Primary Care Corner with Geoffrey Modest MD: Marijuana passing through the generations…

By: Dr. Geoffrey Modest

A pretty striking basic science article was recently published looking at the epigenetic effects of marijuana on rats, which seems to be inherited in the next generation (see doi:10.1038/npp.2015.155​).  There have been a slew of recent articles on marijuana suggesting that its adverse effects are more profound than many of us (myself included) thought (eg, structural changes to the brain, psychosis/scizophrenia, longer-term cognitive problems, risk of addiction to other drugs, lung diseases, etc — see here for some of these articles and critiques), and the positive effects are perhaps overstated by poor-quality studies (see blog, which reviews the data on the beneficial effects of medical marijuana). And, as noted, the marijuana issue is increasingly of concern as marijuana is being promoted as a “safe drug” and is now more commonly smoked than cigarettes by teenagers and young adults. In this context, the rats show us that there may be profound epigenetic effects of marijuana in the offspring of those exposed.  I do not presume to be very knowledgeable about the biochemistry here, so will present the extent of my primitive understanding: basically epigenetics differs from genetics in that there are heritable phenotypic changes that do not reflect genotypic changes (as a brief summary, see here). What I mean is that there can be profound changes in gene expression based on chemical changes to the DNA which typically either turn off or on some section of DNA, resulting in fundamental changes in gene expression. These epigenetic changes, for example, can result from aging, environment, lifestyle, and diseases themselves, and often are mediated by changes in areas of DNA which become methylated (there are other mechanisms as well, such as histone modification). The first epigenetic phenomenon studied in humans was in colon cancer, where DNA hypomethylation can lead to oncogene activation and hypermethylation to silencing tumor suppression genes (in general methylation silences gene expression). There are data from human lung cancers that those with cancer subsequently develop changes in oncogenes and tumor suppressor genes in the lung tissue, which can lead to increasing the potency of the cancer and decreasing the efficacy of chemotherapy (see here for example). There are human data that find that epigenetic modifications are important in the clinical expression of even identified genetic diseases leading to cognitive impairment (eg Prader-Willi syndrome), perhaps in autoimmune diseases, an array of neuropsych problems (schizophrenia, bipolar disease, mood disorders, dementia), etc.  So, as a primary care provider, why is this important???? I think epigenetics really opens the door to the link between the environment/lifestyle and the development of potentially many human effects, including an array of diseases. So, back to the rats…

The impetus of this study was the finding that there were cross-generational effects of parental cannabis exposure in adolescent rats leading to offspring who were more prone to self-administer heroin, have enhanced acute heroin withdrawal, altered striatal synaptic plasticity, and changes in the expression of cannabinoid, dopamine, and glutamatergic receptors (see Neuropsychopharmacology (2014) 39, 1315–1323). The current study used the same rat model, finding that of 16 adolescent rats exposed to tetrahydrocannabinol (THC) before mating, vs 16 non-exposed rats (all rat offspring were raised by non-THC exposed mothers) there were dramatic alterations in differentially methylated regions of the offspring’s brain (specifically, a depletion in gene promotors). They focused on glutmatergic synaptic regulation in the nucleus accumbens (a key area of the brain involved in reward processing and the area most linked to addiction vulnerability), finding profound methylation differences and associated altered mRNA expression in these offspring.

So, basic observations from above:

–the epigenetic effects of various stimuli, including those resulting from environmental exposures, can have profound effects on turning on or off different sections of the DNA, with resulting effects on protein production, etc, and may be associated with a variety of diseases

–although there is “reprogramming” of DNA methylation in offspring to preserve reasonably clean genetic transmission (see 10.1126/science.1229277), there are clearly times when these epigenetic changes do pass through to subsequent generations (well-documented in these rats)

–although I  am not a biological determinist, I think these types of studies do raise important issues about the potential for parental actions to affect offspring directly through epigenetic changes (which is not to say that they determine the behavior of kids. That is really complex and, undoubtedly, the social environment of the kids will play a large role in their own development, including subsequent epigenetic changes)

–it is pretty clear to me in inner-city Boston, that a huge number of people are exposed to the very potent marijuana on the streets now and using that regularly, especially but not only in adolescents. And that usage might increase with the acceptance/legalization of medical marijuana, with perhaps overstated benefits, but providing a more “socially-acceptable” aura, as with cigarettes and alcohol over the years.

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–but, bottom line, we should be aware of these epigenetic changes, aware that they can be passed on to offspring even in the context of not using THC during pregnancy itself, and that the effects on the offspring might at least put them at a significant disadvantage in the longrun.

–and, I wouldn’t be surprised to find these types of epigenetic play a significant role in our common chronic diseases (obesity, hypertension, hyperlipidemia, diabetes…..) in individuals, and perhaps in their offspring as well (ie, it may not just be the genes themselves that predispose people to these diseases, but environmentally-induced changes in methylation etc of the genes which play a big role)