Background: With the shortage of innovator semaglutide or tirzepatide products resolved, compounding pharmacies can only legally sell unique products. Unique products could have a different route of administration or dosing, or could include additional pharmaceutical ingredients. Objective: To identify and characterize compounded semaglutide and tirzepatide products that differ from available FDA-approved products. Methods: We searched compounding sites between February 3, 2025, and March 20, 2025, using key terms ["compounded semaglutide," "compounded tirzepatide," and "compounded GLP-1s"] on Google looking for products with a strength, route of administration, and/or formulation that differed from commercially available products. Results: We identified 33 unique semaglutide and/or tirzepatide products. Two-thirds contained semaglutide, and one-third contained tirzepatide. Forty-eight percent of products contained either semaglutide or tirzepatide with some combination of cyanocobalamin, glycine, niacinamide, docusate, or ondansetron. The 17 single active ingredient products were provided in sublingual (82%) or oral disintegrating tablet (ODT) (18%) formulations. Only 18% of included compounded products reported information about beyond use date and preferred storage conditions. Twenty-eight percent reported preferred storage conditions. Conclusion and Relevance: We found little justification for adding nutrients or docusate sodium to combination subcutaneous semaglutide or tirzepatide products. There is a rationale for adding ondansetron, but evidence for subcutaneous administration is lacking. There is a rationale for fashioning sublingual or ODT formulations, but whether these formulations offer advantages over innovator oral tablets has not been determined. The popularity of these products as an alternative to FDA-approved medications is concerning, given the lack of evidence for safety and efficacy.

A legal loophole allows consumers to purchase peptide semaglutide without a prescription, but websites that sell them do not sell supplies or provide guidance. We assessed the ability and confidence of college students at the University of Connecticut and older adults in performing the required steps from September 1, 2025, through January 30, 2026. Participants looked up information online. We provided various semaglutide and diluent vials and supplies. We assessed 34 steps in the process and assigned 1 point for each step successfully completed. We rated confidence on a scale from 1 (no confidence) to 5 (complete confidence). We evaluated 20 adults aged ≥18 years (12 male, 8 female) with a mean (SD) age of 40 (21) years. Participants completed 15 of the 34 steps correctly (mean [SD] = 44% [50%]). We found errors that could result in incorrect dosing, needle sticks, or infections. Mean (SD) confidence was low before and after the demonstration but not significantly so (2.3 [0.7] vs 1.9 [1.0]; P = .19). Untrained adults without experience injecting medications could be at high risk of adverse events when they try to self-administer grey market peptide semaglutide products using only internet information. Future studies should assess a larger and more diverse population and determine whether the results are similar with other products sold as peptides without a prescription.

We describe major changes in the nitrous oxide market fueling recreational use with a focus on prevalence, desired effects, adverse events, treatments, and public health interventions. Nitrous oxide is currently sold with easy and discreet access for children and young adults in formulations that attract them. Over 13 million people in the United States have ever used nitrous oxide recreationally and inhalants are mostly used by pre-teen to early 20-year-olds. Poison control center calls have increased 1,300% from 2003 to 2024 and deaths have risen 6-fold from 2010 to 2023. There are many acute adverse events ranging from frostbite to asphyxia. Adverse effects from chronic use are related to cobalt oxidation which impairs vitamin B12 functioning. The resulting dysfunction of methionine synthase induces methionine deficiency frequently causing paresthesia, ataxia, unsteady gait, and cognitive issues. Less commonly, paralysis, bladder and erectile dysfunction, macrocytic anemia and thromboembolism can occur. The European Federation of Clinical Chemistry and Laboratory Medicine guidance specifies diagnostic parameters, supportive care, and replenishment of vitamin B12 levels with intramuscular cyanocobalamin. There may be a role for routine direct methionine replenishment, but it is not universally recommended. Routine folic acid supplementation is controversial and should likely be reserved for those with low serum folate concentrations. Clinicians need to be aware of this growing trend to detect adverse events from chronic nitrous oxide use and treat them before they become permanent. Clinicians can provide or advocate for public health information and regulations to prevent adverse events from occurring.

The Dietary Supplement Health and Education Act of 1994 specified that dietary supplements must be swallowed. In this study, we investigated whether kratom-derived products are being sold to consumers in nonswallowed formulations. Kratom is the fresh or dried leaf powder of the Mitragyna speciosa tree. We identified 49 kratom-derived products being sold in the form of sublingual strips (24%), buccal pouches (8%), and vaping products (67%). Most contained 7-hydroxymitragynine (an alkaloid that the US Food and Drug Administration seeks to make a controlled substance), but we also identified mitragynine extract and mitragynine pseudoindoxyl products. The majority had flavoring or a scent, and some had mascots, pictures of fruit or mint, or formulation colors or packaging that could appeal to children. Most products were not sold in child-resistant packaging. Several kratom vaping products additionally contained intoxicating hemp cannabinoids. With no clinical, safety, or pharmacokinetic data for kratom-derived products that bypass first-pass metabolism (ie, where a chemical absorbed through the stomach or intestines is metabolized in the liver before reaching the general bloodstream), people should be advised to avoid these products, and regulatory action is needed to prevent their sale to consumers.

OBJECTIVE:Kratom is the pulverized dried leaves of the Mitragyna speciosa tree and has a bitter taste and high ingestion volume that repels children. Newer products use a single alkaloid extract from the leaves, mitragynine, or oxidize mitragynine to 7-hydroxymitragynine and place it in various oral dosage forms. We identified oral dosage form products containing mitragynine and/or 7-hydroxymitragynine that are marketed in ways that appeal to children and define their alluring characteristics. METHODS:We performed Google searches to identify websites selling kratom products. Products were assessed and included if they had 1 or more features that would be attractive to children and defined their formulations, alkaloids, flavoring/scents, mascots, and packaging. RESULTS:Eighty unique products that appealed to children were found, and 36.3% were gummies, 28.8% were tablets, 18.8% were drink mixes or liquids, 15.0% were miscellaneous candies (saltwater taffies, ice cream cones, noobs, popping crystals, honey sticks, mints, lollipops), and 1.3% were chocolates. Thirty-eight products (47.5%) contained mitragynine, 35 products (43.8%) contained 7-hydroxymitragynine, 6 products (7.5%) contained both, and 1 product (1.3%) did not specify which alkaloid was included. Twenty-six products (32.5%) had a cartoon mascot or symbol. Sixty-six products (82.5%) had brightly colored packaging, 59 products (73.8%) had brightly colored formulations, and 73 formulations (91.3%) had a flavor or scent. CONCLUSIONS:Mitragynine and 7-hydroxymitragynine are present in many products that could cause small children and teens to be exposed.

Consumers precluded from obtaining semaglutide or tirzepatide by clinicians or insurers are turning to natural “GLP-1” transdermal patches. The Dietary Supplement Health and Education Act specifies dietary supplement products must be swallowed, so all these products are illegal. We identified 24 transdermal patch dietary supplement products and 1 transdermal gel product with an average of 7 ± 4 natural ingredients (berberine, glutamine/glutamate, cinnamon, and pomegranate most listed). No certificates of analysis were posted, many products lacked the Food and Drug Administration disclaimer, and many products used deceptive advertising. Several products had 1- to 2-star reviews and consumer comments suggesting lack of efficacy or adverse events.

The Food and Drug Administration (FDA) exists to protect US consumers. However, while drug manufacturing has shifted dramatically to developing countries like India and China, the FDA first silently followed a "trust and not verify" strategy with virtually no overseas inspections until overwhelming evidence of patient harm had occurred. The implementation of the Generic Drug User Fee Act helped alleviate this problem, but the issue recurred after the COVID-19 pandemic set the FDA far behind in foreign inspections. Regardless, the FDA has never attained parity in inspection frequency and rigor in these countries versus the United States. The FDA still over relies on reports of adverse events, whistleblower reports, and independent laboratory findings to prompt an investigation. When serious issues are found in a manufacturing plant, they redact the products manufactured there so clinicians and patients are unprotected. This has directly harmed US citizens, exposed them to cancer-causing agents, and provided products without the expected benefits. When rates of adverse events were recently compared by manufacturer location, they were found to be markedly higher for manufacturers in emerging countries than advanced countries, especially when a drug's patent has been expired for a longer time. Clinicians may be dismissive of patients claiming that a new version of a generic drug isn't as effective as their previous one or is causing new adverse events, but that could be the case. Healthcare professionals should report these cases to the FDA to raise awareness of potential issues.

Background: Potent semi-synthetic alkaloids that stimulate opioid receptors are being sold to consumers in gas stations, smoke shops, and online as the dietary supplement 'kratom'. Objective: We descriptively evaluated the characteristics of products containing mitragynine pseudoindoxyl. Results: Fifty-one unique products met our inclusion criteria. Seventy-one percent of products contained mitragynine pseudoindoxyl plus 7-hydroxymitragynine, 24% contained mitragynine pseudoindoxyl alone (24%), and 6% contained mitragynine pseudoindoxyl with 8-hydroxymitragynine or 11-hydroxymitragynine (with or without 7-hydroxymitragynine). Sixty-nine percent of products had a child appealing flavoring and/or scent, 63% of products were formulated using bright colors or had bright colors on their labeling, 12% of products had food pictures on the label (mainly representing the fruit or mint flavoring/scent), 6% of products had a cartoon mascot, and 6% of products had a food formulation (ice cream cone or chocolate bar). Only 18% of websites disclosed the products stimulated opioid receptors while 45% disclosed they could cause intoxication, tolerance, dependence, withdrawal, or addiction. Conclusions: There are many products that contain mitragynine pseudoindoxyl sold as dietary supplements and many have features that would appeal to children.

INTRODUCTION:Kratom is commonly used by consumers, and the elemental impurity exposure that consumers would have at different kratom ingestion doses has been determined. METHODS:This assessment used original data from independent third-party laboratory testing of kratom products to identify the percentage of products that exceeded permissible daily exposure limits for lead (5 µg/day), nickel (200 µg/day), arsenic (15 µg/day), and cadmium (5 µg/day), the interim reference level for lead in adults (12.5 µg/day), and the tolerable upper intake level for manganese (11 mg/day) and nickel (1 mg/day). We assessed all products regardless of type and then evaluated non-extract products, extract products, and a soda preparation separately for elemental impurities. RESULTS:Three assessments of elemental impurities in kratom products have been published, totaling 68 products. Assessing all products and assuming a 3 g daily dose of kratom, 7.4% would exceed the permissible daily exposure limits for lead, 0% for nickel, 3.1% for arsenic, and 0% for cadmium. At a kratom dose of 25 g daily, 70.6% would exceed the permissible daily exposure limits for lead, 20.6% for nickel, 9.4% for arsenic, and 0% for cadmium. The interim reference level for lead would be exceeded by 1.5% of products at a kratom daily dose of 3 g and 33.8% of products at 25 g. The tolerable upper intake level for manganese would be exceeded by 12.5% of products at a kratom daily dose of 3 g and 41.7% of products at 25 g. Non-extract products generally contain greater concentrations of elemental impurities than extract products or the soda preparation. DISCUSSION:Apart from their concentrations in a gram of product, assessing the amount of exposure to elemental impurities at different kratom ingestion doses is also important. Elemental impurities exceeding regulatory permissible concentrations for many products, especially with greater daily kratom ingestion doses, may impact human health. CONCLUSIONS:Some kratom products contain excessive concentrations of elemental impurities of toxicological concern, such as lead and arsenic. Non-extract products (powders, capsules, tablets) generally contain greater concentrations of elemental impurities than extract products or the soda preparation. Daily use of these products can result in exposures exceeding regulatory thresholds and adverse health effects.

Objective The objective of this article is to evaluate near-infrared spectroscopy (NIRS), a non-invasive technique to assess tissue oxygenation and mitochondrial function, as a diagnostic tool for statin-associated muscle symptoms (SAMS).Methods We verified SAMS in 39 statin-treated patients (23 women) using a double-blind, placebo-controlled, cross-over protocol. Subjects with suspected SAMS were randomised to simvastatin 20 mg/day or placebo for 8 weeks, followed by a 4-week no treatment period and then assigned to the alternative treatment, either simvastatin or placebo. Tissue oxygenation was measured before and after each statin or placebo treatment using NIRS during handgrip exercise at increasing intensities of maximal voluntary contraction (MVC).Results 44% (n=17) of patients were confirmed as having SAMS (11 women) because they reported discomfort only during simvastatin treatment. There were no significant differences in percent change in tissue oxygenation in placebo versus statin at all % MVCs in all subjects. The percent change in tissue oxygenation also did not differ significantly between confirmed and unconfirmed SAMS subjects on statin (−2.4% vs −2.4%, respectively) or placebo treatment (−1.1% vs −9%, respectively). The percent change in tissue oxygenation was reduced after placebo therapy in unconfirmed SAMS subjects (−10.2%) (p≤0.01) suggesting potential measurement variability.Conclusions NIRS in the forearm cannot differentiate between confirmed and unconfirmed SAMS, but further research is needed to assess the usability of NIRS as a diagnostic tool for SAMS.Trial registration number NCT03653663.

Monoclonal antibody Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors reduce total cholesterol (TC), low density lipoproteins (LDL), high density lipoproteins (HDL), and triglycerides (TG). We assessed the ability of berberine, a natural PCSK9 inhibitor, to reduce lipid concentrations either alone or combined with other nutraceuticals. We searched PubMed, Scopus and EMBASE from inception to September 30th, 2022 for randomized controlled trials (RCTs) assessing 8-18 wk of berberine therapy on. A total of 41 RCTs with 4,838 patients met our inclusion criteria. Berberine containing products significantly reduced TC (MD -17.42 mg/dL [95%CI: -22.91 to -11.93]), LDL (MD -14.98 mg/dL [95%CI: -20.67 to -9.28]), and TG (MD -18.67 mg/dL [95%CI: -25.82 to -11.51]) while raising HDL (MD 1.97 mg/dL [95%CI: 1.16 to 2.78]) versus control (I2 > 72% for all analyses). Products with berberine alone had less robust effects on TC (MD -12.08 mg/dL [95%CI: -21.79 to -2.37]), LDL (MD -9.26 mg/dL [95%CI: -20.31 to 1.78]), and HDL (MD 1.38 mg/dL [95%CI: -1.27 to 4.03]) but TG effects were similar (MD -17.40 mg/dL [95%CI: -32.57 to -2.23]). Berberine along with red yeast rice reduced TC (MD -19.62 mg/dL [95%CI: -28.56 to -10.68]) and LDL (MD -18.79 mg/dL [95%CI: -28.03 to -9.54]) as did combination therapy with Silybum maranium for TC (MD -31.81 mg/dL [95%CI: -59.88 to -3.73]) and LDL (MD -30.82 mg/dL [95%CI: -56.48 to -5.16]). Berberine, alone or with other nutraceuticals, can provide a modest positive impact on lipid concentrations.

Introduction: Kratom (Mitragyna speciosa) has generated substantial clinical and scientific interest as a complex natural product. Its predominant alkaloid mitragynine and several stereoisomers have been studied for activity in opioid, adrenergic, and serotonin receptors. While awaiting clinical trial results, the pre-clinical evidence suggests a range of potential therapeutic applications for kratom with careful consideration of potential adverse effects.Areas covered: The focus of this review is on the pharmacology, pharmacokinetics, and potential drug-drug interactions of kratom and its individual alkaloids. A discussion on the clinical pharmacology and toxicology of kratom is followed by a summary of user surveys and the evolving concepts of tolerance, dependence, and withdrawal associated with kratom use disorder.Expert opinion: With the increasing use of kratom in clinical practice, clinicians should be aware of the potential benefits and adverse effects associated with kratom. While many patients may benefit from kratom use with few or no reported adverse effects, escalating dose and increased use frequency raise the risk for toxic events in the setting of polysubstance use or development of a use disorder.

Background: While statin therapy is the preferred treatment for hyperlipidemia, literature supports the lowdensity lipoprotein (LDL) lowering effects associated with red yeast rice, berberine, and Silybum marianum. Dietary supplements may be perceived as a more affordable alternative to prescription medication. Objective: We determined cost-effectiveness of generic pravastatin versus single-ingredient dietary supplements in relation to LDL lowering effect. Methods: Data from meta-analyses and systematic reviews was extracted to calculate pooled weighted mean LDL differences amongst generic pravastatin and single ingredient dietary supplements. The effect was then divided by average 30-day costs and compared amongst agents. Results: The greatest difference was seen in pravastatin 40 mg [MD -57.88 mg/dL (95%CI: - 64.80 to - 50.96)], followed by pravastatin 10 mg [MD -41.30 mg/dL (95%CI: 63.30 to - 19.40)], red yeast rice [MD -25.39 (95%CI: -32.98 to -17.81)], berberine [MD -15.13 (95%CI: -21.78 to -8.48)], and Silybum marianum [MD -9.51 mg/dL (95%CI: -22.13 to - 0.10)]. were divided by mean difference to calculate cost per mg/dL reduction in LDL. Costeffectiveness was greatest for pravastatin 10 mg [$0.66/mg/dL LDL reduction (range: $0.39 to $1.13)], followed by pravastatin 40 mg [$0.74/mg/dL LDL reduction (range: $0.66 to $0.84)], berberine [$0.81/mg/dL LDL reduction (range: $0.56 to $1.44)], red yeast rice [$0.84/mg/dL reduction (range: $0.67 to $1.13)], and Silybum marianum [$0.88/mg/dL LDL reduction (range: $0.38 to $82.02)]. Conclusion: Pravastatin is most cost-effective in each scenario whether or not prescription insurance is utilized.

Previous meta-analyses assessed andexanet alfa (AA) or prothrombin complex concentrate (PCC) products for the treatment of Factor Xa inhibitor (FXaI)-associated major bleeding. However, they did not include recent studies or assess the impact of the risk of bias. We conducted a systematic review with meta-analysis on the effectiveness of AA versus PCC products for FXaI-associated major bleeding, inclusive of the studies' risk of bias. PubMed and Embase were searched for comparative studies assessing major bleeding in patients using FXaI who received AA or PCC. We used the Methodological Index for NOn-Randomized Studies (MINORS) checklist and one question from the Joanna Briggs Institute (JBI) Critical Appraisal of Case Series tool to assess the risk of bias. Random-effects meta-analyses were performed to provide a pooled estimate for the effect of AA versus PCC products on hemostatic efficacy, in-hospital mortality, 30-day mortality, and thrombotic events. Low-moderate risk of bias studies were meta-analyzed separately, as well as combined with high risk of bias studies. Eighteen comparative evaluations of AA versus PCC were identified. Twenty-eight percent of the studies (n = 5) had low-moderate risk and 72% (n = 13) had a high risk of bias. Studies with low-moderate risk of bias suggested improvements in hemostatic efficacy [Odds Ratio (OR) 2.72 (95% Confidence Interval (CI): 1.15-6.44); one study], lower in-hospital mortality [OR 0.48 (95% CI: 0.38-0.61); three studies], and reduced 30-day mortality [OR 0.49 (95% CI: 0.30-0.80); two studies] when AA was used versus PCC products. When studies were included regardless of the risk of bias, pooled effects showed improvements in hemostatic efficacy [OR 1.36 (95% CI: 1.01-1.84); 12 studies] and reductions in 30-day mortality [OR 0.53 (95% CI: 0.37-0.76); six studies] for AA versus PCC. The difference in thrombotic events with AA versus PCC was not statistically significant in the low-moderate, high, or combined risk of bias groups. The evidence from low-moderate quality real-world studies suggests that AA is superior to PCC in enhancing hemostatic efficacy and reducing in-hospital and 30-day mortality. When studies are assessed regardless of the risk of bias, the pooled hemostatic efficacy and 30-day mortality risk remain significantly better with AA versus PCC.

Objective: To compare efficacy and safety outcomes for ketamine anesthesia + electroconvulsive therapy (ECT) versus nonketamine anesthesia + ECT in treatment-resistant depression (TRD) patients. Data Sources: PubMed and Embase were searched from the earliest date through November 27, 2023. Study Selection and Data Extraction: Relevant randomized controlled trials (RCTs) of ketamine + ECT versus nonketamine anesthesia + ECT that reported data on remission (odds ratio [OR]), defined as a Hamilton Depression Rating Scale (HAM-D) and Montgomery-Asburg Depression Rating Scale (MADRS) score <8-10) and mean differences (MDs) in HAM-D scores after several ECT sessions were compared using inverse variance methods. The risk of bias (RoB) was assessed using the Cochrane RoB tool. Data Synthesis: Seventeen RCTs (RoB: Low N = 12, Moderate N = 2, High N = 3) with 1181 total patients met inclusion criteria. Patients receiving ECT experienced greater clinical remission (OR: 1.78, [95% confidence interval (CI): 1.08-2.93], I2 = 11%, N = 9) and lower HAM-D scores after the third through sixth ECT sessions as well as the eighth ECT session when ketamine versus nonketamine anesthesia was used. Ketamine use with ECT significantly increased fear with hallucinations (OR: 1.99, [95% CI: 1.11-3.58], I2 = 0%, N = 7) than with nonketamine anesthesia. Relevance to Patient Care and Clinical Practice: Selecting ketamine-based anesthesia could more quickly and profoundly enhance the beneficial effects of ECT for patients with severe TRD, but the balance of benefits to harm is unclear as there may be additional adverse events. Conclusion: Ketamine is a promising anesthesia adjunct to ECT that may enhance antidepressant effects in exchange for more adverse events.