{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T00:14:55Z","timestamp":1792282495568,"version":"4.4.0"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T00:00:00Z","timestamp":1754438400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T00:00:00Z","timestamp":1754438400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Cannabis Res"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>This study aimed to compare the pharmacokinetics and relative bioavailability of two novel cannabidiol (CBD) formulations including bioavailability-enhanced capsule (CBDNEXT Supra capsule) and a bioavailability-enhanced liquid (CBDNEXT Supra liquid)\u2013 against a standard high-purity CBD isolate capsule in healthy volunteers under fed (low-fat) conditions.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>A single-dose, open-label, randomized, three-period, three-sequence crossover trial was conducted in 12 healthy male volunteers (18\u201350 years). Of the 12 enrolled subjects, 9 completed all three treatment periods per protocol. Each received 40\u00a0mg of CBD as one of three formulations: Test-1 (enhanced CBD capsule), Test-2 (enhanced CBD liquid), or Reference (unformulated CBD isolate capsule with microcrystalline cellulose only as excipient), with a washout of 14 days between treatments. All doses were administered 30\u00a0min after a standardized low-fat (~\u2009300\u2013350 kcal, &lt;\u200910\u00a0g fat) breakfast to minimize the impact of dietary fat on CBD absorption. Blood samples were collected up to 72\u00a0h post-dose for plasma CBD and 7-hydroxy-CBD analysis by a validated LC\u2013MS\/MS method (LLOQ 0.1 ng\/mL). Pharmacokinetic (PK) parameters (C_max, tmax, AUC_0\u201372, and t_1\/2) were determined by non-compartmental analysis. Safety was assessed by adverse events (AEs), vital signs, and laboratory tests (including liver enzymes). Plasma cortisol was measured pre-dose and at 2-, 4-, and 8-hours post-dose as an exploratory pharmacodynamic marker.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Nine subjects completed all treatments (three withdrew: two for positive drug screens and one for an intercurrent moderate infection). Mean plasma CBD concentration\u2013time profiles for the three formulations demonstrated markedly different absorption kinetics. The enhanced capsule achieved the highest peak CBD concentration (C_max 14.1 ng\/mL) and exposure (AUC_0\u201372 38.0\u00a0h\u00b7ng\/mL), compared to the enhanced liquid (C_max 6.2 ng\/mL, AUC_0\u201372 20.2\u00a0h\u00b7ng\/mL) and the reference capsule (C_max 2.4 ng\/mL, AUC_0\u201372 11.7\u00a0h\u00b7ng\/mL). The time to peak concentration (tmax) was shortest for the liquid (median\u2009~\u20091.0\u00a0h), followed by the capsule (2.0\u00a0h), and longest for the reference (6.0\u00a0h). Inter-individual variability in C_max and AUC was substantially lower for both novel formulations (coefficients of variation\u2009~\u200927\u201344%) than for the reference (&gt;\u200990%). Statistical analysis confirmed that both the enhanced capsule and liquid produced significantly greater C_max and AUC_0\u201372 than the reference (geometric mean C_max ratios\u2009~\u2009566% and ~\u2009248%, AUC_0\u201372 ratios\u2009~\u2009328% and ~\u2009166%, respectively; 90% confidence intervals did not include 100%). The 7-hydroxy-CBD metabolite reached much lower plasma levels than parent CBD for all treatments (C_max 0.4\u20131.8 ng\/mL, ~\u20095\u201313% of parent C_max), with a slightly delayed tmax (~\u20092\u20136\u00a0h) and similar elimination half-life. No serious AEs occurred. The only treatment-related AE was mild-to-moderate transient headache in four subjects (1 on capsule, 2 on liquid, 1 on reference), all resolved without intervention. No clinically significant changes in liver function tests or other laboratory values were observed. Plasma cortisol levels remained within normal ranges after all treatments, with a decline over 8\u00a0h consistent with the normal diurnal rhythm and no significant differences between formulations.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Both novel formulations markedly improved CBD oral bioavailability under low-fat fed conditions relative to an unformulated CBD isolate capsule. The enhanced capsule in particular achieved a\u2009~\u20095.7-fold higher C_max and ~\u20093.3-fold higher AUC than the reference, while the enhanced liquid was absorbed\u2009~\u20092.5-fold faster. Variability was reduced with the new formulations, and both were well tolerated at the 40\u00a0mg dose. These results indicate that the surfactant\/acid formulation technology effectively enhances CBD absorption even with a low-fat meal, potentially obviating the need for high-fat co-administration. Further clinical studies (including in female subjects and at steady state) are warranted to confirm these pharmacokinetic advantages in broader populations.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Trial registration<\/jats:title>\n            <jats:p>Not prospectively registered (pilot pharmacokinetic study without therapeutic intent, thus not subject to mandatory registration).<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s42238-025-00312-9","type":"journal-article","created":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T13:36:59Z","timestamp":1754487419000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Randomized single-dose crossover comparative bioavailability study of two novel oral cannabidiol (CBD) formulations in healthy volunteers under fed conditions, compared to a standard CBD isolate capsule"],"prefix":"10.1186","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5444-6452","authenticated-orcid":false,"given":"Mehmet Nevzat","family":"Pisak","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6386-0376","authenticated-orcid":false,"given":"Edibe","family":"Bereket","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9277-1333","authenticated-orcid":false,"given":"Aydin","family":"Erenmemisoglu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,6]]},"reference":[{"issue":"7","key":"312_CR1","first-page":"434","volume":"45","author":"R Abu-Sawwa","year":"2020","unstructured":"Abu-Sawwa R, Scutt B, Park Y. Cannabidiol (Epidiolex) for the treatment of Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex in paediatric patients. P T. 2020;45(7):434\u201341.","journal-title":"P T"},{"issue":"4","key":"312_CR2","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.1007\/s00213-019-05401-6","volume":"237","author":"E Appiah-Kusi","year":"2020","unstructured":"Appiah-Kusi E, Petros N, Wilson R, Colizzi M, Bossong MG, Valmaggia L, et al. Effects of short-term Cannabidiol treatment on response to social stress in subjects at clinical high risk of developing psychosis. Psychopharmacology(Berl). 2020;237(4):1121\u201330. https:\/\/doi.org\/10.1007\/s00213-019-05401-6.","journal-title":"Psychopharmacology(Berl)"},{"issue":"7","key":"312_CR3","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1002\/cpdd.408","volume":"7","author":"J Atsmon","year":"2018","unstructured":"Atsmon J, Heffetz D, Deutsch L, Deutsch F, Sacks H. Single-Dose pharmacokinetics of oral Cannabidiol following administration of PTL101: A new formulation based on gelatin matrix pellets technology. Clin Pharmacol Drug Dev. 2018;7(7):751\u20138. https:\/\/doi.org\/10.1002\/cpdd.408.","journal-title":"Clin Pharmacol Drug Dev"},{"issue":"10","key":"312_CR4","doi-asserted-by":"publisher","first-page":"1008","DOI":"10.1124\/dmd.120.090605","volume":"48","author":"S Bansal","year":"2020","unstructured":"Bansal S, Maharao N, Paine MF, Kunze KL, Perkins EJ, Coutinho DF, et al. Cannabidiol (CBD) as a perpetrator of drug\u2013drug interactions: in-vitro assessment of CYP Inhibition and induction, and the role of P-gp transport. Drug Metab Dispos. 2020;48(10):1008\u201316. https:\/\/doi.org\/10.1124\/dmd.120.090605.","journal-title":"Drug Metab Dispos"},{"issue":"4","key":"312_CR5","doi-asserted-by":"publisher","first-page":"237","DOI":"10.2174\/157488611798557748","volume":"6","author":"MM Bergamaschi","year":"2011","unstructured":"Bergamaschi MM, Queiroz RHC, Chagas MH, De Lima Os\u00f3rio F, Nardi AE, Crippa JA. Safety and side effects of cannabidiol, a cannabis sativa constituent. Curr Drug Saf. 2011;6(4):237\u201349. https:\/\/doi.org\/10.2174\/157488611798557748.","journal-title":"Curr Drug Saf"},{"issue":"8","key":"312_CR6","doi-asserted-by":"publisher","first-page":"1586","DOI":"10.1111\/epi.16355","volume":"60","author":"AK Birnbaum","year":"2019","unstructured":"Birnbaum AK, Roslawski M, Karanam A, Butler R, Ranatunga DK, Gramling-Aiken B, et al. Food effect on pharmacokinetics of Cannabidiol oral capsules in adult patients with refractory epilepsy. Epilepsia. 2019;60(8):1586\u201392. https:\/\/doi.org\/10.1111\/epi.16355.","journal-title":"Epilepsia"},{"issue":"1","key":"312_CR7","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1007\/s00213-020-05712-8","volume":"238","author":"SC Britch","year":"2021","unstructured":"Britch SC, Babalonis S, Walsh SL. Cannabidiol: Pharmacology and therapeutic targets. Psychopharmacology. 2021;238(1):9\u201328. https:\/\/doi.org\/10.1007\/s00213-020-05712-8.","journal-title":"Psychopharmacology"},{"issue":"7","key":"312_CR8","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1023\/A:1007584408155","volume":"17","author":"SM Caliph","year":"2000","unstructured":"Caliph SM, Charman WN, Porter CJH. Effect of short-, medium-, and long-chain fatty acid\u2013based vehicles on the lymphatic transport of a poorly water-soluble drug. Pharm Res. 2000;17(7):831\u20137. https:\/\/doi.org\/10.1023\/A:1007584408155.","journal-title":"Pharm Res"},{"issue":"21","key":"312_CR9","doi-asserted-by":"publisher","first-page":"2011","DOI":"10.1056\/NEJMoa1611618","volume":"376","author":"O Devinsky","year":"2017","unstructured":"Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, et al. Trial of Cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376(21):2011\u201320. https:\/\/doi.org\/10.1056\/NEJMoa1611618.","journal-title":"N Engl J Med"},{"key":"312_CR10","unstructured":"European Medicines Agency (EMA). Guideline on the investigation of bioequivalence. Volume 20. London: EMA; 2010 Jan. [Accessed 2025 May 12]. Report No.: CPMP\/EWP\/QWP\/1401\/98 Rev.1\/Corr."},{"issue":"7","key":"312_CR11","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1002\/phar.1765","volume":"36","author":"PS Fasinu","year":"2016","unstructured":"Fasinu PS, Phillips S, ElSohly MA, Walker LA. Current status and prospects for Cannabidiol preparations as new therapeutic agents. Pharmacotherapy. 2016;36(7):781\u201396. https:\/\/doi.org\/10.1002\/phar.1765.","journal-title":"Pharmacotherapy"},{"key":"312_CR12","doi-asserted-by":"publisher","first-page":"865980","DOI":"10.3389\/fphar.2022.865980","volume":"13","author":"VL Hegde","year":"2022","unstructured":"Hegde VL, Nagarkatti PS, Nagarkatti M. Pharmacokinetics and novel delivery systems of Cannabidiol. Front Pharmacol. 2022;13:865980. https:\/\/doi.org\/10.3389\/fphar.2022.865980.","journal-title":"Front Pharmacol"},{"issue":"1","key":"312_CR14","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1089\/can.2016.0034","volume":"2","author":"K Iffland","year":"2017","unstructured":"Iffland K, Grotenhermen F. An update on safety and side effects of cannabidiol: a review of clinical data and relevant animal studies. Cannabis Cannabinoid Res. 2017;2(1):139\u201354. https:\/\/doi.org\/10.1089\/can.2016.0034.","journal-title":"Cannabis Cannabinoid Res"},{"key":"312_CR13","unstructured":"International Conference on Harmonisation. ICH harmonised guideline: guideline for good clinical practice E6(R1). Geneva: ICH. 1996. [Accessed 2025 May 12]."},{"key":"312_CR15","doi-asserted-by":"publisher","first-page":"1365","DOI":"10.3389\/fphar.2018.01365","volume":"9","author":"SA Millar","year":"2018","unstructured":"Millar SA, Stone NL, Yates AS, O\u2019Sullivan SE. A systematic review on the pharmacokinetics of Cannabidiol in humans. Front Pharmacol. 2018;9:1365. https:\/\/doi.org\/10.3389\/fphar.2018.01365.","journal-title":"Front Pharmacol"},{"issue":"2","key":"312_CR17","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1038\/sj.bjp.0707442","volume":"153","author":"RG Pertwee","year":"2008","unstructured":"Pertwee RG. The diverse CB1 and CB2 receptor Pharmacology of three plant cannabinoids: \u22069-THC, Cannabidiol and \u22069-THCV. Br J Pharmacol. 2008;153(2):199\u2013215. https:\/\/doi.org\/10.1038\/sj.bjp.0707442.","journal-title":"Br J Pharmacol"},{"issue":"8","key":"312_CR16","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1007\/s40263-020-00754-2","volume":"34","author":"E Perucca","year":"2020","unstructured":"Perucca E, Bialer M. Critical aspects affecting Cannabidiol oral bioavailability and metabolic elimination, and related clinical implications. CNS Drugs. 2020;34(8):795\u2013800. https:\/\/doi.org\/10.1007\/s40263-020-00754-2.","journal-title":"CNS Drugs"},{"key":"312_CR18","unstructured":"Pisak MN. Cannabinoid compositions with high solubility and bioavailability. European patent EP3886839A1. 2021 Oct 6. [Accessed 2025 May 12]."},{"key":"312_CR19","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1186\/1741-7015-8-18","volume":"8","author":"KF Schulz","year":"2010","unstructured":"Schulz KF, Altman DG, Moher D, CONSORT Group. CONSORT 2010 statement: updated guidelines for reporting parallel-group randomised trials. BMC Med. 2010;8:18. https:\/\/doi.org\/10.1186\/1741-7015-8-18.","journal-title":"BMC Med"},{"issue":"5","key":"312_CR20","doi-asserted-by":"publisher","first-page":"1135","DOI":"10.1007\/s00228-012-1432-9","volume":"69","author":"C Stott","year":"2013","unstructured":"Stott C, Guy G, Wright S, Whittle B, Rennison R. A phase I study to assess the single and multiple dose pharmacokinetics of THC\/CBD oromucosal spray. Eur J Clin Pharmacol. 2013;69(5):1135\u201347. https:\/\/doi.org\/10.1007\/s00228-012-1432-9.","journal-title":"Eur J Clin Pharmacol"},{"issue":"11","key":"312_CR21","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.1007\/s40263-018-0578-5","volume":"32","author":"L Taylor","year":"2018","unstructured":"Taylor L, Gidal B, Blakey G, Tayo B, Morrison G. A phase I, randomized, double-blind, placebo-controlled, single ascending-dose, multiple-dose, and food-effect trial of the safety, tolerability and pharmacokinetics of highly purified Cannabidiol in healthy subjects. CNS Drugs. 2018;32(11):1053\u201367. https:\/\/doi.org\/10.1007\/s40263-018-0578-5.","journal-title":"CNS Drugs"},{"key":"312_CR22","unstructured":"U.S. Food and drug administration. Guidance for industry: bioavailability and bioequivalence studies for orally administered drug products\u2014general considerations. Silver Spring (MD): FDA; 2003. [Accessed 2025 May 12]."},{"issue":"1","key":"312_CR23","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1210\/jcem-33-1-14","volume":"33","author":"ED Weitzman","year":"1971","unstructured":"Weitzman ED, Fukushima D, Nogeire C, Roffwarg H, Gallagher TF, Hellman L. Twenty-four-hour pattern of the episodic secretion of cortisol in normal subjects. J Clin Endocrinol Metab. 1971;33(1):14\u201322. https:\/\/doi.org\/10.1210\/jcem-33-1-14.","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"312_CR24","doi-asserted-by":"publisher","first-page":"35","DOI":"10.3390\/ph14010035","volume":"14","author":"NB Williams","year":"2021","unstructured":"Williams NB, Ewell TR, Abbotts KS, Harms KJ, Woelfel KA, Dooley GP, et al. Comparison of five oral Cannabidiol preparations in adult humans: pharmacokinetics, body composition, and heart-rate variability. Pharmaceuticals (Basel). 2021;14(1):35. https:\/\/doi.org\/10.3390\/ph14010035.","journal-title":"Pharmaceuticals (Basel)"},{"issue":"9","key":"312_CR25","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1080\/03639040701320018","volume":"33","author":"L Yuan","year":"2007","unstructured":"Yuan L, Li J, Xiao X, Zhang Y, Liu X, Yu C, et al. Effects of surfactants on P-glycoprotein Inhibition and bioavailability enhancement of a P-gp substrate. Drug Dev Ind Pharm. 2007;33(9):947\u201356. https:\/\/doi.org\/10.1080\/03639040701320018.","journal-title":"Drug Dev Ind Pharm"},{"key":"312_CR26","doi-asserted-by":"publisher","first-page":"26839","DOI":"10.1038\/srep26839","volume":"6","author":"A Zgair","year":"2016","unstructured":"Zgair A, Wong JC, Lee JB, Mistry J, Sivak O, Wasan KM, et al. Dietary fats and pharmaceutical lipid excipients increase systemic exposure to orally administered cannabis and its major psychoactive constituent THC in rats. Sci Rep. 2016;6:26839. https:\/\/doi.org\/10.1038\/srep26839.","journal-title":"Sci Rep"},{"key":"312_CR27","doi-asserted-by":"publisher","first-page":"14542","DOI":"10.1038\/s41598-017-15026-z","volume":"7","author":"A Zgair","year":"2017","unstructured":"Zgair A, Lee JB, Wong JC, Taha DA, Aram J, Di Virgilio D, et al. Oral administration of cannabis with lipids leads to high levels of cannabinoids in the intestinal lymphatic system. Sci Rep. 2017;7:14542. https:\/\/doi.org\/10.1038\/s41598-017-15026-z.","journal-title":"Sci Rep"}],"container-title":["Journal of Cannabis Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s42238-025-00312-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s42238-025-00312-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s42238-025-00312-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T13:37:03Z","timestamp":1754487423000},"score":1,"resource":{"primary":{"URL":"https:\/\/jcannabisresearch.biomedcentral.com\/articles\/10.1186\/s42238-025-00312-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,6]]},"references-count":27,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["312"],"URL":"https:\/\/doi.org\/10.1186\/s42238-025-00312-9","relation":{},"ISSN":["2522-5782"],"issn-type":[{"value":"2522-5782","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,6]]},"assertion":[{"value":"22 October 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 July 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 August 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study protocol was approved by the Institutional Review Board\/Independent Ethics Committee\/(lRB\/IEC) at APIC\/PRU clinical site. All participants provided written informed consent prior to any study procedures. The trial was conducted in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. While the study adhered to ethical principles, it was not prospectively registered in a publicly accessible database before recruitment of the first subject. The EMA bioequivalence guidance and CONSORT recommendations were followed in the design and reporting of the trial.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable (no individual patient data are reported that would require personal consent for publication).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Mehmet Nevzat Pisak is the Chairman of Imuneks Farma Pharmaceuticals Industry and Trade Inc. Edibe Bereket, Pharm is Regulatory Affairs Director and Clinical Research Director at Imuneks Farma. Aydin Erenmemisoglu declares that he has no conflict of interest, and he has no financial or employment ties with the company or the other two authors.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"54"}}