Trial of a Novel Oral Cannabinoid Formulation in Patients with Hypertension: A Double-Blind, Placebo-Controlled Pharmacogenetic Study
Abstract
:1. Introduction
2. Results
2.1. Visual Analog Scale (VAS)
2.2. CBD Concentrations
2.3. The Effect of CBD on Blood Pressure (BP)
2.4. SNP Genotyping
2.5. Association of CBD Concentrations with CYP Genotype and Phenotype of Subjects
3. Discussion
3.1. CBD Effect on Cardiovascular System
3.2. SNP Genotyping
3.3. Medication Influence
3.4. Side Effects
3.5. Study Limitations
4. Materials and Methods
4.1. Participants
4.2. Anthropometrics and Background
4.3. Research Design
4.4. Supplementation and Dosing
4.5. Sample Collection and Storage
4.6. Standard Solution
4.7. CBD Extraction
4.8. GC-MS Analysis
4.9. SNP Genotyping
4.10. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Abbotts, K.S.S.; Ewell, T.R.; Butterklee, H.M.; Bomar, M.C.; Akagi, N.; Dooley, G.P.; Bell, C. Cannabidiol and Cannabidiol Metabolites: Pharmacokinetics, Interaction with Food, and Influence on Liver Function. Nutrients 2022, 14, 2152. [Google Scholar] [CrossRef]
- Soleymanpour, M.; Saderholm, S.; Kavuluru, R. Therapeutic Claims in Cannabidiol (CBD) Marketing Messages on Twitter. In Proceedings of the 2021 IEEE International Conference on Bioinformatics and Biomedicine (BIBM), Houston, TX, USA, 9–12 December 2021; pp. 3083–3088. [Google Scholar]
- Pertwee, R.G. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br. J. Pharmacol. 2008, 153, 199–215. [Google Scholar] [CrossRef] [PubMed]
- Gray, R.A.; Heal, D.J.; Maguire, D.R.; Gerak, L.R.; Javors, M.A.; Smith, S.; France, C.P. Preclinical Assessment of the Abuse Potential of Purified Botanical Cannabidiol: Self-Administration, Drug Discrimination, and Physical Dependence. J. Pharmacol. Exp. Ther. 2022, 382, 54–65. [Google Scholar] [CrossRef]
- Jadoon, K.A.; Tan, G.D.; O’Sullivan, S.E. A single dose of cannabidiol reduces blood pressure in healthy volunteers in a randomized crossover study. JCI Insight 2017, 2, e93760. [Google Scholar] [CrossRef]
- Devinsky, O.; Cross, J.H.; Laux, L.; Marsh, E.; Miller, I.; Nabbout, R.; Scheffer, I.E.; Thiele, E.A.; Wright, S. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. N. Engl. J. Med. 2017, 376, 2011–2020. [Google Scholar] [CrossRef] [PubMed]
- Massi, P.; Solinas, M.; Cinquina, V.; Parolaro, D. Cannabidiol as potential anticancer drug. Br. J. Clin. Pharmacol. 2013, 75, 303–312. [Google Scholar] [CrossRef]
- Leweke, F.M.; Piomelli, D.; Pahlisch, F.; Muhl, D.; Gerth, C.W.; Hoyer, C.; Klosterkötter, J.; Hellmich, M.; Koethe, D. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl. Psychiatry 2012, 2, e94. [Google Scholar] [CrossRef] [PubMed]
- McGuire, P.; Robson, P.; Cubala, W.J.; Vasile, D.; Morrison, P.D.; Barron, R.; Taylor, A.; Wright, S. Cannabidiol (CBD) as an Adjunctive Therapy in Schizophrenia: A Multicenter Randomized Controlled Trial. Am. J. Psychiatry 2018, 175, 225–231. [Google Scholar] [CrossRef]
- Manzanares, J.; Julian, M.; Carrascosa, A. Role of the cannabinoid system in pain control and therapeutic implications for the management of acute and chronic pain episodes. Curr. Neuropharmacol. 2006, 4, 239–257. [Google Scholar] [CrossRef]
- Devinsky, O.; Marsh, E.; Friedman, D.; Thiele, E.; Laux, L.; Sullivan, J.; Miller, I.; Flamini, R.; Wilfong, A.; Filloux, F.; et al. Cannabidiol in patients with treatment-resistant epilepsy: An open-label interventional trial. Lancet Neurol. 2016, 15, 270–278. [Google Scholar] [CrossRef]
- Khalsa, J.H.; Bunt, G.; Blum, K.; Maggirwar, S.B.; Galanter, M.; Potenza, M.N. Review: Cannabinoids as Medicinals. Curr. Addict. Rep. 2022, 9, 630–646. [Google Scholar] [CrossRef]
- Sultan, S.R.; Millar, S.A.; England, T.J.; O’Sullivan, S.E. A Systematic Review and Meta-Analysis of the Haemodynamic Effects of Cannabidiol. Front. Pharmacol. 2017, 8, 81. [Google Scholar] [CrossRef]
- Rosenberg, E.C.; Louik, J.; Conway, E.; Devinsky, O.; Friedman, D. Quality of Life in Childhood Epilepsy in pediatric patients enrolled in a prospective, open-label clinical study with cannabidiol. Epilepsia 2017, 58, e96–e100. [Google Scholar] [CrossRef]
- Sultan, S.R.; O’Sullivan, S.E.; England, T.J. The effects of acute and sustained cannabidiol dosing for seven days on the haemodynamics in healthy men: A randomised controlled trial. Br. J. Clin. Pharmacol. 2020, 86, 1125–1138. [Google Scholar] [CrossRef] [PubMed]
- 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, 1053–1067. [Google Scholar] [CrossRef] [PubMed]
- Watkins, P.B.; Church, R.J.; Li, J.; Knappertz, V. Cannabidiol and Abnormal Liver Chemistries in Healthy Adults: Results of a Phase I Clinical Trial. Clin. Pharmacol. Ther. 2021, 109, 1224–1231. [Google Scholar] [CrossRef]
- Millar, S.A.; Maguire, R.F.; Yates, A.S.; O’Sullivan, S.E. Towards Better Delivery of Cannabidiol (CBD). Pharmaceuticals 2020, 13, 219. [Google Scholar] [CrossRef]
- Patrician, A.; Versic-Bratincevic, M.; Mijacika, T.; Banic, I.; Marendic, M.; Sutlović, D.; Dujić, Ž.; Ainslie, P.N. Examination of a New Delivery Approach for Oral Cannabidiol in Healthy Subjects: A Randomized, Double-Blinded, Placebo-Controlled Pharmacokinetics Study. Adv. Ther. 2019, 36, 3196–3210. [Google Scholar] [CrossRef]
- Kumric, M.; Dujic, G.; Vrdoljak, J.; Svagusa, K.; Kurir, T.T.; Supe-Domic, D.; Dujic, Z.; Bozic, J. CBD supplementation reduces arterial blood pressure via modulation of the sympatho-chromaffin system: A substudy from the HYPER-H21-4 trial. Biomed. Pharm. 2023, 160, 114387. [Google Scholar] [CrossRef] [PubMed]
- Kumric, M.; Bozic, J.; Dujic, G.; Vrdoljak, J.; Dujic, Z. Chronic Effects of Effective Oral Cannabidiol Delivery on 24-h Ambulatory Blood Pressure and Vascular Outcomes in Treated and Untreated Hypertension (HYPER-H21-4): Study Protocol for a Randomized, Placebo-Controlled, and Crossover Study. J. Pers. Med. 2022, 12, 1037. [Google Scholar] [CrossRef]
- Jiang, R.; Yamaori, S.; Takeda, S.; Yamamoto, I.; Watanabe, K. Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes. Life Sci. 2011, 89, 165–170. [Google Scholar] [CrossRef]
- Bachtiar, M.; Lee, C.G.L. Genetics of Population Differences in Drug Response. Curr. Genet. Med. Rep. 2013, 1, 162–170. [Google Scholar] [CrossRef]
- Sukprasong, R.; Chuwongwattana, S.; Koomdee, N.; Jantararoungtong, T.; Prommas, S.; Jinda, P.; Rachanakul, J.; Nuntharadthanaphong, N.; Jongjitsook, N.; Puangpetch, A.; et al. Allele frequencies of single nucleotide polymorphisms of clinically important drug-metabolizing enzymes CYP2C9, CYP2C19, and CYP3A4 in a Thai population. Sci. Rep. 2021, 11, 12343. [Google Scholar] [CrossRef] [PubMed]
- Pratt, V.M.; Cavallari, L.H.; Del Tredici, A.L.; Hachad, H.; Ji, Y.; Moyer, A.M.; Scott, S.A.; Whirl-Carrillo, M.; Weck, K.E. Recommendations for Clinical CYP2C9 Genotyping Allele Selection: A Joint Recommendation of the Association for Molecular Pathology and College of American Pathologists. J. Mol. Diagn. JMD 2019, 21, 746–755. [Google Scholar] [CrossRef] [PubMed]
- Ionova, Y.; Ashenhurst, J.; Zhan, J.; Nhan, H.; Kosinski, C.; Tamraz, B.; Chubb, A. CYP2C19 Allele Frequencies in Over 2.2 Million Direct-to-Consumer Genetics Research Participants and the Potential Implication for Prescriptions in a Large Health System. Clin. Transl. Sci. 2020, 13, 1298–1306. [Google Scholar] [CrossRef]
- Zanger, U.M.; Schwab, M. Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol. Ther. 2013, 138, 103–141. [Google Scholar] [CrossRef]
- Nasrin, S.; Watson, C.J.W.; Perez-Paramo, Y.X.; Lazarus, P. Cannabinoid Metabolites as Inhibitors of Major Hepatic CYP450 Enzymes, with Implications for Cannabis-Drug Interactions. Drug Metab. Dispos. Biol. Fate Chem. 2021, 49, 1070–1080. [Google Scholar] [CrossRef]
- PharmGKB. Available online: https://www.pharmgkb.org/vip/PA166169770 (accessed on 9 January 2023).
- Bozina, N.; Granić, P.; Lalić, Z.; Tramisak, I.; Lovrić, M.; Stavljenić-Rukavina, A. Genetic polymorphisms of cytochromes P450: CYP2C9, CYP2C19, and CYP2D6 in Croatian population. Croat. Med. J. 2003, 44, 425–428. [Google Scholar] [PubMed]
- Bonomo, Y.; Norman, A.; Collins, L.; O’Neill, H.; Galettis, P.; Trinca, J.; Strauss, N.; Martin, J.; Castle, D. Pharmacokinetics, Safety, and Tolerability of a Medicinal Cannabis Formulation in Patients with Chronic Non-cancer Pain on Long-Term High Dose Opioid Analgesia: A Pilot Study. Pain Ther. 2022, 11, 171–189. [Google Scholar] [CrossRef] [PubMed]
- Millar, S.A.; Stone, N.L.; Yates, A.S.; O’Sullivan, S.E. A Systematic Review on the Pharmacokinetics of Cannabidiol in Humans. Front. Pharmacol. 2018, 9, 1365. [Google Scholar] [CrossRef]
- Bioscience, L. DehydraTECH. Available online: https://lexariabioscience.com/ (accessed on 7 December 2022).
- Skadrić, I.; Stojković, O. Defining screening panel of functional variants of CYP1A1, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 genes in Serbian population. Int. J. Leg. Med. 2020, 134, 433–439. [Google Scholar] [CrossRef] [PubMed]
- Beers, J.L.; Fu, D.; Jackson, K.D. Cytochrome P450-Catalyzed Metabolism of Cannabidiol to the Active Metabolite 7-Hydroxy-Cannabidiol. Drug Metab. Dispos. Biol. Fate Chem. 2021, 49, 882–891. [Google Scholar] [CrossRef] [PubMed]
- PharmGKB. Available online: https://www.pharmgkb.org/labelAnnotation/PA166104784 (accessed on 11 January 2023).
- PharmGKB. Available online: https://www.pharmgkb.org/labelAnnotation/PA166127647 (accessed on 11 January 2023).
- Takahashi, N.; Inui, N.; Morita, H.; Takeuchi, K.; Uchida, S.; Watanabe, H.; Nakamura, H. Effect of thyroid hormone on the activity of CYP3A enzyme in humans. J. Clin. Pharmacol. 2010, 50, 88–93. [Google Scholar] [CrossRef] [PubMed]
- Flack, J.M.; Adekola, B. Blood pressure and the new ACC/AHA hypertension guidelines. Trends Cardiovasc. Med. 2020, 30, 160–164. [Google Scholar] [CrossRef]
- Sutlović, D. Osnove Forenzične Toksikologije, Potvrdne Metode Analize; Sutlović, D., Ed.; Tisak: Split, Croatia, 2011; Volume 1, pp. 111–114. [Google Scholar]
- Sutlović, D. Osnove Forenzične Toksikologije, Potvrdna Analitička Metoda, Plinska Kromatografija-Spektrometrija Masa; Tisak: Split, Croatia, 2011; Volume 1, pp. 394–396. [Google Scholar]
- One Way Anova Calculator. Available online: https://goodcalculators.com/one-way-anova-calculator/ (accessed on 31 January 2023).
- Hardy-Weinberg Equilibrium. Available online: http://www.dr-petrek.eu/documents/HWE.xls (accessed on 15 December 2022).
Dose | BL | 90 min | 180 min | Dose | Time | Inter | |
---|---|---|---|---|---|---|---|
GI | A | 0 ± 0 | 0.8 ± 4.1 | 1.3 ± 6.1 | 0.154 | 0.464 | 0.579 |
B | 0 ± 0 | 0 ± 0 | 0.1 ± 0.6 | ||||
Anxiety | A | 8.1 ± 14 | 3.3 ± 8.6 | 3.3 ± 8.6 | 0.523 | 0.083 | 0.663 |
B | 5.5 ± 10.1 | 3.2 ± 7.8 | 3.6 ± 7.9 | ||||
Sleepiness | A | 7.1 ± 14.2 | 32.9 ± 27.6 | 29.1 ± 21.9 | 0.380 | <0.001 | 0.763 |
B | 3.6 ± 8.5 | 26.8 ± 30.9 | 28.6 ± 28.2 |
Samples n = 24 | Minimum ng/mL | Maximum ng/mL | Median | IQR | Mann–Whitney U Test p Value | |
---|---|---|---|---|---|---|
Plasma at 120 min. | A | 5.91 | 225.22 | 73.73 | 99.80 | 0.853 |
B | 0.05 | 715.91 | 65.79 | 83.73 | ||
Plasma at 180 min. | A | 44.03 | 807.24 | 177.48 | 132.45 | 0.322 |
B | 51.22 | 612.98 | 134.78 | 105.76 | ||
Urine at 180 min. | A | 8.49 | 3678.50 | 545.76 | 1000.02 | 0.680 |
B | 12.16 | 3750.64 | 327.35 | 971.45 |
CBD Formulation | Parameters | Baseline (Mean ± SD) | At 120 min (Mean ± SD) | At 180 min (Mean ± SD) | p * (Baseline—120 min) | p * (Baseline—180 min) |
---|---|---|---|---|---|---|
CBD (n = 24) | Diastolic BP (mmHg) | 84.08 ± 8.53 | 84.58 ± 8.69 | 85.54 ± 8.78 | 0.842 | 0.562 |
Systolic BP (mmHg) | 136.21 ± 10.54 | 131.67 ± 10.36 | 133.5 ± 10.8 | 0.156 | 0.403 | |
Heart rate (bpm) | 73.33 ± 11.02 | 66.54 ± 9.38 | 66.79 ± 8.41 | 0.238 | 0.024 | |
DehydraTECH™2.0 CBD (n = 24) | Diastolic BP (mmHg) | 84.38 ± 7.76 | 84.42 ± 6.58 | 85.58 ± 8.68 | 0.984 | 0.614 |
Systolic BP (mmHg) | 134.67 ± 9.25 | 130.17 ± 7.52 | 132.58 ± 9.82 | 0.071 | 0.453 | |
Heart rate (bpm) | 74.33 ± 11.90 | 68.08 ± 9.34 | 66.96 ± 9.18 | 0.048 | 0.020 |
Gene | SNP | Genotype | N | Minor Allele | Minor Allele Frequency (MAF) % | Hardy–Weinberg Equilibrium | |
---|---|---|---|---|---|---|---|
p Allele Frequency | χ2 p-Value | ||||||
CYP3A4 | rs2740574 | TT | 23 | C | 2.08 | 0.977 | 0.011 0.917 |
CT | 1 | ||||||
CC | 0 | ||||||
CYP2C9*2 | rs1799853 | CC | 17 | T | 16.67 | 0.833 | 0.24 0.624 |
CT | 6 | ||||||
TT | 1 | ||||||
CYP2C9*3 | rs1057910 | AA | 19 | C | 12.50 | 0.875 | 1.361 0.243 |
AC | 4 | ||||||
CC | 1 | ||||||
CYP2C19*2 | rs4244285 | GG | 19 | A | 10.42 | 0.896 | 0.325 0.569 |
GA | 5 | ||||||
AA | 0 | ||||||
CYP2C19*3 | rs4986893 | GG | 24 | A | 0 | 1.00 | 0.000 0.569 |
GA | 0 | ||||||
AA | 0 | ||||||
CYP2C19*17 | rs12248560 | CC | 15 | T | 20.83 | 0.792 | 0.003 0.959 |
CT | 8 | ||||||
TT | 1 |
n | Age (Years) | Height (cm) | Weight (kg) | BMI (kg/m2) | |
---|---|---|---|---|---|
Females | 12 | 55 ± 8 | 167 ± 4 | 81 ± 9 | 29.2 ± 3.8 |
Males | 12 | 52 ± 6 | 182 ± 6 | 101 ± 15 | 30.3 ± 4.2 |
Total | 24 | 54 ± 7 | 175 ± 9 | 91 ± 16 | 29.7 ± 4 |
Current smokers (n) | 0 |
Used to smoke (n (%)) | 6 |
Years since smoked | 20 ± 10; range: 6–33 |
Pack years when smoking | 13 ± 5; range: 5–20 |
Uses CBD (n (%)) | 1 † |
On medications (n (%)) | 6 |
Diazepam (n; dose) | 1 (5 mg) |
Levothyroxin (n; dose) | 3 (25 µg and 100 µg) |
Lorazepam (n; dose) | 1 (1 mg) |
Celecoxib (n; dose) | 1 (200 mg) |
Acidum salicylicum (n; dose) | 1 (100 mg) |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Batinic, A.; Sutlović, D.; Kuret, S.; Matana, A.; Kumric, M.; Bozic, J.; Dujic, Z. Trial of a Novel Oral Cannabinoid Formulation in Patients with Hypertension: A Double-Blind, Placebo-Controlled Pharmacogenetic Study. Pharmaceuticals 2023, 16, 645. https://doi.org/10.3390/ph16050645
Batinic A, Sutlović D, Kuret S, Matana A, Kumric M, Bozic J, Dujic Z. Trial of a Novel Oral Cannabinoid Formulation in Patients with Hypertension: A Double-Blind, Placebo-Controlled Pharmacogenetic Study. Pharmaceuticals. 2023; 16(5):645. https://doi.org/10.3390/ph16050645
Chicago/Turabian StyleBatinic, Ana, Davorka Sutlović, Sendi Kuret, Antonela Matana, Marko Kumric, Josko Bozic, and Zeljko Dujic. 2023. "Trial of a Novel Oral Cannabinoid Formulation in Patients with Hypertension: A Double-Blind, Placebo-Controlled Pharmacogenetic Study" Pharmaceuticals 16, no. 5: 645. https://doi.org/10.3390/ph16050645