Cannabis use alters DNA methylation, with implications beyond smoking effects

In a recent study published in the journal Molecular Psychiatry, a team of researchers conducted a large-scale meta-analysis consisting of an epigenome-wide association study to understand whether lifetime use of cannabis was linked to deoxyribonucleic acid (DNA) methylation observed in peripheral blood.

Study: rans-ancestry epigenome-wide association meta-analysis of DNA methylation with lifetime cannabis use. Image Credit: Juan Gaertner / ShutterstockStudy: Trans-ancestry epigenome-wide association meta-analysis of DNA methylation with lifetime cannabis use. Image Credit: Juan Gaertner / Shutterstock

Background

With an increasing number of states in the United States (U.S.), as well as countries across the world legalizing the medicinal use of cannabis, cannabis usage has become exceedingly prevalent. However, while the therapeutic benefits of cannabis through medicinal use have been well-studied, its recreational use also raises numerous concerns, especially regarding problems associated with addiction, cognitive deficits, and mental health disorders such as depression, anxiety, psychosis, mania, and schizophrenia.

DNA methylation is an indicator of the impact of environmental factors on health, and some forms of DNA methylation due to environmental factors are long-lasting, while others are transient. It occurs when a methyl group gets added to the fifth carbon of cytosine in regions with cytosine and guanine (CpG) repeats. Studies have reported that cigarette smoking results in both persistent and transient DNA methylation at CpG sites across the genome. DNA methylation patterns in specific genes have also been observed in groups such as adolescents who frequently use cannabis and patients who are dependent on cannabis.

About the study

In the present study, the team built on the methods from their previous study, where they performed the first epigenome-wide association study using peripheral blood samples and investigated a large study population consisting of seven cohorts of individuals of different ancestries. They examined the association between lifetime cannabis use and DNA methylation patterns while adjusting for factors such as age, sex, technical covariates, blood cell proportions, and cigarette smoking behavior.

The data was obtained from seven cohorts that participated in the study, spanning diverse study groups such as twins, older adults, parents and children, and adult twins. The final study population comprised 4,190 individuals who reported using cannabis in their lifetime and 5,246 individuals who had never used cannabis in their lifetime, constituting a total of 9,436 participants. Cannabis use was characterized based on reports by the participants or parents, and an individual with a minimum of one cannabis use event before the collection of peripheral blood samples was defined as an ever-user.

DNA methylation was measured in the peripheral blood samples, and the β-values, which is the percentage of methylated DNA at the targeted CpG sites, were calculated. The association between lifetime cannabis use and DNA methylation levels was tested using linear models or a generalized estimating equations model in cohorts where the participants were related. The epigenome-wide association study analyses were stratified according to the European-American and African-American genetic ancestry groups, and the analyses were adjusted for sex, age, cigarette smoking, and blood cell type estimates.

The meta-analysis summarized the ancestry and cohort-specific results from the epigenome-wide association study, and statistical analyses were conducted to assess. The methylation score, which is the weighted sum of the CpG sites significantly linked to cannabis use, was also calculated. Additionally, DNA methylation correlations between whole blood and regions of the brain, such as the prefrontal cortex, cerebellum, superior temporal gyrus, and entorhinal cortex were examined.

Results

Four CpG sites showed significant associations with cannabis use, none of which were previously reported as being significant in cigarette smoking epigenomic analyses. These included CpG sites in the disintegrin and metalloprotease 12 (ADAM12) and alpha-actinin 1 (ACTN1) genes and near the adhesion G protein-coupled receptor F1 (ADGRF1) gene and long noncoding ribonucleic acid (RNA) LINC01132. In addition to these four CpG sites, upon analyzing the blood of lifetime cannabis users who had never smoked cigarettes, an additional CpG site of cg14237301 in the apolipoprotein B receptor (APOBR) gene was identified.

Importantly, the CpGs associated with cannabis use in this study showed significant overlap with CpGs previously associated with cigarette smoking. Other enriched traits that significantly overlapped with the results of this study included those observed in Crohn’s disease, alcohol consumption, body mass index (BMI) and multiple sclerosis.

To elucidate the role of an individual’s genetics in these DNA methylation changes, the researchers examined the methylation quantitative trait loci (meQTLs) for the five CpGs that were significantly associated with lifetime cannabis use. None of these meQTLs were significantly associated with cannabis use, thus indicating that the study findings are likely not influenced by genetic variants.

The five genes containing DNA-methylated CpG sites associated with cannabis use have significant roles in various health outcomes. For example, LINC01132 functions as an oncogene and is linked to malignancy in hepatocellular carcinoma and ovarian cancer, although cannabis use has been reported to lower the incidence of hepatocellular carcinomas.

Genetic variation in the ACTN1 gene, which encodes the cytoskeletal protein that binds actin fibers to cell membranes, has been linked to various diseases such as Bowen disease, Angelman syndrome, systemic lupus erythematosus, and congenital macrothrombocytopenia, as well as coronavirus disease 2019 (COVID-19). Genetic variants of APOBR have been associated with obesity, bladder cancer, pneumonia, allergies, and lifetime cannabis use.

Conclusions

Five significant cigarette smoking-independent CpGs were significantly associated with cannabis use. These CpG sites have also been implicated in cigarette smokers; therefore, both cannabis use and cigarette smoking may independently influence DNA methylation at these CpGs.

A key advantage of the current study is its large and diverse study cohort. However, this heterogeneity may have prevented the researchers from identifying ancestry-specific DNA methylation associations in cannabis users.

Overall, the study findings provide important insights into the shared DNA methylation profiles between cannabis users and cigarette smokers. Nevertheless, future studies are needed to better understand the potential health impacts of DNA methylation at these CpG sites.

Journal reference:
  • Fang, F., Quach, B., Lawrence, K. G., Dongen, van, Marks, J. A., Lundgren, S., Lin, M., Odintsova, V. V., Costeira, R., Xu, Z., Zhou, L., Mandal, M., Xia, Y., Vink, J. M., Bierut, L. J., Ollikainen, M., Taylor, J. A., Bell, J. T., Kaprio, J., & Boomsma, D. I. (2023). Trans-ancestry epigenome-wide association meta-analysis of DNA methylation with lifetime cannabis use. Molecular Psychiatry. https://doi.org/10.1038/s4138002302310w, https://www.nature.com/articles/s41380-023-02310-w  

Article Revisions

  • Nov 14 2023 - The results were clarified to emphasize that the DNA methylation effects were specific to cannabis users and their potential health effects. The need for additional studies was also emphasized to demonstrate that these findings reflect a large sample study but must be explored further.
Dr. Chinta Sidharthan

Written by

Dr. Chinta Sidharthan

Chinta Sidharthan is a writer based in Bangalore, India. Her academic background is in evolutionary biology and genetics, and she has extensive experience in scientific research, teaching, science writing, and herpetology. Chinta holds a Ph.D. in evolutionary biology from the Indian Institute of Science and is passionate about science education, writing, animals, wildlife, and conservation. For her doctoral research, she explored the origins and diversification of blindsnakes in India, as a part of which she did extensive fieldwork in the jungles of southern India. She has received the Canadian Governor General’s bronze medal and Bangalore University gold medal for academic excellence and published her research in high-impact journals.

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Comments

  1. Jerry Merrill Jerry Merrill United States says:

    But the study does not indicate the modality of use.  Since the same effects occur with cigarette smoking, we can only presume that the measure effects are more about the delivery method than the drug.  The body doesn't like inhaling burning leaves.  We get it.

  2. Esteban G Esteban G United States says:

    So, what does all this mean for the average person, is a tumor going to grow out of my neck?.

  3. Dylan Eliot Dylan Eliot United States says:

    I find it sickening that they've gotten away with it for years.

  4. Dylan Eliot Dylan Eliot United States says:

    By which point, one might as well fully legalize recreational use and see what happens.

    Nothing Ill happens when one does by the way, even for Texas.

  5. Luke Burnett Luke Burnett Mexico says:

    This study focuses on the SMOKING of cannabis not the several other (more effective and less toxic) methods of use / ingestion. Perhaps a proper title to refelct the nature of the study vs the broadcast assumption that all cannabis use is limited to smoking.

  6. KENNETH MARTIN KENNETH MARTIN United States says:

    Person smoke maryJ since 12 and has no other drugs in there life. The person was forced to stop or loose there job at the age of 61 after being reported at work. Within 6 month the user who quite cold turkey was having trouble standing up or walking with motor skills issues showing. Person was falling and experiencing symptoms like Parkinsons. They had to quite there job due to safety risk and started seeing doctors who originally diagnosed as parkinson's but they where un aware of the long term use of maryJ. The drugs proscribed did not help so after a long talk they began using again to try and see if it improved or stopped symptoms progression.
    After about a week or two it had stopped progression but did not reverse symptoms. The person has made ther doctors aware of his long term use and now is on medical MaryJ but motor skills are slowly declining. Now 66 the user seems stuck in a hopeless situation, this study and ones like it could expose the darker side of MaryJ.
    It is noted that there is not proof the user did not have parkinson's underlying and the use was preventing it from showing itself. But there are also reports of parkinson's symptoms with long term drug use or head trauma wich this person's has had both in there life.
    Hope this study and ones like it leads to a better understanding for future generations.
    Here's to a better world for the future,

  7. Ida Know Ida Know United States says:

    It's funny how this doesn't actually say if there's any evidence of these changes causing harm, or studies on how long this lasts, or anything to rule out other causational factors like diet, lifestyle, ect beyond the few mentioned (like cigarette usage). This seems much more of a correlation than causation situation. Give me more evidence, otherwise I'm going to throw this in with the whole "vaccines cause autism" studies.

  8. anon beej anon beej United States says:

    Yes, the outcomes of changes in DNA methylation due to cannabis use could potentially be either beneficial or negative. DNA methylation is a complex process that plays a crucial role in gene regulation and expression. Changes in methylation patterns can have diverse effects on health, depending on various factors, including which genes are affected and the context of these changes.

    1. **Potential Negative Outcomes:** Altered DNA methylation patterns have been associated with various health issues, including an increased risk of certain diseases. For example, abnormal methylation in certain genes could potentially contribute to the development of cancers or impact immune function.

    2. **Potential Beneficial Outcomes:** On the other hand, some changes in DNA methylation might have protective or therapeutic effects. For instance, methylation changes could potentially downregulate harmful genes or be involved in adaptive responses to environmental factors.

    It's important to recognize that the relationship between cannabis use, DNA methylation, and health outcomes is still not fully understood. The specific outcomes of DNA methylation changes due to cannabis use would depend on a variety of factors, including the individual's genetic background, overall health, and environmental interactions. More research is needed to elucidate these relationships and to understand the broader implications of cannabis use on human health.

  9. kev c kev c United States says:

    How about the inhalation of vaporized FlouroCarbons that are concentrated within the cannabis flowers and plant?
    Any studies being done on this. We are well aware of the effects of being exposed by our drinking water.
    Bread and circuses for the masses

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
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