frequencies in these selected record groups. The adjusted ratio comes from a regression model accounting for maternal age, prepregnancy body mass index, education, insurance, parity, chronic hypertension and preexisting diabetes.

A ratio of 3.53 is not a 353% chance of morbidity. Nor can the adjusted ratio simply be multiplied by an unrelated patient’s baseline risk to produce a reliable personal forecast. The observed comparison frequency belongs to this cohort, and the adjusted estimate belongs to its model.

Why does the composite require care?

Different components can carry different clinical meanings and mechanisms. An association with the combined endpoint does not establish an identical increase for every component. It also does not identify which event a particular patient will experience.

This distinction matters when explaining research to a client. “More severe maternal morbidity” can be a faithful summary only if the reader understands that the study grouped several diagnoses and procedures together. Replacing that endpoint with death, permanent disability or one named complication would change the claim.

Does the large sample establish causation?

No. Coding may miss use, misclassify exposure or reflect differences in screening and clinical recognition. Excluding recorded polysubstance use does not prove that every remaining exposure was chemically isolated. The authors also identified unmeasured confounding and an inability to reconstruct dose or temporal patterns.

Large numbers reduce some sampling uncertainty; they do not recover information that the records never contained. The result supports a historical population association within the study’s eligibility rules, rather than an experimental demonstration that methamphetamine caused a particular complication.

Source

Prenatal methamphetamine use increases risk of adverse maternal and neonatal outcomes. American Journal of Obstetrics and Gynecology. 2024;231(3):356.e1–356.e15. DOI: 10.1016/j.ajog.2024.05.033. Full text; verified bibliographic record.

A follow-up study can associate a negative drug test with improved heart function without establishing continuous abstinence throughout the interval. That measurement issue is central to a historical methamphetamine-associated heart-failure cohort reported by Bhatia and colleagues.

How was cessation classified?

The retrospective study separated reduced ejection fraction, defined as below 50%, from preserved ejection fraction, defined as at least 50%. Baseline methamphetamine exposure required positive urine toxicology. Cessation meant a negative urine test nearest the end of the initial 12-month follow-up, rather than continuous verified nonuse.

There were 28 methamphetamine-associated reduced-EF patients: 14 classified as continuing use and 14 as cessation. A separate preserved-EF group contained 28 patients, with 15 continuing and 13 classified as cessation. Echocardiographic follow-up extended to one year; later clinical outcomes covered months 12–24.

What improved, and in whom?

In the reduced-EF cessation group, mean absolute EF change was +10.6 percentage points, SD 13.1, with p = 0.009 for change from baseline. The continuing group changed by −1.7 points, SD 12.5, p = 0.616. These are changes in the proportion pumped, not relative percentage increases or measurements of fibrosis disappearing.

Later heart-failure admissions were lower in the cessation group: median 0 per year, interquartile range 0–1, versus 2, interquartile range 1–3, with continuing use; p = 0.039. That comparison had 12 patients per methamphetamine group, fewer than the 14 per group in the EF analysis.

Why does the changing denominator matter?

The pumping and admission results concern different follow-up measurements and available samples. Reporting the initial 28 as though every patient contributed equally to every later outcome hides attrition. A claim about admissions should retain the relevant clinical-outcome denominator.

The study also selected patients with serial echocardiograms. People who died or were lost before providing that sequence were not represented in the same way. Observed improvement among retained patients cannot automatically become a prognosis for all newly presenting patients.

Did preserved-EF patients show the same pattern?

No corresponding significant improvement in echocardiographic measures and clinical outcomes was demonstrated after cessation in the preserved-EF group. Preserved and reduced EF should therefore remain separate evidence categories. Combining them into a single statement that methamphetamine-associated heart failure reversed would omit an important null finding.

Can the urine result establish why improvement occurred?

A negative test near one year cannot reconstruct every exposure between visits. The authors expressly identified this limitation and documented recurrent positive tests during later follow-up in some patients initially classified as cessation.

Medical treatment, medication adherence, access to care and baseline illness may also differ between observational groups. Prescription documentation did not verify actual medication use. The authors’ adjusted clinical analyses were exploratory, with small samples limiting their interpretation.

What is the defensible conclusion?

This cohort documented an encouraging association in selected reduced-EF patients, using a specific toxicological definition of cessation. It did not measure a universal probability of recovery, demonstrate continuous abstinence, or isolate cessation from all accompanying changes. For a scientific opinion, preserve the exposure definition, cardiac phenotype, follow-up window and denominator before discussing reversibility.

Source

Bhatia and colleagues. Clinical and echocardiographic outcomes in heart failure associated with methamphetamine use and cessation. Heart. 2021;107(9):741–747. Published online October 5, 2020. DOI: 10.1136/heartjnl-2020-317635. Full text; bibliographic record.

A paper’s title can be more specific than the toxicological measurement reported in its case narrative. That is a critical reading issue in a 2025 report of bilateral corneal ulcers associated with methamphetamine. The documented eye disease was serious, but the exposure measurement and competing explanations require separate attention.

What eye findings were documented?

Conner and Foutch described a 48-year-old man reporting four weeks of progressive bilateral visual loss. At the initial ophthalmology visit, uncorrected acuity was 20/400 in the right eye and 20/800 in the left, without pinhole improvement. Slit-lamp examination showed central stromal ulcers, measuring approximately 1 mm in the right eye and 4 × 3 mm in the left.

The patient declined corneal cultures because of cost and lack of insurance. Records from an earlier emergency visit documented uncontrolled type 2 diabetes, with fasting glucose reported as 311 mg/dL, bacterial conjunctivitis and recurrent bacterial sepsis. Those findings complicate attribution to a single exposure.

What did the toxicology actually identify?

The records-review section reports a positive screen for amphetamines. It does not provide a drug-specific quantitative methamphetamine result, a confirmatory analytical method, a dose or a verified administration route. The abstract’s description of laboratory-confirmed methamphetamine use should therefore be read alongside the less specific testing detail.

An amphetamine-class result and a confirmed methamphetamine identification are different evidential statements. Without the analytical particulars, a reader cannot independently assess specificity, distinguish possible sources, or convert the result into a concentration at the eye.

Why do missing cultures matter?

The authors considered bacterial, drug-associated and neurotrophic processes, among other possibilities. Without corneal cultures, an organism was not identified from the ulcers. That gap does not prove that the ulcers were sterile, and it does not prove that infection caused them.

Diabetes also remains relevant to the differential assessment. A report that contains a plausible drug-associated pathway alongside another condition affecting corneal health cannot estimate their separate causal contributions from this one patient. Several explanations may coexist rather than compete as mutually exclusive labels.

Did improvement establish the proposed mechanism?

The patient received multiple interventions, including amniotic membranes, bandage contact lenses and combination eye drops. By day 35, the report described resolved ulcers with residual corneal edema. Uncorrected acuity had improved to 20/80+ right and 20/100 left; pinhole values were 20/40+ and 20/60, respectively.

Those are important follow-up observations, but they do not identify which component produced improvement or establish the initial cause. Keeping corrected and uncorrected acuity separate also prevents an apparently larger improvement created by comparing unlike measurements.

Can physical appearance establish methamphetamine exposure?

Skin lesions, dental condition, body habitus and behavior informed the authors’ suspicion. The case does not validate those observations as a diagnostic test. Their sensitivity, specificity and alternative explanations were not measured in a comparison population.

For forensic interpretation, suspicion should remain distinct from exposure identification, and exposure identification should remain distinct from injury causation. A person’s appearance cannot fill in a missing confirmatory laboratory result or demonstrate the mechanism of an ulcer.

What is the case’s defensible contribution?

It documents severe corneal disease in a patient whose records also contained an amphetamine-class screen and substantial comorbidity. Its value lies in the detailed examination, the records review and the unresolved diagnostic questions. As single-patient evidence, it supplies neither a complication rate nor proof that methamphetamine alone produced the observed injury.

Source

Conner A, Foutch BK. Methamphetamine-Associated Corneal Ulcer: Case Report. Reports. 2025;8(3):147. DOI: 10.3390/reports8030147. Publisher full text; PMC full text.

A model can reproduce one set of measurements and still make an unverified prediction for another condition. In amphetamine pharmacokinetics, that distinction is especially important when urine excretion results are used to support a conclusion about plasma exposure. A historical 2020 modeling study made its verification boundaries unusually explicit.

What did the researchers build?

Huang, Czuba and Isoherranen integrated a mechanistic kidney model with a full-body parent–metabolite model for methamphetamine and amphetamine. It represented filtration, secretion and pH-dependent passive reabsorption. This was computational research evaluated against published human data, not a newly conducted randomized pH intervention.

The simulations used a representative physiology and specified tubular pH gradients. Acidic, uncontrolled and alkaline scenarios ended at urine pH values of 5.0, 6.5 and 8.0, respectively. The pH values were model conditions, rather than a description of every participant’s continuously measured renal environment.

What was predicted for amphetamine plasma exposure?

After a modeled oral dose of 11 mg amphetamine base, predicted plasma area under the concentration–time curve from zero to infinity was 361 microgram·hour/L with acidic urine, 692 with uncontrolled urine, and 1,325 with alkaline urine. All three values are simulation outputs.

For acidic and uncontrolled conditions, plasma simulations were compared with historical observations from two people using a twofold acceptance criterion. The investigators had no clinical plasma data for the alkaline-urine condition and therefore did not verify that systemic-exposure prediction.

Was there no human evidence for the alkaline condition?

There was evidence for a different endpoint. Under alkaline conditions, the model predicted a 97% decrease in urinary amphetamine excretion relative to uncontrolled urine pH; the historical observed decrease was 91%. That urinary comparison must remain separate from the unavailable alkaline-condition plasma comparison.

The distinction is substantive. Measuring how much drug leaves in urine is not the same as measuring the complete plasma concentration–time curve. Agreement on one can support the plausibility of a mechanism without directly validating every output that depends on it.

What does a model acceptance criterion mean?

An acceptance rule defines how close predictions must be to selected observations for the investigators’ purpose. A twofold rule is not a statement that the model is exact, and it is not an individual prediction interval. Passing it cannot guarantee that an unknown person’s result will fall within that range.

The small historical verification samples also matter. Comparing many simulated time points with two people’s measurements does not create a large human cohort. The number of plotted values and the number of independent participants describe different strengths of evidence.

Can a urine pH measurement reconstruct a person’s dose?

This study did not validate that use. A representative-physiology simulation with a known oral dose answers a different question from reconstructing an uncertain dose, route and dosing history in a particular person. A single urine sample cannot supply the full renal pH trajectory or every physiological input assumed by the model.

The model likewise did not measure driving impairment or establish a clinical protocol for changing urine pH. Its useful contribution is mechanistic and quantitative: it shows why specimen disposition can depend on a factor that a simple concentration comparison may omit.

How should the finding be reported?

Keep a verification map beside the conclusion: the analyte, urine or plasma endpoint, pH condition, observed sample size and model criterion. Label alkaline-condition amphetamine plasma exposure as a prediction lacking direct clinical verification in this paper. That account preserves both the model’s explanatory value and the limits of its human evidence.

Source

Huang W, Czuba LC, Isoherranen N. Mechanistic PBPK Modeling of Urine pH Effect on Renal and Systemic Disposition of Methamphetamine and Amphetamine. Journal of Pharmacology and Experimental Therapeutics. 2020;373(3):488–501. DOI: 10.1124/jpet.120.264994. Full text; bibliographic record.

Knowing where a prodrug is converted is different from knowing which enzyme performs the conversion. A historical 2014 study of lisdexamfetamine made progress on the first question while leaving the second unresolved. That distinction matters when a pharmacological explanation is presented as an established molecular identity.

What experiment was performed?

Sharman and Pennick studied lisdexamfetamine dimesylate, a prodrug in which d-amphetamine is linked to l-lysine. This was an in-vitro investigation using blood pooled from three healthy male donors, rather than a clinical dosing trial. Blood and prepared fractions were incubated with lisdexamfetamine at 1 microgram/mL, at 37°C, for up to four hours.

The researchers measured intact lisdexamfetamine and released d-amphetamine using liquid chromatography–tandem mass spectrometry. Preparation included plasma, blood-cell lysate, cytosolic extract and a membrane fraction. Other blood cells were not separately removed; the paper’s attribution to red blood cells also relied on earlier research.

What did the fractions show?

Conversion was prominent in whole blood and cytosolic extract. Plasma remained stable over four hours, with d-amphetamine below the reported 10 ng/mL detection limit. In the membrane fraction, there was no detectable loss of intact prodrug, although a small d-amphetamine signal was measured. The authors acknowledged that fraction purity had not been verified.

A sample below a detection limit should retain that qualifier. It is not the same claim as proving that no molecule was present. Likewise, a small product signal in a prepared fraction cannot establish a second biological pathway when contamination between fractions has not been excluded.

Did the inhibitor results identify aminopeptidase B?

No. A protease-inhibitor mixture reduced conversion. Bestatin and EDTA also strongly inhibited d-amphetamine production in cytosolic extract, a pattern consistent with aminopeptidase-like activity. But purified recombinant aminopeptidase B did not generate detectable d-amphetamine from lisdexamfetamine, despite activity against a separate reporter substrate.

The reporter control matters: a negative result with lisdexamfetamine was not simply accompanied by an inactive enzyme preparation. Even so, the experiment did not identify the responsible enzyme. Inferring a class of activity from an inhibitor profile is a narrower conclusion than assigning the reaction to a named protein.

Do pooled donors establish consistency between people?

Pooling can provide material for comparing laboratory conditions, but it removes the donor-by-donor contrast. Three donors contributing to a pool are not three independently characterized conversion curves. Replicate incubations assess repeatability of the prepared material, not the distribution of responses across patients.

The authors also performed no statistical comparisons between measured concentrations in different sample types. The experiment therefore should not be recast as a population study quantifying sex differences, individual variability, anemia effects, or the probability of an unusual clinical response.

Can these laboratory findings date use or establish impairment?

They cannot. Incubating a known starting concentration in blood outside the body differs from oral administration, absorption, distribution and elimination in a living person. A laboratory conversion curve supplies no direct measure of a patient’s attention, driving performance or symptom duration.

The practical lesson is to preserve both analytes and the experimental setting. Lisdexamfetamine disappearance and d-amphetamine appearance describe prodrug activation in the tested preparation. This paper supports a cytosolic site and a constrained enzyme hypothesis; it does not provide an individual dosing recommendation or a forensic time-since-use calculator.

Source

Sharman J, Pennick M. Lisdexamfetamine prodrug activation by peptidase-mediated hydrolysis in the cytosol of red blood cells. Neuropsychiatric Disease and Treatment. 2014;10:2275–2280. DOI: 10.2147/NDT.S70382. Full text; bibliographic record.

A positive drug screen, an abnormal chest scan and a negative contrast-swallow study are not interchangeable evidence. Each addresses a different question. A historical 2024 case of pneumomediastinum after reported methamphetamine vapor inhalation shows why the final account should preserve those distinctions.

What happened in the reported patient?

Shahnazi and colleagues described a 25-year-old man with a history of polysubstance use who presented after a reported nine-day methamphetamine binge. He developed worsening chest pain and breathlessness. Examination identified palpable crepitation around the neck and right upper back, and radiography showed soft-tissue and mediastinal air.

Computed tomography demonstrated a moderate volume of mediastinal air extending toward the lower neck and right chest wall. It did not show pleural separation suggesting pneumothorax. Repeated vomiting before admission raised concern for an esophageal rupture, so a Gastrografin esophagogram was performed on day two. No contrast leak was demonstrated. Symptoms improved without surgery, and discharge occurred on day three.

Why separate pneumomediastinum from pneumothorax?

The location of air is central to the finding. Air in the mediastinum and surrounding soft tissues does not automatically establish air in the pleural space. The CT description is therefore more informative than a broad statement that the patient had a drug-related “collapsed lung.”

This also illustrates how to handle inconsistent wording within a paper. Although the introduction refers to pneumothorax as well as pneumomediastinum, the detailed case description expressly reports no CT evidence of pleural separation. An evidence-based summary should follow the actual reported imaging rather than silently add a second diagnosis.

What did the negative esophagogram mean?

It addressed a plausible competing explanation prompted by the vomiting history. The authors interpreted the negative study as excluding Boerhaave’s syndrome in their clinical assessment. The measured observation was that contrast leakage was not demonstrated in this patient at that examination.

That distinction prevents two opposite errors. The absence of demonstrated leakage should not disappear from the account, because it affected the authors’ interpretation. But it should not become a general rule that every future patient with vomiting and mediastinal air has no esophageal injury. A single case cannot validate a diagnostic pathway or establish a test’s sensitivity.

Did toxicology identify the cause of the air leak?

The report describes a positive urine methamphetamine screen and an inhalation history. It supplies no quantified methamphetamine concentration or controlled dose. A urine result documents a toxicological finding; it does not show the physical sequence that produced mediastinal air.

Pressure changes during inhalation and vomiting are mechanistic possibilities discussed in the report. Their individual contributions were not measured. The history of polysubstance use also belongs in the interpretation rather than being removed to create an apparently isolated methamphetamine exposure.

What can this case contribute to a forensic review?

The strongest contribution is the sequence of objective observations: soft-tissue crepitation, radiographic air, CT localization and a contrast study without a demonstrated leak. Improvement without surgery describes this patient’s course. It does not prove that similar presentations are benign, quantify complication rates, or establish a concentration threshold for lung injury.

For a case-based opinion, separate the confirmed anatomical finding, the reported exposure and the proposed mechanism. That structure preserves the report’s clinical value while avoiding a causal conclusion stronger than the evidence.

Source

Shahnazi A, Bayrakdar K, Cortorreal P, Burmaster K, Junko G. A 25-Year-Old Man with a History of Substance Abuse Presenting with Pneumomediastinum Due to Methamphetamine Vapor Inhalation. American Journal of Case Reports. 2024;25:e941509. DOI: 10.12659/AJCR.941509. Publisher full text; PMC full text.