{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T02:37:33Z","timestamp":1791859053611,"version":"4.3.4"},"reference-count":32,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,10,11]],"date-time":"2022-10-11T00:00:00Z","timestamp":1665446400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: The increase in the medical use of cannabis has revealed a number of beneficial effects, a variety of adverse side effects and great inter-individual variability. Association studies connecting consumption, addiction and side effects related to recreational cannabis use have led to the identification of several polymorphic genes that may play a role in the pharmacodynamics and pharmacokinetics of cannabis. Method: In total, 600 patients treated with cannabis were genotyped for several candidate polymorphic genes (single-nucleotide polymorphism; SNP), encoding receptors CNR1 and TRPV1; for the ABCB1 transporter; for biotransformation, bioactivation and biosynthesis; and CYP3A4, COMT and UGT2B7 conjugation. Results: Three polymorphic genes (ABCB1, TRPV1 and UGT2B7) were identified as being significantly associated with decline in pain after treatment with cannabis. Patients simultaneously carrying the most favourable allele combinations showed a greater reduction (polygenic effect) in pain compared to those with a less favourable combination. Considering genotype combinations, we could group patients into good responders, intermediate responders and poor or non-responders. Results suggest that genetic makeup is, at the moment, a significant predictive factor of the variability in response to cannabis. Conclusions: This study proves, for the first time, that certain polymorphic candidate genes may be associated with cannabis effects, both in terms of pain management and side effects, including therapy dropout. Significance: Our attention to pharmacogenetics began in 2008, with the publication of a first study on the association between genetic polymorphisms and morphine action in pain relief. The study we are presenting is the first observational study conducted on a large number of patients involving several polymorphic candidate genes. The data obtained suggest that genetic makeup can be a predictive factor in the response to cannabis therapy and that more extensive and planned studies are needed for the opening of new scenarios for the personalization of cannabis therapy.<\/jats:p>","DOI":"10.3390\/genes13101832","type":"journal-article","created":{"date-parts":[[2022,10,11]],"date-time":"2022-10-11T22:18:13Z","timestamp":1665526693000},"page":"1832","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["The Pharmacogenetics of Cannabis in the Treatment of Chronic Pain"],"prefix":"10.3390","volume":"13","author":[{"given":"Paolo","family":"Poli","sequence":"first","affiliation":[{"name":"POLIPAIN CLINIC, SIRCA Italian Society of Cannabis Research, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luana","family":"Peruzzi","sequence":"additional","affiliation":[{"name":"Department of Chemical Biotechnology and Pharmacy, Siena University, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierdomenico","family":"Maurizi","sequence":"additional","affiliation":[{"name":"Occupational Medicine and Palliative Care Unit, Arezzo Hospital, 52100 Arezzo Tuscany, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Mencucci","sequence":"additional","affiliation":[{"name":"Occupational Medicine and Palliative Care Unit, Arezzo Hospital, 52100 Arezzo Tuscany, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2060-5923","authenticated-orcid":false,"given":"Antonella","family":"Scocca","sequence":"additional","affiliation":[{"name":"POLIPAIN CLINIC, SIRCA Italian Society of Cannabis Research, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Carnevale","sequence":"additional","affiliation":[{"name":"POLIPAIN CLINIC, SIRCA Italian Society of Cannabis Research, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0263-7107","authenticated-orcid":false,"given":"Ottavia","family":"Spiga","sequence":"additional","affiliation":[{"name":"Department of Chemical Biotechnology and Pharmacy, Siena University, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6976-9086","authenticated-orcid":false,"given":"Annalisa","family":"Santucci","sequence":"additional","affiliation":[{"name":"Department of Chemical Biotechnology and Pharmacy, Siena University, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,11]]},"reference":[{"key":"ref_1","first-page":"1161","article-title":"Medical use of cannabis: Italian and European Legislation","volume":"22","author":"Zaami","year":"2018","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1179544120906461","DOI":"10.1177\/1179544120906461","article-title":"Cannabinoids in Chronic Non-Cancer Pain: A Systematic Review and Meta-Analysis","volume":"13","author":"Johal","year":"2020","journal-title":"Clin. Med. Insights Arthritis Musculoskelet. Disord."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Brown, J.D., and Winterstein, A.G. (2019). Potential Adverse Drug Events and Drug-Drug Interactions with Medical and Consumer Cannabidiol (CBD) Use. J. Clin. Med., 8.","DOI":"10.3390\/jcm8070989"},{"key":"ref_4","unstructured":"MacDonald, E., and Adams, A. (2022, August 29). The Use of Medical Cannabis with Other Medications: A Review of Safety and Guidelines\u2014An Update. Canadian Agency for Drugs and Technologies in Health, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK549545\/."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"216","DOI":"10.3109\/15360288.2014.941130","article-title":"The Pharmacokinetics, Efficacy, Safety, and Ease of Use of a Novel Portable Metered-Dose Cannabis Inhaler in Patients with Chronic Neuropathic Pain: A Phase 1a Study","volume":"28","author":"Eisenberg","year":"2014","journal-title":"J. Pain Palliat. Care Pharmacother."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"25","DOI":"10.2174\/157488912798842269","article-title":"Cannabinoid-related Agents in the Treatment of Anxiety Disorders: Current Knowledge and Future Perspectives","volume":"7","author":"Tambaro","year":"2012","journal-title":"Recent Pat. CNS Drug Discov."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1016\/j.amjmed.2019.05.017","article-title":"Cannabis and Cannabinoids: Kinetics and Interactions","volume":"132","author":"Foster","year":"2019","journal-title":"Am. J. Med."},{"key":"ref_8","first-page":"27","article-title":"Cannabis and Neuropsychiatric Disorders: An Updated Review","volume":"28","author":"Chayasirisobhon","year":"2019","journal-title":"Acta Neurol. Taiwan"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"395","DOI":"10.2217\/pmt-2020-0110","article-title":"Cannabis-based medicines and pain: A review of potential synergistic and entourage effects","volume":"11","author":"Anand","year":"2021","journal-title":"Pain Manag."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s13318-017-0416-z","article-title":"Pharmacogenetics of Cannabinoids","volume":"43","author":"Hryhorowicz","year":"2018","journal-title":"Eur. J. Drug Metab. Pharmacokinet."},{"key":"ref_11","first-page":"2522","article-title":"Pharmacogenetic-guided cannabis usage in the community pharmacy: Evaluation of a pilot program","volume":"3","author":"Papastergiou","year":"2020","journal-title":"J. Cannabis Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/sj.clpt.6100385","article-title":"Association of ABCB1\/MDR1 and OPRM1 gene polymorphisms with morphine pain relief","volume":"83","author":"Campa","year":"2008","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_13","unstructured":"(2021, June 18). SIFAP (Societ\u00e0 Italiana Farmacisti Preparatori) Estratto Oleoso di Infiorescenze Femminili di Cannabis 2021. Available online: https:\/\/www.sifap.org\/procedure\/estrazione-oleosadi-infiorescenze-femminili-di-cannabis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1089\/can.2016.0020","article-title":"Decarboxylation Study of Acidic Cannabinoids: A Novel Approach Using Ultra-High-Performance Supercritical Fluid Chromatography\/Photodiode Array-Mass Spectrometry","volume":"1","author":"Wang","year":"2016","journal-title":"Cannabis Cannabinoid Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3473","DOI":"10.1073\/pnas.97.7.3473","article-title":"Functional polymorphisms of the human multidrug-resistance gene: Multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo","volume":"97","author":"Hoffmeyer","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1097\/j.pain.0000000000001750","article-title":"A functional polymorphism in the ATP-Binding Cassette B1 transporter predicts pharmacologic response to combination of nortriptyline and morphine in neuropathic pain patients","volume":"161","author":"Benavides","year":"2020","journal-title":"Pain"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/j.psychres.2017.09.006","article-title":"ABCB1 C3435T polymorphism is associated with tetrahydrocannabinol blood levels in heavy cannabis users","volume":"262","author":"Kebir","year":"2018","journal-title":"Psychiatry Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2466","DOI":"10.1158\/1078-0432.CCR-13-3232","article-title":"Replication of genetic polymorphisms reported to be associated with taxane-related sensory neuropathy in patients with early breast cancer treated with Paclitaxel","volume":"20","author":"Abraham","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1111\/papr.12546","article-title":"Relationship Between ABCB1 Polymorphisms and Cold Pain Sensitivity Among Healthy Opioid-naive Malay Males","volume":"17","author":"Zahari","year":"2017","journal-title":"Pain Pract."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1093\/chemse\/bjs090","article-title":"Genetic Variation in Putative Salt Taste Receptors and Salt Taste Perception in Humans","volume":"38","author":"Dias","year":"2013","journal-title":"Chem. Senses"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Binder, A., May, D., Baron, R., Maier, C., T\u00f6lle, T.R., Treede, R.D., Berthele, A., Faltraco, F., Flor, H., and Gierthm\u00fchlen, J. (2011). Transient Receptor Potential Channel Polymorphisms Are Associated with the Somatosensory Function in Neuropathic Pain Patients. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0017387"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1136\/ard.2010.148122","article-title":"The Ile585Val TRPV1 Variant Is Involved in Risk of Painful Knee Osteoarthritis","volume":"70","author":"Valdes","year":"2011","journal-title":"Ann. Rheum. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1080\/19336950.2019.1619436","article-title":"Diverse TRPV1 Responses to Cannabinoids","volume":"13","author":"Starkus","year":"2019","journal-title":"Channels"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1080\/19336950.2019.1654347","article-title":"Myrcene and terpene regulation of TRPV1","volume":"13","author":"Jansen","year":"2019","journal-title":"Channels"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.1007\/s40265-019-01171-4","article-title":"Pharmacological and Therapeutic Properties of Cannabidiol for Epilepsy","volume":"79","author":"Franco","year":"2019","journal-title":"Drugs"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/s11910-018-0882-y","article-title":"Cannabis for the Treatment of Epilepsy: An Update","volume":"18","year":"2018","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1111\/j.1742-4658.2007.05670.x","article-title":"Substrate specificity of the human UDP-glucuronosyltransferase UGT2B4 and UGT2B7. Identification of a critical aromatic amino acid residue at position 33","volume":"274","author":"Barre","year":"2007","journal-title":"FEBS J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"879","DOI":"10.2217\/pgs.12.69","article-title":"UGT2B7 Genetic Polymorphisms Are Associated With the Withdrawal Symptoms in Methadone Maintenance Patients","volume":"13","author":"Tian","year":"2012","journal-title":"Pharmacogenomics"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.2217\/pgs.14.115","article-title":"Effect of UGT2B7 -900G>A (-842G>A; rs7438135) on morphine glucuronidation in preterm newborns: Results from a pilot cohort","volume":"15","author":"Matic","year":"2014","journal-title":"Pharmacogenomics"},{"key":"ref_30","first-page":"3720","article-title":"Effect of opioid-related gene polymorphisms on patients with high-dose opioid-tolerant cancer pain","volume":"99","author":"Xie","year":"2019","journal-title":"Zhonghua Yi Xue Za Zhi"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1016\/j.euroneuro.2008.05.003","article-title":"Cannabinoid Receptor 1 (CNR1) Gene: Impact on Antidepressant Treatment Response and Emotion Processing in Major Depression","volume":"18","author":"Domschke","year":"2008","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/2045-5380-3-19","article-title":"Translational Evidence for the Involvement of the Endocannabinoid System in Stress-Related Psychiatric Illnesses","volume":"3","author":"Hill","year":"2013","journal-title":"Biol. Mood Anxiety Disord."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/10\/1832\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:49:49Z","timestamp":1760143789000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/10\/1832"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,11]]},"references-count":32,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["genes13101832"],"URL":"https:\/\/doi.org\/10.3390\/genes13101832","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,11]]}}}