Author: toxlaw

A behavioral trial can improve a health outcome without demonstrating improvement on every drug-use measure. The historical ARTEMIS trial is an example: its HIV viral-load findings, self-reported stimulant-use findings and urine results answered different questions.

What comparison was randomized?

Carrico and colleagues randomized 110 sexual minority men living with HIV who had biologically confirmed recent methamphetamine use: 55 to five positive-affect intervention sessions and 55 to an attention-control condition. Both groups received three months of community-based contingency management, including incentives for stimulant abstinence.

The experimental contrast was therefore the added intervention versus the attention control on that shared background. It was not positive-affect training alone versus no care, nor a comparison assigning participants to take or stop methamphetamine.

What happened to HIV outcomes?

The intervention group had lower log10 HIV viral load at six, twelve and fifteen months. Risk of at least one unsuppressed measurement, defined as HIV RNA of at least 200 copies/mL, was lower: risk ratio 0.33, 95% confidence interval 0.15–0.69.

That endpoint concerns one or more qualifying viral-load measurements over follow-up. It is not a 67-percentage-point reduction in an individual’s probability, a measure of methamphetamine abstinence or proof of a particular behavioral mechanism.

Did urine testing tell the same story?

There were no significant between-group differences in the proportion with a reactive urine stimulant result at each follow-up assessment. For at least one reactive specimen over fifteen months, the risk ratio was 0.80, 95% interval 0.63–1.02, p = 0.056. This result did not meet the study’s significance criterion.

The endpoint concerned stimulant-reactive toxicology, rather than a quantified methamphetamine dose or a continuous record of abstinence. A favorable HIV outcome cannot be substituted for that laboratory drug-use outcome, and a non-significant urine result should not erase the viral-load finding.

Which other findings require separation?

The investigators reported decreases in self-reported stimulant-use frequency at selected follow-ups. However, the group-by-time test for methamphetamine craving was not significant, p = 0.100, and the corresponding CD4-cell analysis was also non-significant, p = 0.584.

These results show why a broad statement that the intervention improved “methamphetamine outcomes” is insufficient. A reader needs to know whether the claim concerns self-report, urine reactivity, craving, viral load or immune-cell count. Different endpoints can change differently.

How do selection and follow-up affect interpretation?

Of 136 eligible consenting participants, 110 completed a run-in and were randomized. That process selected people able to engage with several preliminary visits. Follow-up retention fell to 71% at fifteen months, and the viral-load table contained 74 measurements at that time, rather than results from all 110 randomized participants.

The study also took place in a well-resourced San Francisco setting and included only sexual minority men with HIV who used methamphetamine. The authors identified the need for broader effectiveness research and more objective assessment of antiretroviral adherence. Their proposed pathways were not established merely because several outcomes changed together.

What is the defensible conclusion?

This 2019 phase II trial supports a specific added behavioral intervention within an incentive-based program for a selected population. It does not establish universal abstinence, identify which component caused each benefit or provide current treatment instructions. Its scientific value is strongest when the positive primary result remains beside the null and uncertain secondary findings.

Source

Carrico AW and colleagues. Randomized controlled trial of a positive affect intervention to reduce HIV viral load among sexual minority men who use methamphetamine. Journal of the International AIDS Society. 2019;22(12):e25436. DOI: 10.1002/jia2.25436. Full text; bibliographic record.

A change in a probe drug’s peak concentration is not automatically evidence that an enzyme was inhibited or induced. A historical 2015 lisdexamfetamine interaction study examined several probes and showed why peak, exposure area and administration route must remain separate.

What was administered?

Thirty healthy adults entered a randomized, open-label, two-period crossover study; 29 completed it. Each participant received a four-drug Cooperstown cocktail alone and with a single oral 70-mg dose of lisdexamfetamine dimesylate, separated by a seven-day washout.

Caffeine 200 mg, dextromethorphan 30 mg and omeprazole 40 mg were given orally. Midazolam 0.025 mg/kg was given intravenously. Blood sampling continued for 72 hours. The probes were selected to examine CYP1A2, CYP2D6, CYP2C19 and CYP3A-related disposition under these conditions.

What happened to omeprazole?

Its geometric least-squares mean peak plasma concentration was 677.9 ng/mL without lisdexamfetamine and 466.9 ng/mL with it. In contrast, area under the concentration–time curve extrapolated to infinity was 1,428 versus 1,499 ng·h/mL. These are geometric model estimates, distinct from the arithmetic means also tabulated in the paper.

A lower peak with a similar exposure area can reflect a change in the shape or timing of the concentration curve. It does not necessarily mean less drug reached the systemic circulation overall. Nor does the peak alone distinguish altered absorption from altered metabolism.

Did every endpoint meet the same comparison criterion?

No. The authors assessed geometric mean ratios and 90% confidence intervals using a 0.80–1.25 bioequivalence range. Omeprazole and dextromethorphan peak endpoints were exceptions to the otherwise generally similar exposure comparisons. Omitting those exceptions would overstate the uniformity of the results.

The authors interpreted the exposure-area findings as showing no alteration of CYP1A2, CYP2D6 or CYP3A activity under the tested conditions. For omeprazole and CYP2C19, they left an enzyme-versus-absorption explanation open. A research summary should preserve that distinction rather than announce that every CYP pathway was definitively unaffected.

Why is the intravenous route important?

The midazolam probe bypassed oral absorption. Its findings cannot be treated as an experiment on every process affecting an orally administered CYP3A substrate. The route is part of the experimental question, not a detail to remove when generalizing the result.

Similarly, this study examined how lisdexamfetamine affected the probes. It was not a direct test of how a strong inhibitor of a metabolic pathway would affect amphetamine exposure. Reversing the direction of an interaction question requires additional evidence.

What does the experiment leave unresolved?

The participants were healthy, doses were given once and the sample was small. Chronic coadministration, different probe doses, disease states and complex prescribing histories were not reproduced. The absence of serious or severe treatment-emergent events in this short experiment cannot establish long-term safety.

For toxicological interpretation, identify the administered prodrug salt, the measured probe and metabolite, route, plasma endpoint and statistical comparison. The study supplies a constrained pharmacokinetic result. It does not establish equivalent clinical effects, rule out every interaction or convert a concentration into an impairment measure.

Source

Ermer J, Corcoran M, Martin P. Lisdexamfetamine dimesylate effects on cytochrome P450 substrate pharmacokinetics in healthy adults. Drugs in R&D. 2015;15(2):175–185. DOI: 10.1007/s40268-015-0090-z. Full article and complete title; bibliographic record.

A negative urine test and a positive hair test need not answer the same exposure question. A 2013 study of children referred after suspected household methamphetamine exposure compared three biological matrices and illustrates why the specimen, analytical threshold and available denominator belong beside every result.

Who was examined, and which specimens were available?

Castaneto and colleagues studied 91 children referred for medical and forensic evaluation. All three matrices were available for 67. Within that complete-specimen subgroup, 12 were negative in every matrix, 41 were positive in one, 12 in two and two in all three. These counts concerned any qualifying target analyte, not methamphetamine alone.

The research panel included methamphetamine, amphetamine, MDMA, MDA and MDEA. Urine and oral fluid were analyzed by gas chromatography–mass spectrometry; hair was analyzed by liquid chromatography–tandem mass spectrometry. This was an observational detection study, not controlled administration to children.

Why do the analytical limits matter?

The study’s limits of quantification were 25 ng/mL for urine and 15 ng/mL for oral fluid. Hair limits differed by analyte: methamphetamine, MDMA and MDEA at 0.1 ng/mg, amphetamine at 0.025 ng/mg and MDA at 0.02 ng/mg. Results at or above the applicable limit were counted as positive.

The hair denominator measures mass per mass; urine and oral-fluid results measure mass per volume. Comparing the numerical values alone cannot establish that one assay was a specified number of times more sensitive. The matrices and their incorporation and elimination processes differ.

What did discordant specimens show?

All five positive oral-fluid specimens and 18 of the 19 positive urine specimens also had positive hair findings. Hair therefore added exposure information that the shorter-window specimens often did not show. That is a finding about this selected study population and its methods, rather than a universal diagnostic-performance estimate.

A negative result means the specified targets were not quantified at the method’s reporting threshold in that specimen at collection. It cannot establish that exposure never occurred, and it cannot reconstruct what a different specimen would have shown at an earlier time.

Did washing hair prove ingestion?

The laboratory washed the hair before analysis. That procedure is relevant to contamination assessment, but it does not by itself identify the route or absorbed dose. The authors discussed environmental contact, possible ingestion and adolescent self-administration as explanations requiring consideration.

De-identification also limited detailed age-based interpretation. The study could not fully distinguish accidental or environmental exposure from self-administration among older children. A scientifically careful account should retain that limitation rather than assign one exposure history to every positive sample.

Can a hair result date a specific event?

Not from this study alone. The investigators collected proximal hair segments, but variability in children’s hair growth and other biological factors complicates calendar interpretation. A positive segment cannot automatically identify a particular day, household incident or person responsible for the exposure.

Likewise, detection is not a measurement of clinical injury, impairment or the amount administered. Those questions require other evidence. The useful contribution here is the side-by-side specimen comparison and the demonstration that a single negative matrix could leave important exposure questions unresolved.

Source

Castaneto MS and colleagues. Identifying methamphetamine exposure in children. Therapeutic Drug Monitoring. 2013;35(6):823–830. DOI: 10.1097/FTD.0b013e31829685b2. Full text; bibliographic record.

Hundreds of blood samples can describe individual concentration curves in detail without creating a large patient population. A case series published online in 2024, with a 2025 issue date, illustrates that distinction in research on ADHD medicines after bariatric surgery.

How many patients contributed the samples?

Krabseth and colleagues analyzed 409 samples from eight patients: four taking lisdexamfetamine, one dexamphetamine, one methylphenidate and two atomoxetine. Five underwent sleeve gastrectomy and three Roux-en-Y gastric bypass. The central amphetamine finding concerned the four prodrug-treated patients, rather than all eight participants or 409 independent people.

Serial serum measurements covered 24 hours before surgery and at one, six and twelve months afterward. For lisdexamfetamine, the measured analyte was active dexamphetamine, not the intact prodrug. The primary endpoint was change in area under the serum concentration–time curve over 0–24 hours.

What exposure patterns were observed?

Dexamphetamine exposure increased after surgery in the four lisdexamfetamine patients. The authors described increases of roughly 50%–100% in two and approximately 30% in the other two. Peak concentrations also increased. There was no clear-cut shortening of time to peak, and reliable timing data were limited by twice-daily dosing in some patients.

No corresponding increase in exposure area was observed in the one participant taking dexamphetamine directly. That single observation is an important contrast, but it cannot establish a reliable difference between formulations or identify a prodrug-specific mechanism.

Were the doses fixed?

The four lisdexamfetamine regimens began at 100 mg once daily, 30 mg twice daily, 50 mg once daily and 30 mg once daily. The 50-mg regimen increased to 60 mg at twelve months. Three of these patients underwent sleeve gastrectomy and one gastric bypass.

When daily doses changed, the investigators adjusted concentrations to the main dose for that patient before calculation, assuming linear pharmacokinetics. The resulting comparisons therefore included a modeling assumption. They should not be described as entirely unadjusted observations after identical doses at every visit. The reported regimens are study histories, not prescribing guidance.

Did surgery itself cause the increase?

The longitudinal design compared each person with their own preoperative profile. That reduces some between-person differences, but surgery was accompanied by weight loss and changes in body composition. There was no comparison group losing weight through other means.

The authors could not distinguish the operation’s effects from those accompanying changes. They discussed absorption and elimination hypotheses, but did not experimentally isolate a transporter mechanism or measure a causal urinary-pH pathway in these patients.

What can repeated sampling establish?

Repeated measurements help estimate peak concentration, timing and exposure area for a particular observation period. They do not supply independent replications of surgery in new people. With four lisdexamfetamine patients, a large-looking laboratory workload cannot support a precise population effect estimate.

The investigators accordingly presented descriptive statistics rather than a definitive statistical comparison for each drug. The approximate percentage changes should remain individual observations, without an invented confidence interval or claim of a universally doubled exposure.

What is useful for a toxicology review?

The study challenges an automatic assumption that bariatric surgery must reduce oral-drug exposure. It does not establish that exposure always rises, specify an individual’s postoperative dose, or connect serum changes directly to impairment. A case-specific review should retain the drug formulation, actual dosing schedule, serum analyte, operation type, time since surgery and dose-normalization method.

Source

Krabseth HM, Strømmen M, Helland A, Spigset O. Effect of bariatric surgery on the pharmacokinetics of drugs used for attention-deficit hyperactivity disorder—A case series. Basic & Clinical Pharmacology & Toxicology. 2025;136(1):e14099. Published online November 4, 2024. DOI: 10.1111/bcpt.14099. Full text; bibliographic record.

A combination can leave measured drug exposure largely unchanged while producing different physiological responses. A 2013 lisdexamfetamine–venlafaxine study illustrates why a finding of pharmacokinetic equivalence should not be shortened to “no interaction.”

What combination was studied?

Ermer and colleagues enrolled 80 healthy adults aged 18–45; 77 entered the pharmacokinetic and safety analyses. This was an open-label investigation with randomization to two treatment sequences. Each sequence began with one drug alone, followed by coadministration.

Oral lisdexamfetamine dimesylate was titrated through 30, 50 and 70 mg/day, while venlafaxine extended-release was titrated through 75, 150 and 225 mg/day. Each step lasted five days. Combination treatment occupied days 16–30, with final daily doses of 70 mg lisdexamfetamine and 225 mg venlafaxine extended-release. These describe the historical protocol, not a dosing recommendation.

What did the plasma measurements show?

The investigators measured the prodrug, active d-amphetamine, venlafaxine and O-desmethylvenlafaxine. In Table 3, combination-to-alone ratios for d-amphetamine were 0.967 for peak concentration, with a 90% confidence interval of 0.821–1.139, and 0.95 for exposure over the sampled dosing interval, with an interval of 0.806–1.121. Both met the prespecified 0.80–1.25 bioequivalence criterion.

Venlafaxine exposure increased and its metabolite exposure decreased in the comparison, while their combined measure met the equivalence criterion. A statement about the combined analytes should therefore not be substituted for a statement that neither component changed.

Did cardiovascular observations remain the same?

No. The largest mean pulse increases were approximately 9–13 beats/minute during single-drug treatment and 18–21 during combination treatment across the two sequences. Maximum mean systolic-pressure increases were approximately 4–7 mmHg alone and 13–14 mmHg combined.

These are maxima of group mean changes under a scheduled observation protocol. They are not individual patient ranges, a frequency of adverse reactions, or estimates of long-term cardiovascular events. The study reported no discontinuation because of a vital-sign increase.

Why does equivalence not settle the physiological question?

A concentration–time comparison describes pharmacokinetics. Pulse and pressure are separate outcomes. Similar active-amphetamine exposure does not logically require identical responses when a second active medicine is present.

The equivalence test also applies to specified endpoints and confidence limits. It does not prove identical concentrations at every moment, identical effects in every participant, or absence of every possible interaction. Extending it to those claims changes the question the experiment answered.

How should the serious event be placed in the timeline?

One participant experienced presyncope during day-five lisdexamfetamine titration at 30 mg/day and discontinued. That occurred before combination treatment. Assigning the event to coadministration merely because it appeared in a combination-study report would misstate its chronology.

What limits clinical or forensic interpretation?

The sample consisted mainly of healthy white men, and exposure was short term. Treatment proceeded from a single drug to the combination within each sequence. The experiment did not establish long-term safety in people with psychiatric or medical comorbidity, and it did not measure driving impairment.

A faithful conclusion preserves both findings: active-amphetamine exposure met the study’s equivalence rule, and observed vital-sign changes were larger during coadministration. Neither finding should erase the other or become an individual causal opinion without the person’s actual clinical and exposure record.

Source

Ermer J and colleagues. Lisdexamfetamine dimesylate and venlafaxine extended-release pharmacokinetics, alone and combined, in healthy adults. Clinical Drug Investigation. 2013;33(4):243–254. DOI: 10.1007/s40261-013-0073-1. Full article and complete title; bibliographic record.

A lower concentration of a prodrug does not necessarily mean less exposure to its active product. A historical 2016 crossover study of lisdexamfetamine provides a direct example: the prodrug and d-amphetamine gave different bioequivalence results after capsule contents were mixed with orange juice or yogurt.

What administration conditions were compared?

Thirty healthy adults entered an open-label, randomized, three-period crossover study. Each treatment used a 70-mg lisdexamfetamine dimesylate capsule: swallowed intact with water, or with its contents mixed into four ounces of orange juice or yogurt. Treatment periods had seven-day washouts, and serial blood sampling extended to 96 hours.

Participants followed controlled fasting and ingestion schedules. All 30 entered the pharmacokinetic analysis set; one withdrew after dosing in the third period. The study did not administer 70 mg of d-amphetamine: the stated dose was the prodrug salt.

What did active d-amphetamine show?

The prespecified criterion required the 90% confidence interval for a geometric mean ratio to fall within 0.80–1.25. Peak d-amphetamine concentration and both exposure-area measures met that criterion for orange juice and yogurt relative to the intact capsule.

For example, the d-amphetamine exposure-area ratio extrapolated to infinity was 0.986 with orange juice, 90% interval 0.955–1.019, and 0.945 with yogurt, interval 0.915–0.976. Those are relative pharmacokinetic estimates, not concentrations in ng/mL or percentages of a clinical response.

What did the intact prodrug show?

Lisdexamfetamine itself gave a different result. With orange juice, its peak-concentration ratio was 0.641, 90% interval 0.582–0.707, and its extrapolated exposure-area ratio was 0.716, interval 0.647–0.792. Both intervals fell below the acceptance range. With yogurt, the prodrug peak interval also extended below the lower boundary.

Relabeling these prodrug findings as reduced active-amphetamine exposure would reverse the study’s central distinction. The identity of the measured compound is therefore essential, even when both results come from the same blood draw and administration.

Does bioequivalence mean identical curves?

No. It means the specified intervals satisfied the study’s predefined comparison rule for the tested endpoints. The yogurt d-amphetamine exposure estimate illustrates the point: its interval was below a ratio of 1 but remained inside the accepted range. Numerical difference and failure of a bioequivalence criterion are different statements.

These are group comparisons under controlled conditions. They do not guarantee identical concentrations at every time point for every individual, and the 90% interval is not an individual’s prediction interval.

What limits the practical interpretation?

The experiment involved healthy adults, a single dose and two specific mixing vehicles. The authors identified uncertainty about lower doses and other foods or liquids. It was not a trial comparing symptom control, driving ability or long-term safety across administration methods.

Reported adverse events were mild, but the small single-dose sample cannot establish the absence of uncommon or delayed harms. Nor does the experiment support attributing an unusual individual concentration solely to what the capsule was mixed with.

What should be preserved in a toxicology account?

Identify the administered salt, the measured analyte, the specimen, the endpoint and the comparison rule. This study supports a constrained pharmacokinetic conclusion about active d-amphetamine under its tested conditions. It does not supply a dosing instruction or a rule for converting prodrug concentrations into impairment.

Source

Ermer J, Corcoran M, Lasseter K, Martin PT. Study of lisdexamfetamine and d-amphetamine relative bioavailability after mixing capsule contents with food or drink. Therapeutic Drug Monitoring. 2016;38(6):769–776. DOI: 10.1097/FTD.0000000000000343. Full article with complete title; bibliographic record.

Agreement between a person’s account and urine testing depends on what each measurement covers. A historical validation analysis of methamphetamine self-report illustrates both the value of a short recall window and the danger of turning disagreement into a claim about honesty.

What was the study unit?

Rowe and colleagues analyzed 327 visits from 90 adults enrolled in a pharmacotherapy trial. This was a secondary validation analysis within a randomized trial, not an experiment randomly assigning people to give accurate or inaccurate accounts. Individuals contributed up to four monthly observations.

Self-report came from audio computer-assisted interviews. Recent use was defined as any use during the preceding three days. Weekly urine samples were screened with VERDICT-II assays. The reference was urine screening under the study’s procedures, not continuously observed ingestion.

What agreement was found?

For three-day self-report compared with urine toxicology, sensitivity was 86.7%, 95% confidence interval 81.4%–91.4%; specificity was 85.3%, interval 77.7%–91.3%. Positive predictive value was 91.5%, interval 86.9%–94.8%, and negative predictive value was 78.0%, interval 69.4%–86.1%. Kappa was 0.71.

Those measures answer different conditional questions. Sensitivity concerns reports among urine-positive visits. Negative predictive value concerns urine results among visits with a report of no recent use. Neither is simply the percentage of people who tell the truth.

Why do repeated visits matter?

Four observations from one person are not equivalent to observations from four independent people. The investigators accounted for repeated observations through participant-level resampling for relevant confidence intervals and longitudinal regression methods.

Calling the sample “327 methamphetamine users” would exaggerate its breadth. The visit count increases information about repeated reporting, while the 90-person denominator defines the number of individuals represented. Both numbers belong in the account.

Did a longer recall window give the same result?

For reports of no use over the longer interval between monthly interviews, negative predictive value was 70.6%, with a wide 95% interval of 48.0%–85.7%. That analysis used intervening weekly urine results and different eligibility rules, so it was not an identical test with only one variable changed.

Weekly sampling also left gaps between urine detection opportunities. A set of negative weekly results could not verify every day of the month. A longer self-report interval and intermittent biological testing therefore require careful temporal alignment.

Can discordance establish dishonesty?

No. Recall, interpretation of questions, assay characteristics, exposure timing and detection windows can all matter. This study measured correspondence between two operational definitions; it did not adjudicate each participant’s intent.

The study population was also selected. Entry required acknowledged methamphetamine use and a positive urine test, and participants knew urine testing would occur. The authors identified these conditions as limits on generalizing the findings to other settings.

What is the useful conclusion?

Recent self-report showed substantial agreement with urine screening in this treatment-research setting. Validity differed across recall periods, follow-up and some participant characteristics, but those group associations cannot diagnose an individual’s credibility. For scientific or forensic use, preserve the person-versus-visit denominator, the recall window and the actual biological reference before assigning meaning to agreement or disagreement.

Source

Rowe C, Vittinghoff E, Colfax G, Coffin PO, Santos GM. Correlates of Validity of Self-Reported Methamphetamine Use among a Sample of Dependent Adults. Substance Use & Misuse. 2018;53(10):1742–1755. DOI: 10.1080/10826084.2018.1432649. Full text; bibliographic record.

A medication can affect cigarette smoking without demonstrating benefit for methamphetamine dependence. A historical phase II trial of varenicline tested those outcomes separately. Keeping them separate prevents a positive secondary finding from replacing negative primary findings.

What treatment was tested?

Briones and colleagues randomized 52 treatment-seeking adults with methamphetamine dependence to varenicline, 27 participants, or placebo, 25. The target dose was oral varenicline 1 mg twice daily after titration. Both groups were offered weekly individual cognitive behavioral therapy during the nine-week medication phase.

The protocol also included an inpatient abstinence-initiation period. Participants provided urine at frequent clinic visits. Missing specimens were treated as methamphetamine-positive for the primary analyses. Twenty-six participants completed the study and 26 dropped out.

What were the primary outcomes?

End-of-treatment abstinence required methamphetamine-negative urine specimens during weeks eight and nine. It was achieved by 4/27 varenicline participants, 15%, and 5/25 placebo participants, 20%; p = 0.9.

The treatment effectiveness score counted methamphetamine-negative urine specimens across treatment. Mean scores were 8.6 with varenicline and 8.1 with placebo. Treatment was not a significant predictor of this count: incidence rate ratio 1.01, 95% confidence interval 0.39–2.70, p = 0.9.

Why preserve the missing-specimen rule?

The analysis did not treat an absent sample as laboratory-confirmed abstinence. Its rule combined observed positive results with missing visits for outcome purposes. A report should therefore distinguish a convention used to calculate treatment success from an actual analytical detection.

Substantial dropout also matters. The assigned-group denominators keep the randomized comparison visible, whereas reporting only completers could answer a different, selected-sample question. Neither approach should be substituted without explanation.

What happened to cigarette smoking?

The investigators observed a greater decline in reported cigarette consumption with varenicline than placebo. That finding concerned a different substance and endpoint. It did not demonstrate that methamphetamine urine outcomes improved, nor did it validate the proposed biological mechanisms for treating methamphetamine dependence.

This is a useful example of why “the medication worked” is incomplete. A meaningful claim must identify the outcome, comparison and time window. A secondary benefit can coexist with failure to demonstrate the primary benefit being tested.

Did adherence explain away the null findings?

The study measured urinary varenicline for adherence analysis. Some associations suggested better outcomes with higher medication exposure, but they were not statistically conclusive. Adherence was not randomly assigned, so those analyses could not replace the medication-versus-placebo comparison.

The authors also calculated Bayes factors for the primary hypotheses. They leaned toward no treatment difference but did not cross the paper’s stated threshold for persuasive evidence. This is more nuanced than declaring proof that the treatments were identical or that every possible benefit was excluded.

How should this historical trial be used?

It did not demonstrate improved methamphetamine abstinence at the tested dose in this selected population. Its sample size, dropout, accompanying therapy and uncertainty constrain broader conclusions. It supplies evidence about a particular trial regimen, not a current prescribing recommendation or an estimate of benefit for an individual patient.

Source

Briones M and colleagues. Varenicline treatment for methamphetamine dependence: A randomized, double-blind phase II clinical trial. Drug and Alcohol Dependence. 2018;189:30–36. DOI: 10.1016/j.drugalcdep.2018.04.023. Full text.

Atrial fibrillation and reduced ventricular pumping are different cardiac findings. A lower frequency of one does not exclude the other as a possible contributor to embolic stroke. A 2024 retrospective study examined both in patients already admitted with acute ischemic stroke.

Who was included?

Lee and colleagues reviewed admissions at one medical center during 2019–2022. Of 973 consecutive patients, 35 were excluded for incomplete data, absent echocardiography, cocaine use or loss to follow-up, leaving 938. Forty-six were classified as having methamphetamine use; 892 were in the comparison group.

Classification used history or a urine drug screen. The methods identify the EMIT II Plus Amphetamines Assay, a class screen, rather than reporting quantitative confirmatory methamphetamine concentrations. Cardiomyopathy was operationally defined as left ventricular ejection fraction of 45% or less on the clinical echocardiography report.

What cardiac differences were observed?

Cardiomyopathy was found in 14/46 methamphetamine-classified patients, 30.4%, versus 125/892 comparison patients, 14.0%. Recorded atrial fibrillation showed the opposite pattern: 8.7% versus 33.4%. The methamphetamine group was substantially younger, with mean age 52.8 versus 69.7 years.

These percentages belong to people admitted with ischemic stroke. They are not estimates of cardiomyopathy or stroke frequency among all people who use methamphetamine. Starting with a diseased population changes the question and the denominator.

What did the regression estimate describe?

Methamphetamine-associated cardiomyopathy was associated with cardioembolic stroke classification in the adjusted model: odds ratio 1.79, 95% confidence interval 1.04–3.06. The modeled factor combined the exposure classification with the cardiac finding. It should not be relabeled as an odds ratio for all methamphetamine use causing any stroke.

An association with a classified stroke mechanism also differs from observing a drug-to-thrombus-to-brain sequence. The study did not experimentally establish that temporal pathway in each patient.

Why did poorer pumping coexist with better function?

Among patients with cardiomyopathy, the methamphetamine group had lower mean ejection fraction but more favorable three-month functional outcomes: modified Rankin score 0–2 in 9/14, versus 44/125 in the comparison cardiac group. The authors considered younger age and fewer comorbidities a likely explanation.

The corresponding three-month mortality difference was not statistically significant, p = 0.13. Better observed functional outcome therefore should not become a claim that methamphetamine was protective or that mortality was demonstrably lower.

What remains uncertain?

The investigators lacked detailed route, frequency and duration of methamphetamine use, and follow-up ended at three months. The retrospective design could not exclude alcohol use and other cardiac comorbidity as confounding influences or establish causation. Exposure classification itself also requires the distinction between history, screening and analytical confirmation.

The practical contribution is a reminder to keep cardiac phenotypes separate. Less recorded atrial fibrillation did not eliminate a cardiomyopathy-associated embolic pattern in this selected cohort. It did not create a diagnostic shortcut from a positive drug screen to the cause of an individual stroke.

Source

Lee SJ and colleagues. Cardiomyopathy in Patients With Acute Ischemic Stroke and Methamphetamine Use: Relevance for Cardioembolic Stroke and Outcome. Journal of the American Heart Association. 2024;13:e033667. DOI: 10.1161/JAHA.123.033667. Full text; bibliographic record.

A database marker can identify records worth reviewing without being a definitive methamphetamine test. A 2025 study from an integrated safety-net health system examined that distinction by comparing combinations of diagnosis, laboratory, assessment and clinical-note markers with manual chart review.

What did the study count?

Among 510,885 patients seen in 2021, investigators identified 29,602 with at least one selected marker during 2018–2021. They sampled 814 charts for review, representing 713 unique patients, across eight marker-combination groups. The 814 reviews must not be presented as 814 independent people.

The markers included nonspecific stimulant diagnosis codes, clinical impressions, hospital urine screens, more specific outsourced testing, self-reported assessments and mentions in clinical notes. Extracting a structured code required less computational effort than searching and cleaning free text.

How much did predictive value vary?

Positive predictive values ranged from 0.21 for the hospital urine-screen-only group to 1.00 for a group combining clinical impression with a positive assessment or the more specific behavioral-health urine testing. Four groups exceeded 0.70. These values describe selected electronic definitions compared with the study’s chart-review reference.

The 0.21 result was not an estimate that 79% of the laboratory assays malfunctioned. A class-positive amphetamine screen can correspond to a prescribed amphetamine without establishing methamphetamine use. The record-classification question was narrower and drug-specific.

Does a predictive value of 1.00 mean perfect detection?

No. Positive predictive value asks how often a selected positive definition corresponds to the reference classification. It does not, by itself, establish how many people with methamphetamine use were missed, which would require a sensitivity assessment with an appropriate denominator.

The result also belongs to the sampled records and local documentation practices. A definition that performs well in one health system may behave differently where prescribing, prevalence, coding and assessment practices differ. The point estimate should not become a guarantee for every future record.

Was chart review a gold standard?

The authors expressly identified the absence of a gold standard for retrospective identification. Reviewers applied a standardized process, but the underlying records could not always establish intensity of use. When a clinician suspected use but the patient denied it, the investigators deferred to the patient report for classification.

That is a transparent operational choice rather than proof that either suspicion or denial was invariably correct. The authors used a probabilistic approach in recognition of the reference’s uncertainty. A forensic summary should preserve the reference process instead of describing every algorithm discrepancy as a known falsehood.

Why is free text particularly difficult?

The researchers searched notes for methamphetamine-related terms while removing negations, irrelevant matches and template material. A word can refer to current use, remote use, a family member, a denied history or a test order. Finding the word is not equivalent to establishing current personal exposure.

More elaborate extraction also does not automatically mean better performance. The study compared practical accuracy with the effort needed to obtain each marker, rather than declaring one technical approach universally superior.

What can the study support?

It supports careful selection and local evaluation of research case definitions. A marker-positive chart is neither a measured methamphetamine concentration nor a diagnosis of impairment. The useful unit is the explicitly defined record classification, with its time window, reference method and known uncertainties.

Source

Evaluating markers for methamphetamine use in electronic health records. Drug and Alcohol Dependence. 2025;276:112876. DOI: 10.1016/j.drugalcdep.2025.112876. Full text; bibliographic record.