Cannabis use carries no risk of primary open-angle glaucoma

“Our data provided evidence for a lack of association of genetic liability to lifetime cannabis use and cannabis use disorder with POAG," investigators said. Image credit: ©YARphotographer – stock.adobe.com

European investigators, led by first author Andreas Katsimpris, MD, did not identify an association of genetic liability to lifetime cannabis use and cannabis use disorder with primary open-angle glaucoma (POAG), the most common type of glaucoma.¹ Dr Katsimpris is from the Princess Alexandra Eye Pavilion, Edinburgh, Scotland.

The association between cannabis use and intraocular pressure (IOP) has been studied before, but the association with POAG is not clear, the investigators pointed out.

The use of cannabis was suggested to protect against POAG by a salutary effect on IOP,² without knowing the exact pathogenetic mechanism of this phenomenon. IOP decreases were hypothesised to result from activation of the cannabinoid-related receptors in the ciliary body by Δ9-tetrahydrocannabinol, the psychoactive constituent of cannabis,³ with resultant decreased aqueous humor production by the ciliary body and IOP decreases. Another theory forwarded the notion that the IOP-lowering effect of cannabis is mediated through a decrease in blood pressure.⁴ However, this mechanism might increase the risk of POAG because it lowers ocular perfusion pressure, thus compromising optic nerve head perfusion.⁵

Dr Katsimpris and colleagues explained that the rationale for the study under discussion, considering the high incidence of glaucoma and the limitations of the current antiglaucoma agents, was the focus on identifying novel treatments that would work against glaucoma, which includes cannabis. They noted that although cannabinoids exert a lowering effect on IOP when administered intravenously, orally, or by smoking,² no long-term and adequately sized clinical trials have tested cannabinoid treatment in POAG.

Study design

To determine the association, the investigators explained that they used human genetic data to assess through Mendelian randomisation (MR) if cannabis use affects POAG. MR, according to the authors, is a form of instrumental variable analysis that uses genetic variants as instruments.⁶

The study was a two-sample, summary-based MR and used summary statistics from 3 large genome-wide association studies (GWAS) of lifetime cannabis use,⁷ cannabis use disorder⁸ and POAG.⁹ The investigators calculated the causal association between cannabis use and cannabis use disorder with POAG by combining these estimates. The investigators used 5 single-nucleotide polymorphism (SNP) data obtained from 184,765 individuals of European descent who used cannabis over their lifetime in the International Cannabis Genome Research Consortium, 23andMe and UK Biobank.⁷

Eleven SNPs associated with cannabis use disorder were obtained from a GWAS meta-analysis of 17,068 cases and 357,219 controls of European descent, derived from the Psychiatric Genomics Consortium Substance Use Disorders working group, Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) and deCODE.⁸ Finally, SNP-POAG associations were taken from a GWAS meta-analysis of 16,677 POAG cases and 199,580 controls of European ancestry⁹ from 16 participating studies, they explained.

Analysis findings

Data analysis showed “no evidence for a causal association of lifetime cannabis use and cannabis use disorder with POAG (odds ratio of outcome per doubling of the odds of exposure [95% confidence interval]: 1.04 [0.88; 1.23] for lifetime cannabis use and 0.97 [0.92; 1.03] for cannabis use disorder).”

The investigators found that the 5 selected SNPs explained 0.09% of the variance in the lifetime cannabis use and the F-statistics for all SNPs were 30.7 or greater. The 11 selected SNPs for cannabis use disorder explained 0.08% of the phenotypic variance and had an F-statistic of 25.5 or greater.

The investigators found that the MR analysis suggested no evidence for a causal association of lifetime cannabis use and cannabis use disorder with POAG (odds ratio [OR] of outcome/doubling of the odds of exposure [95% confidence interval]: 1.04 [0.88; 1.23] for lifetime cannabis use and 0.97 [0.92; 1.03] for cannabis use disorder).

“We concluded that our data provided evidence for a lack of association of genetic liability to lifetime cannabis use and cannabis use disorder with POAG. Triangulation of evidence from different types of research studies, with different key sources of bias, is warranted to confirm these results,” Dr Katsimpris and colleagues commented.

References

1. Katsimpris A, Baumeister SE, Baurecht H, et al.Cannabis use and the risk of primary open-angle glaucoma: a Mendelian randomization study. Sci Rep. 2023;13(1):19605. doi:10.1038/s41598-023-45872-z

2. Novack GD. Cannabinoids for treatment of glaucoma. Curr Opin Ophthalmol. 2016;27:146–150. https://doi.org/10.1097/icu.0000000000000242

3. Miller S, Daily L, Leishman E, Bradshaw H, Straiker A. ∆9-Tetrahydrocannabinol and cannabidiol differentially regulate intraocular pressure. Invest Ophthalmol Vis Sci. 2018;59:5904–5911. https://doi.org/10.1167/iovs.18-24838

4. Sun X, Xu CS, Chadha N, Chen A, Liu J. Marijuana for glaucoma: a recipe for disaster or treatment? Yale J Biol Med. 2015;88:265–269

5. Leske MC. Ocular perfusion pressure and glaucoma: clinical trial and epidemiologic findings. Curr Opin Ophthalmol. 2009;20:73–78; https://doi.org/10.1097/ICU.0b013e32831eef82

6. Sanderson E, Glymour MM, Holmes MV, et al. Mendelian randomization. Nat Rev Methods Primer. 2022;2:6; https://doi.org/10.1038/s43586-021-00092-5

7. Pasman JA, Verweij KJH, Gerring Z, et al. GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability. Nat Neurosci. 2018;21:1161–1170. https://doi.org/10.1038/s41593-018-0206-1

8. Johnson EC, Demontis D, Thorgeirsson TE, et al. A large-scale genome-wide association study meta-analysis of cannabis use disorder. Lancet Psychiatr. 2020;7:1032–1045.https://doi.org/10.1016/s2215-0366(20)30339-4

9. Gharahkhani P, Jorgenson E, Hysi P, et al. Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries. Nature Commun. 2021;12:1258; https://doi.org/10.1038/s41467-020-20851-4