Kratom (Mitragyna speciosa) is increasingly used in the United States as a dietary supplement for pain, mood regulation, and opioid withdrawal. Its alkaloids, mitragynine and 7-hydroxymitragynine (7-OH), demonstrate μ-opioid receptor activity, with 7-OH exhibiting substantially greater opioid-like potency than mitragynine. There are concerns from the US Food and Drug Administration (FDA) regarding dependence and adverse effects. Purified 7-OH products may bypass metabolic pathways and deliver disproportionately strong opioid effects compared with natural kratom preparations, increasing the risk of dependence. Despite these concerns, 7-OH remains federally unscheduled, though listed as a "Drug of Concern" by the DEA. Although there is no standardized clinical guidance, buprenorphine has been used to manage kratom and 7-OH withdrawal with varying initiation strategies. To describe the clinical course and outcomes of buprenorphine initiation among patients with problematic 7-OH use, focusing on initiation timing, dosing strategies, and symptom monitoring. Retrospective chart review of patients treated at a low-barrier telehealth addiction medicine clinic between April and October 2025. Nine patients with purified 7-OH product use (as opposed to kratom use) met the inclusion criteria. The mean age was 33.5 years; 7 patients were identified as male. Low-dose initiation was used in 6 cases and standard initiation in 3 cases. Successful initiation and stabilization occurred in 88.9%, with no precipitated withdrawal or adverse events. Symptom improvement was reported in 8 of the total cases at a median 6-week follow-up. Buprenorphine initiation for problematic 7-OH use was feasible, well tolerated, and associated with symptom improvement, supporting development of pragmatic clinical approaches for this emerging substance use disorder.
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Reliable methods for measuring plasma concentrations of cannabidiol (CBD) and its metabolites are essential for pharmacokinetic studies. Several methods have been published, some involve complex procedures. This study aimed to develop a simple yet robust method for quantitating CBD, 7-OH-CBD and 7-COOH-CBD in human plasma. Sample preparation was evaluated using various solvent systems. Analytical parameters were examined and optimized. The method was validated for sensitivity, accuracy, precision, selectivity, specificity, carryover, dilution integrity, long-term stability, freeze-thaw stability and recovery. A simple protein precipitation method using acetonitrile provided optimal sample preparation. All analytes were quantified in negative ionization mode, with complete separation achieved on a C18 column within 3.5 minutes using an isocratic mobile phase. The method met all validation criteria. Analytes remained stable under long-term storage at -30°C, through freeze-thaw cycles and at refrigerated temperatures, although 7-COOH-CBD showed a slight decrease after two months at refrigerated temperatures. This study presents a simple, rapid and robust bioanalytical method for the simultaneous quantification of CBD and its major metabolites across clinically relevant plasma concentrations. The method's reliability and efficiency make it highly suitable for routine clinical use and pharmacokinetic applications. Cannabidiol (CBD) is a compound found in cannabis that is being studied for its potential health benefits. It is already approved as an add-on treatment for certain types of epilepsy. To improve how CBD is used in healthcare, researchers need reliable ways to measure CBD and its breakdown products, called metabolites, in the blood. In this study, researchers developed a simple and accurate method to measure CBD and its metabolites in human blood. Existing methods are sometimes complex, and this study aimed to develop a simpler method as an alternative. It uses a technique called liquid chromatography coupled to mass spectrometry, which helps separate and identify substances in blood samples. The sample preparation was straightforward, using a solvent called acetonitrile. The method was carefully tested to make sure it was accurate, consistent, and able to detect even small amounts of CBD. It also worked well under different storage conditions, including freezing and long-term refrigeration. The results showed that this method can quickly and reliably measure CBD and its breakdown products in a single test. This makes it a useful tool for clinical studies and future research on CBD treatments.
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Products containing semi-synthetic 7-hydroxymitragynine (7-OH), a potent mu-opioid receptor (MOR) agonist, have proliferated in the United States. In kratom leaf, trace amounts of 7-OH are formed by spontaneous oxidization of kratom's primary alkaloid, mitragynine. Hepatic and intestinal microsomes also convert mitragynine to 7-OH. Some products have sublingual and nasal administration routes that circumvent hepatic first-pass metabolism, increasing bioavailability and accelerating effect onset, features that increase risk. We report a patient who developed substance use disorder (SUD) related to a 7-OH sublingual film. A 35-year-old man with supraventricular tachycardia and profound urinary retention described using "Hydroxie," a novel, semi-synthetic 7-OH product. He currently vaped cannabis and nicotine, and reported injection heroin addiction a decade prior. He used kratom 6 months before trying Hydroxie, which began 10 weeks before hospitalization. Within days of initiating use, he noticed tolerance; within 2 weeks, he was using one film every 1-2 hours. The patient met criteria for severe SUD related to Hydroxie and was inducted onto buprenorphine. Analysis confirmed 7-OH in the product and blood. The MOR selectivity and brief duration of action of some 7-OH formulations support our observation that repeated use may lead to physical dependence. Standard laboratory testing can detect mitragynine but not 7-OH due to its relatively shorter half-life, an issue that may confuse semi-synthetic 7-OH use with kratom. Novel 7-OH products are not kratom. The potency of 7-OH places unwitting consumers who may believe they are using kratom, not a partial MOR agonist, at risk.
7-Hydroxymitragynine (7-OH), a minor alkaloid in kratom (Mitragyna speciosa (Korth.) Havil.) (Rubiaceae) and an active metabolite of mitragynine, is a critical transient precursor to mitragynine pseudoindoxyl, which exhibits >2-fold μ-opioid receptor-biased agonism and improved isoform selectivity relative to its precursors. Although present only in trace amounts in kratom leaves, a recent survey identified hundreds of consumer products with semisynthetic 7-OH and mitragynine pseudoindoxyl. Their high potency, ease of access, and risk of addiction have prompted the US FDA to recommend scheduling 7-OH as a Schedule I controlled substance. To address this public health crisis and the associated analytical challenges, a comprehensive analysis of commercially available kratom products was performed. The results revealed substantial inconsistencies between the quantities claimed on the products' labels and the actual 7-OH amount detected in several of these products. Along with 7-OH and mitragynine pseudoindoxyl, several (over)oxidized byproducts were detected, providing crucial insights into their synthetic origins. Analysis of >98% of 7-OH-labeled products indicated a semisynthetic origin, with labeled doses ranging from 0.001 to 33.6 mg per serving. Furthermore, consistent with the prior report, 7-OH degrades into the potentially toxic byproduct 3-dehydromitragynine under simulated gastric conditions. These findings underscore significant safety concerns over oral 7-OH products and necessitate validated analytical monitoring to guide regulatory oversight and consumer protection.
7-Hydroxymitragynine (7-OH) is a highly selective mu opioid receptor agonist with binding affinity greater than morphine. Although trace amounts of 7-OH are found in kratom, it is formed by metabolism in humans after kratom ingestion. Novel semi-synthetic 7-OH products are manufactured by mono-oxidation of kratom's primary alkaloid, mitragynine. Formulations include sublingual tablets, powders, and liquid shots. We report a case of a study participant with self-reported 7-OH use. A 23-year-old man using kratom for 3 years was enrolled into a clinical trial evaluating kratom pharmacokinetics, behavioral pharmacology, and withdrawal. He typically used 1.5-2g of kratom whole-leaf powder 6 times/day. Following scheduled kratom product self-administration during the study, several outcomes were atypical, including blunted subjective kratom effects. He reported recent initiation of a "new kratom product" ("Opia") identified as semi-synthetic 7-OH; he was using 20 mg 3 times/day for 4 days before study admission. Mitragynine (29.7 ng/mL) plasma concentration peaked at 1.5 hours post kratom self-administration, while 7-OH Cmax (11.7 ng/mL) occurred before self-administration, confirming prior ingestion of 7-OH. The participant reported withdrawal symptoms and requested early discharge from the study, but refused the study protocol kratom "rescue dose," stating he preferred to take his "stronger" product. Clinicians must obtain detailed self-reports from patients who report any kratom use. As 7-OH products are misleadingly marketed as kratom, and as both long-time kratom consumers and kratom-naive individuals may experiment with these novel products, improved assessment methods are urgently needed in the absence of real-time confirmatory testing.
This study aimed to report acute opioid withdrawal after an abrupt cessation of high-dose 7-hydroxymitragynine (7-OH) in a patient who transitioned from kratom and to outline pharmacist-focused assessment, management, and regulatory counseling strategies including a formal causality assessment. A 43-year-old male with opioid use disorder presented with nausea, diarrhea, abdominal cramping, restlessness, chills/clamminess, and anxiety after discontinuing concentrated 7-OH (360 mg/d, last 30 mg dose ∼ 48 hours earlier). Vital signs were blood pressure of 138/93 mm Hg, temperature of 37.7°C, heart rate of 84 beats/min, respiratory rate of 16 breaths/min, and pupils of 2-3 mm, with a clinical opioid withdrawal scale score of 5. He had transitioned from kratom to 7-OH approximately 18 months earlier. He met the DSM-V criteria for moderate opiate use disorder, although he never engaged in formal treatment. The patient reported that he transitioned from kratom to concentrated 7-OH products because he perceived stronger, faster opioid-like effects and required smaller quantities to avoid withdrawal. Emergency department management included sublingual buprenorphine-naloxone 4-1 mg, adjuncts (clonidine, ondansetron, loperamide, methocarbamol, nonsteroidal anti-inflammatory drugs, acetaminophen), counseling on precipitated withdrawal, and referral for treatment. A Naranjo assessment supported probable causality (score 6). Concentrated 7-OH products differ from kratom leaf and can produce dependence and withdrawal; pharmacists should screen for these products, time buprenorphine initiation to moderate withdrawal, provide harm-reduction counseling, and incorporate evolving state regulations into patient education.
Increased glycolytic metabolism in synovial fibroblasts contributes to their activated phenotype in rheumatoid arthritis (RA). Our previous results revealed that the activation of the dopamine D3 receptor (D3R) in mast cells reduced inflammation in a mouse model of RA. In this study, we explored the role of D3R in regulating dopamine-induced activation and glycolysis in synovial fibroblasts from patients with RA (RASFs). RASFs were cultured in the presence of dopamine. Pharmacological modulation of D3R-by-D3R agonist (7-OHDPAT) and antagonist (NGB2904) was used to investigate the regulatory role of D3R in dopamine-induced activation and glycolysis in RASFs. Dopamine stimulation induced a dose-dependent increase in cell viability and α-SMA expression in RASFs. Dopamine also caused significant and dose-dependent upregulation of glycolysis-related enzymes in RASFs. Treatment with 7-OH-DPAT inhibited dopamine-induced increases in α-SMA expression and inflammatory response in RASFs, whereas NGB2904 treatment resulted in the enhanced effects stimulated by dopamine. NGB2904 treatment upregulated glycolysis and the expression of glycolytic enzymes induced by dopamine, whereas 7-OH-DPAT treatment downregulated glycolysis and glycolytic enzymes in RASFs. NGB2904 attenuated the ability of 7-OH-DPAT to inhibit the dopamine-induced elevation in cAMP levels of RASFs. Involvements of the cAMP pathway was confirmed by findings that H89 (a PKA inhibitor) abrogated the upregulation of activation, glycolysis, and expression of glycolytic enzymes mediated by the D3R antagonist, NGB2904, in RASFs. D3R downregulates dopamine-induced activation and glycolysis of RASFs by suppressing PKA activity. Therefore, inhibition of glycolysis by manipulating the D3R pathway may provide a novel therapeutic strategy to reduce the activation of RASFs.
Kratom, a medicinal Southeast Asian plant, gained interest in the United States for its analgesic and stimulant effects. Previous clinical studies characterized mitragynine and 7-hydroxy-mitragynine (7-OH-MTG) plasma pharmacokinetics following kratom tea and dried kratom leaf powder intake; however, to date, there are no kratom extract data. In the current study, mitragynine and 7-OH-MTG plasma pharmacokinetics are characterized in humans following increasing single doses (SD) and 15 multiple daily doses (MD) of concentrated kratom extract (39.5% mitragynine) containing 9.9, 29.6, and 59.2 mg mitragynine. Mean mitragynine plasma Cmax after single escalating doses increased dose-dependently, 32.8 ± 17.0, 93.2 ± 38.6, and 196 ± 77.4 ng/ml at a median Tmax of 1.3 h, with mean 7-OH-MTG Cmax of 6.8 ± 2.7, 13.7 ± 3.3, and 30.5 ± 12.2 ng/mL at a median Tmax of 1.3-1.7 h. Mean mitragynine plasma Cmax after 15 escalating multiple doses increased dose-dependently, 27.4 ± 10.9, 125 ± 79.7, and 277 ± 48.8 ng/mL at a median Tmax of 1.7-2.0 h, with mean 7-OH-MTG Cmax of 5.4 ± 1.9, 16.6 ± 6.1, and 33.9 ± 5.5 ng/mL at a median Tmax of 1.7-2.3 h. Cmax and AUC increased dose-dependently following SD and MD but were less than 1.4X greater than expected for both analytes and all doses based on strict dose proportionality. Half-lives were best reflected at higher doses due to the ability to measure low analyte concentrations longer but also suggested possible enzyme saturation. Higher 7-OH-MTG to mitragynine ratios were observed after multiple doses compared to SD and at lower compared to higher doses. These data indicate that concentrated kratom extracts may yield greater overall mitragynine exposure than dried kratom leaf powder or kratom tea preparations administered at comparable doses.
While cannabidiol (CBD) is widely used globally as a therapeutic agent, sex as a biological variable remains underexplored in determining its metabolism and overall pharmacokinetic patterns. The present study systematically evaluated sex differences in the pharmacokinetics of CBD and its major metabolites, 7-hydroxy-CBD (7-OH-CBD) and 7-carboxy-CBD (7-COOH-CBD), in a mouse model. Male and female C57BL/6J mice received an intraperitoneal dose of CBD (120 mg/kg) and plasma concentrations of CBD and its metabolites were quantified by UPLC-MS/MS. Pharmacokinetic parameters were derived using non-compartmental analysis and compared between sexes. Females exhibited significantly higher early exposure to CBD, with a ~ 1.5-fold higher [Formula: see text]than male mice (p = 0.03). The apparent clearance (CL/F) and ultimate total systemic exposure[Formula: see text] were comparable between sexes. In contrast, male mice demonstrated a markedly larger apparent volume of distribution (Vz/F; ~2.2-fold increase, p = 0.02) and consequently a longer terminal half-life (t1/2; ~2.2-fold increase, p = 0.04), indicating greater tissue sequestration. Both metabolites were significantly higher in female vs. male mice (7-OH-CBD [Formula: see text]~1.6-fold, p = 0.03; 7-COOH-CBD [Formula: see text] ~1.7-fold, p = 0.03). The [Formula: see text] tended to be higher for 7-OH-CBD in female mice but was not significant (~ 1.4-fold, p = 0.11), whereas the 7-COOH-CBD [Formula: see text] was significantly greater in females (~ 1.8-fold, p = 0.04). Male mice displayed substantially longer terminal half-lives for both metabolites (7-OH-CBD ~2.4-fold, p = 0.0051; 7-COOH-CBD ~3.7-fold, p = 0.02). These results demonstrate that sex is a critical determinant of CBD pharmacokinetics and highlight the need for sex-informed dosing considerations in both preclinical study design and potentially for future clinical applications of CBD.
Kratom (Mitragyna speciosa) products have become widely available in diverse commercial formulations, raising increasing analytical and regulatory interest due to the presence of potent alkaloids such as mitragynine (MG), 7-hydroxymitragynine (7-OH), and mitragynine pseudoindoxyl (MGP). The accurate identification of these compounds is analytically challenging because kratom matrices contain numerous structurally related alkaloids and isomeric species that produce similar mass spectral features. In this study, an ultrahigh-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) workflow was developed to characterize kratom alkaloids in authentic leaf materials and 38 commercial kratom products representing multiple formulations. Chromatographic separation combined with accurate mass measurement and diagnostic MS/MS fragmentation enabled reliable differentiation of MG, 7-OH, MGP, and related isomers. Multiple overlapping chromatographic peaks were observed at m/z 415.2227, demonstrating that reliance solely on accurate mass or commonly monitored transitions such as m/z 415 → 190 can lead to false-positive identification of 7-OH in complex botanical matrices. Application of the multicriteria confirmation strategy revealed substantial variability in alkaloid composition across commercial products, including the presence of 7-OH and MGP in several tablet and capsule formulations. Untargeted metabolomic profiling further distinguished kratom plant extracts, including the authentic leaf materials, from processed products enriched in specific alkaloids. These results highlight the importance of integrating chromatographic resolution with orthogonal MS/MS criteria for reliable identification of kratom alkaloids and provide an analytical framework for the characterization of complex botanical products.
Kratom (Mitragyna speciosa), native to Southeast Asia, has traditionally been consumed as fresh leaves or teas. Under those conditions, exposure to 7-hydroxymitragynine (7-OH)-a potent μ-opioid receptor agonist-is minimal, as it occurs only at trace levels in leaf material. By contrast, the U.S. market offers chemically enriched or semi-synthetic 7-OH products, often marketed as 'kratom' yet chemically distinct from botanical preparations. '7-OH', '7-hydroxymitragynine', and 'kratom' were used as keywords; relevant literature was obtained from PubMed, Web of Science, and Google Scholar. Pharmacological studies consistently identify 7-OH as a partial μ-opioid receptor agonist with nanomolar affinity, greater efficacy than mitragynine, and often exceeding the potency of morphine. Animal experiments demonstrate robust antinociceptive effects, respiratory depression, tolerance, dependence, and reinforcing properties characteristic of opioids. Human pharmacokinetic studies show systemic exposure after kratom ingestion, but concentrated 7-OH products bypass metabolic formation, producing markedly higher exposures. Regulatory surveillance, poison-center data, and marketplace audits confirm a rapid increase in availability and use of these products. State health departments have reported severe intoxications and fatalities. Clinical cases describe escalating use, medically managed withdrawal, and psychiatric destabilization, while forensic investigations document postmortem concentrations consistent with fatal opioid toxicity. Pediatric risk is amplified by developmental susceptibility, absence of age restrictions, and marketing in confectionary formats. Emerging analogues such as MGM-15 further extend this trajectory. Collectively, the evidence demonstrates that concentrated 7-OH products are pharmacologically and toxicologically distinct from kratom leaf and pose significant risks of morbidity and mortality under typical conditions of use.
Background: Hemp extracts are used topically as cosmetic products and may be ingested as dietary supplements. Some users report positive carboxy delta-9-tetrahydrocannabinol (COOH-THC) urinary tests following their use. This study evaluated systemic exposure to natural hemp extract-based cosmetic (NHEC) bioactive molecules following a single dose of oral or topical application and assessed urine THC positivity. Methods: Twenty healthy adults (18-50 years, males and females) of a randomized, open-label, single-dose, crossover study received the NHEC orally or topically with a 15-day washout period. Plasma samples were analyzed for cannabidiol (CBD), tetrahydrocannabinol (THC), and their metabolites using a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were calculated by non-compartmental analysis (Phoenix® WinNonlin® 8.4, Pharsight Inc., Chatham, NJ, USA). Urine samples were tested for COOH-THC using commercial test strips. Results: All analytes, except CBD and 7-hydroxy cannabidiol (7-OH-CBD), were below the limit of quantification. Oral NHEC administration resulted in a faster Tmax (3 h vs. 24 h) and a higher AUC0-24 (281 vs. 19 h·ng/mL) for CBD compared to topical administration. Urine was positive for COOH-THC in 38% of participants receiving an oral dose. Conclusions: A single oral dose resulted in detectable plasma CBD and 7-OH-CBD, whereas topical administration produced low and frequently BLQ CBD concentrations with 7-OH-CBD and THC-related analytes not quantifiable. Urine COOH-THC tests were positive only in participants after oral use of an NHEC but not with topical use. Given the absence of THC in the product and the lack of CBD-to-THC conversion in humans, the cause of urine positivity remains unclear.
Cushing's disease (CD) is associated with high rates of depression and anxiety that often persist despite biochemical remission, yet the underlying mechanisms remain unclear. This study aims to characterize circulating neurosteroid (NS) profiles in CD and examine their associations with psychological symptoms. This is a cross-sectional study of 37 patients with CD (22 active, 15 remission) and 21 nonfunctioning pituitary adenoma (NFA) controls. NS levels were quantified by mass spectrometry; psychological symptoms were assessed using the 21-item Depression Anxiety Stress Scale (DASS-21). Discriminatory NS were identified by partial least squares discriminant analysis (PLS-DA), with a variable importance in projection (VIP) score > 1.0 used as the selection threshold. Patients with CD exhibited higher depression (14 vs. 7.5, p = 0.03) and stress scores (17 vs. 8.5, p = 0.03) than NFA. PLS-DA identified five discriminatory NS: 4-androstenedione (VIP = 2.0), 11-deoxycorticosterone (DOC) (VIP = 1.8), 7-OH-pregnenolone (VIP = 1.8), corticosterone (VIP = 1.7), and androsterone (VIP = 1.1); the first four were elevated, and androsterone decreased in CD. Despite biochemical remission, most NS alterations persisted, with 7-OH-pregnenolone paradoxically increasing further (121 vs. 22.5 ng/mL, p = 0.008). Mood symptoms did not correlate with cortisol, adrenocorticotropic hormone (ACTH), or urinary free cortisol (UFC). However, dehydroepiandrosterone (DHEA) correlated positively with depression (r = 0.4, p = 0.02) and stress (r = 0.4, p = 0.02), whereas allopregnanolone correlated negatively with depression (r = -0.4, p = 0.03) and stress (r = -0.4, p = 0.04). Among discriminatory NS, only 7-OH-pregnenolone correlated with stress (r = 0.3, p = 0.04). These NS-mood associations were absent in NFA. CD is characterized by a distinct and persistent steroid signature that persists beyond biochemical remission, reflecting hypercortisolism-driven epigenetic remodeling of steroidogenic pathways. The dissociation between ACTH-driven steroid alterations and mood-associated NS suggests that cortisol reduction alone may inadequately address psychiatric symptoms, warranting investigation of NS-targeted therapies.
The non-nucleoside reverse transcriptase inhibitor efavirenz (EFV) is used in antiretroviral therapy (ART) against HIV. EFV is mainly metabolized by CYP2B6 to 8-hydroxyefavirenz (8-OH-EFV) and to a lesser extent by CYP2A6 to 7-hydroxyefavirenz (7-OH-EFV). Previous studies have only examined these metabolites in adults, indicating that EFV-hydroxy-metabolites might contribute to central nervous system (CNS) toxicity. This study aimed to quantify EFV and its metabolites including a recently identified EFV metabolite named EFAdeg in plasma and to explore their association with CYP2B6 metabolizer phenotypes and CNS adverse effects, in Ugandan children. Additionally, we examined signs of EFV autoinduction. We prospectively followed 99 Ugandan ART-naïve children in 2015-2016, aged 3-12 years with plasma sampling at 2, 6, 12, and 24 weeks after initiating-EFV-based ART. Using liquid chromatography high-resolution tandem mass spectrometry, we quantified EFV, 8-OH-EFV, 7-OH-EFV and EFAdeg in both unconjugated and conjugated forms. Genotyping for single nucleotide polymorphisms (SNP) in CYP2B6 and CYP2A6 was performed. CYP2B6 metabolizer phenotypes were predicted by the composite genotype of the two SNPs CYP2B6 c.516G>T and CYP2B6 c.983T>C. CNS adverse effects were assessed via a questionnaire. Autoinduction was investigated in a multivariate restricted maximum likelihood regression model (REML) with log(e) ((8-OH-EFV + EFAdeg)/EFV) as the outcome variable. Metabolite/EFV ratios in plasma varied significantly with CYP2B6 metabolizer phenotypes. Conjugated 8-OH-EFV (8-OH-EFV -glucuronide and 8-OH-EFV-sulfate) and conjugated EFAdeg constituted the major circulating forms of EFV in extensive and intermediate metabolizers, while the parent drug EFV dominated in slow metabolizers, who also displayed the highest levels of 7-OH-EFV. CNS symptoms were common, transient and mild and significantly associated with EFV plasma concentrations above 4,000 ng/mL and slow CYP2B6 metabolizer phenotype. None of the metabolites in plasma were associated with an increased risk of CNS toxicity. Evidence of autoinduction of EFV metabolism was observed among extensive metabolizers. This first study of EFV metabolites in children revealed distinct distribution patterns influenced by CYP2B6 metabolizer phenotype. Mild CNS-related adverse effects were associated with high EFV levels and slow CYP2B6 metabolizer phenotype, but not with EFV hydroxy metabolites. Autoinduction of EFV metabolism was observed in CYP2B6 extensive metabolizers.
Emerging evidence indicates that cannabidiol (CBD) may offer meaningful therapeutic benefits across neurological, pain, and psychiatric disorders. Cannabidiol is already approved for the treatment of pediatric epilepsy. Owing to its high lipophilicity, it is typically delivered in oil-based formulations to overcome the low oral bioavailability of pure CBD. However, pharmacokinetic (PK) and safety data remain limited across different CBD formulations. This study evaluated the PK profile, tolerability, and safety of an encapsulated powdered emulsion formulation (CBtru®) compared with a marketed oil-based formulation (Epidyolex®/Epidiolex®) under fasted and fed conditions in healthy adults. This Phase I, single-center, open-label, randomized, 4-way crossover PK trial was conducted in healthy adults. All participants received a single 400-mg dose of CBtru® and Epidyolex® under both fasted and fed conditions, with a minimum 14-day washout between administrations. Pharmacokinetic parameters and safety were assessed throughout. Under fasted conditions, CBtru® trended to higher CBD exposure (AUC0-24) and maximum concentration in plasma (Cmax) relative to Epidyolex®. CBtru® demonstrated significantly greater metabolite exposure (7-OH-CBD, 7-COOH-CBD), along with higher active drug exposure (ADE = CBD + 7-OH-CBD) and higher total drug exposure (TDE=CBD + 7-OH-CBD + 7-COOH-CBD). Median tmax was shorter with CBtru® (3 h vs 3.5 h), indicating faster absorption. In line with previous studies, CBD exposure and concentrations were significantly higher in fed rather than in fasted conditions. Under fed conditions, median tmax was shorter with CBtru® (5 h vs 8 h), while CBD and metabolite exposure were comparable. CBtru® also showed lower interindividual variability in plasma CBD profiles, suggesting more predictable PK across both conditions. Both formulations were well tolerated, with no safety concerns reported. Both formulations demonstrated distinct PK profiles under fasted and fed conditions. CBtru® showed comparable bioavailability to Epidyolex®, with faster absorption in fasted and fed conditions, higher metabolite exposure in fasted conditions, and more consistent systemic levels in the fasted condition. These findings support further development of CBtru® as a novel oral CBD formulation for clinical use in relevant indications. gov ID number: NCT06578455.
Mu-opioid receptor (MOR) agonists remain the mainstay treatment for severe acute pain but are limited by adverse effects including respiratory depression and constipation. Compounds with improved therapeutic profiles have been reported, and reduced intrinsic efficacy has been proposed as one factor contributing to greater separation between antinociceptive and adverse effects. To investigate the contribution of receptor reserve and intrinsic efficacy to the in vivo effects of opioid agonists, we used the pseudo-irreversible MOR antagonist methocinnamox (MCAM) to progressively deplete functional MORs and examined the effects of three MOR agonists-morphine, 7-OH mitragynine, and tianeptine-across multiple behavioural assays in mice. MCAM pretreatment inhibited agonist-induced effects in a dose-dependent manner across all assays. Lower doses of MCAM preferentially attenuated the antinociceptive, forced swim, and gastrointestinal effects of the lower-efficacy agonist 7-OH mitragynine, consistent with increased sensitivity of these behaviours to receptor depletion. In contrast, locomotor activation and respiratory depression induced by all three agonists were inhibited by similar MCAM doses, indicating comparable susceptibility to receptor depletion despite differences in intrinsic efficacy. Together, these findings suggest that differences in functional receptor reserve contribute to some, but not all, MOR-mediated behavioural outcomes. While reduced intrinsic efficacy and receptor reserve can partially explain separation between antinociception and certain adverse effects, additional ligand-dependent factors likely influence the expression of specific opioid-induced behaviours in vivo.