A large-scale genome-wide association study meta-analysis of cannabis use disorder.

[NNadir]

The paper to which I will refer is this one: A large-scale genome-wide association study meta-analysis of cannabis use disorder, Lancet, Psychiatry, Vol 7, Is 12, P1032-1045, DECEMBER 2020

I realize that at DU, marijuana is popular with a subset of people. I am a critic of the drug, which is not to say that I support treating it as a criminal matter. I object to the claim that it is harmless, or even worse, that it's an overall positive.

Recently, citing the fact that I am greatly disturbed by my nephew's addiction to the drug - he is addicted inasmuch it is a struggle for him to stop using it - I was called out for being unscientific in employing anecdotes, in this case an anecdotal account of my nephew's problems.

Actually the scientific literature is replete with descriptions of health problems associated with marijuana abuse, which is a real thing. This should not be surprising for a psychoactive substance. This paper, which is interesting because of the exercise in gene mapping and behavioral consequences is open sourced. It is available in full text for free. It indicates that there is a genetic component for people who do get addicted, even though, there are people who can use the drug without becoming addicted. This should not be overly surprising, considering alcohol use and abuse. This does not imply treatment is impossible; only that it is often necessary.

An excerpt:

Introduction
Cannabis use is common, but most users do not progress to cannabis use disorders. About 50–70% of liability to cannabis use disorders is due to genetic factors.1 Three genome-wide association studies (GWASs) of cannabis use disorders2, 3, 4 have identified variants reaching genome-wide significance, but inadequate sample sizes (sample size from largest study to date: 51 372, with 2387 cases) and heterogeneity among samples have contributed to a paucity of replicable findings: only one locus, tagged by a cis-eQTL for CHRNA2 (encoding a nicotinic acetylcholine receptor), has been robustly identified.3

A GWAS of lifetime cannabis use (184 765 total sample size, 43 380 cases) identified eight genome-wide significant loci and 35 significant genes.5 Twin studies suggest high genetic correlations between early stages of cannabis experimentation and later cannabis use disorder.6 However, casual cannabis use is affected by a variety of socioenvironmental influences and age-period-cohort effects, whereas progression to cannabis use disorder is related to other psychopathologies. Findings have suggested partially distinct genetic causes underlying alcohol consumption and alcohol use disorder, including different genetic associations with other psychiatric disorders and traits.7, 8 Thus, in addition to examining the genomic liability for cannabis use disorder, we tested whether the genetic influences underlying cannabis use and cannabis use disorder diverge with respect to behavioural and brain measures.

Research in context

Evidence before this study

Cannabis use disorder is heritable (50–70% according to twin and family studies), yet identification of genomic variants associated with cannabis use disorder from genome-wide association studies (GWASs) remains sparse. We surveyed all peer-reviewed journal publications in English on GWASs of cannabis use disorder or cannabis dependence using Google Scholar and PubMed, published between Jan 1, 1990, and April 1, 2020. Search terms included “cannabis dependence”, “cannabis abuse”, “cannabis use disorder”, “marijuana dependence”, “marijuana abuse”, “marijuana use disorder”, and “GWAS”. The most promising finding to date is a variant that is a cis-eQTL for CHRNA2 (Demontis and colleagues), which was replicated in an independent dataset for cannabis use disorder. Independently, GWAS of cannabis use have identified multiple genetic risk loci; however, the extent to which the genetics of cannabis use correlates with liability to cannabis use disorder has not been determined. Although GWASs of cannabis use have been studied in the context of a variety of psychiatric and psychosocial correlates, it is expected that some divergent associations will be seen when looking at cannabis use disorder. Previous studies have drawn causal links between cannabis exposure and brain volume, but the relationship between genetic liability to cannabis use disorder and brain volume in individuals naive to cannabis has not yet been studied.

Added value of this study

Our study is the current largest GWAS of cannabis use disorder and the first to include a transancestral component. We found a novel risk locus on chromosome 7. The lead risk variant at this locus is an eQTL for FOXP2—a gene previously implicated in risk-taking behaviours. Contrasting cannabis use and cannabis use disorder, we found that increased liability for cannabis use disorder is genetically correlated with low educational attainment, early age at first birth, and high body-mass index, traits that show opposite directions of association with lifetime cannabis ever-use. We also found that genetic liability for cannabis use disorder is associated with increased risk of mental health problems, infectious diseases, and respiratory illnesses in a large independent sample. Finally, we found a significant association between increased polygenic liability for cannabis use disorder and low white matter volume in cannabis-naive children, suggesting a potential role of cannabis-related genetic predisposition in early brain development...

And so on. It is as difficult sometimes at DU to criticize marijuana use, just as it is difficult and controversial to criticize so called "renewable energy."

Nonetheless, my liberalism is not connected with lockstep fondness for certain activities or practices, but is rather connected to my values for a sustainable world, with a healthy and well informed populace, living in an environment of opportunity and tolerance, free of the weight of bigotry, brutality and injustice.

I am not by any means a genetic reductionist, genetic reductionism often translating into racism; I believe we drive our genes rather than having our genes drive us; but I do believe that we should be aware of predispositions our genes enhance that we must learn to manage. (I do hope my nephew will overcome his addiction; I know it is possible.)

The article is open for anyone to read; the author list is rather long.

If someone would like to object to it; and I'm sure people will be so inclined if experience at DU teaches me anything, fire away.

It is what it is.

Have a nice day tomorrow.

[hlthe2b]

1. Ive have had issues with "Cannabis Use Disorders" as nonspecific suggestion of "addiction" (despite

adverse physical or mental impacts) but whose definition does not differentiate between "Can't" stop and "Won't" stop. And yes, I do see issues with heavy cumulative cannabis use, especially in the very young, but if the outcome is not well defined, I'm less impressed with the findings. Particularly with meta-analyses. And yes, there is a difference between "can't" and "won't"... I see it all the time and for many years.

[NNadir]

2. I don't buy this putative "difference" at all.

There is can't stop, as in very, very, very difficult to stop. I do hope my nephew will find that path to stop, but I think as a family we're very clear that it isn't just a matter of will.

This is hardly the only article on the subject in the scientific literature, as opposed to "I see it all the time."

It's not like I haven't had half a century of exposure to this issue myself, but I am not relying on anecdote and nonsystematic opinion.

Most addicts to any substance will claim that they can stop using an addictive substance that has become an abuse issue, but when tested on the topic, they fall short of their self described ability to manage use. Reason they can't stop isn't because they are weak willed; they can't stop for reasons that are clearly involve molecular biology.

[hlthe2b]

3. I said I see cases in real people I treat. NOT as you misinterpreted my meaning

Reread what I said. You are wayyyyy off base as to what I am saying. And believe me, I know my epidemiology and methods. And garbage in, garbage out, no matter how good the genetic correlations especially if you don't start with a clear definition of your outcome.

[NNadir]

4. I believe I read what you said.

I personally don't think that the Lancet journals publish "garbage."

You may wish to read the paper.

[hlthe2b]

5. I said it is a flawed analysis. Not that the Lancet is garbage

And I have the digital copy of paper right here, thank you very much. Meta analyses are especially prone to comparison of apples and oranges--especially without a clearly defined outcome that is consistent across all studies. And "Cannabis Use Disorder" is a classification that includes a lot of "lumping."

And yes, the epidemiological adage that "garbage in (in terms of inputs) = Garbage out (in terms of results) does apply.

[NNadir]

6. Well, of course, you are entitled to the opinion that no one anywhere at any time should publish...

...meta analysis or reviews, because, um, they don't stand up to cursory reads but nevertheless the world scientific community, despite your objections based on your treatment of patients, seems to disagree.

So do I.

You can write to Lancet Psychiatry if you wish to suggest a retraction of the paper on the grounds that meta analyses are garbage, but I don't think the majority of the authors - and there are many - will agree to your objection.

[hlthe2b]

7. You can reword what I say all you wish. I said a common problem with meta analyses is

as I described--not that all are invalid. I'm done with your trying to attribute what I did not say to me and create false arguments.

It is a very deceptive tactic. SO have a good evening but I will waste no more time with you.

[Warpy]

8. Apparent psychological dependence has been well known for many decades,

but the phenomenon is completely separate from addiction. Cannabis produces no tolerance and sudden withdrawal produces no physical consequences, although the psychological consequences can be acute and painful and most likely reveal why the cannabis user was self medicating by titrating his/her own cannabis dose.

Cannabis is well tolerated by most people, extremely poorly tolerated by others, and is no panacea.

One hopes the end of the WoD in some states will produce scholarly articles on what the various alkaloids in the plant actually do to us or for us. Those are the studies I'm waiting for. It will take longer still for the censorious aftereffects of the WoD to disappear.

I think that's what bothers me about studies like this, and there are many of them, that they assume cannabis use is counterproductive and fail to consider it just might be an attempt to medicate psychological distress that we have few good other options for.

[multigraincracker]

10. "Medicate psychological distress"

That is what the gray term of addiction is about.
As a former addict, once I discovered what that distress was and to finally come to terms with it, recovery was a piece of cake. I didn’t need programs or meetings.

But that was just me and like I said, addiction is a gray area.

[IbogaProject]

9. I'm sorry for your nephew's issues

First I suggest he take a melatonin sublingusl and a small dose of vitamin e before he goes to sleep. Melatonin can get depleted in heavy cannabis users and it will free him from the most severe withdrawal symptoms while typically mild can be serious for an individual with phase shifted insomnia. And nudge him to consider to delaying use to later in the day, sort of like the Navy notion of not drinking until the Sun is under the arm. There is a chicken and egg like thing is he sick from cannabis or does he abuse cannabis because he is sick. I had issues when I was younger as I'm a type 1 diabetic and I became dependent on it. It didn't wreck my life but if I ran out I had horrible insomnia and other symptoms like slightly elevated body temp. Once I started melatonin I was able to moderate and stopped regular use. Some other ideas are sunlight on the eyes 20 min three times a week. That loads an enzyme that helps serotonin production. I've heard essential fatty acids help with hyperactivity in children they help the body put stuff on the nerve sides that sort of insulates them, maybe they could help? And final idea maybe a short trip with something like outward bound. Best wishes with your family helping him to move on with his life.

[NNadir]

11. While I am a chronic insomniac, I'm not sure that this is my nephew's problem.

He is my nephew by marriage; and is not genetically related to me.

I do not know his sleep habits.

As for myself, as a lifelong chronic insomniac, I do, when I know I am not going to sleep, take the pharmaceutical isostere of melatonin myself, zolpidem, (ambien.) I have never found melatonin itself to be effective; but zolpidem is marginally effective, sometimes. I try to avoid zolpidem whenever possible, and sometimes will take OTC antihistamines formulated for sleep induction. They also work marginally. At the core however, I am an insomniac and nothing can change that, despite decades of advice.

My nephew definitely has a problem with depression, a severe problem, and there is definitely a genetic component, actually on both sides of his family, my wife's family and my former brother's-in-law family, where there does seem to be a history of psychological symptoms. My nephew's grandmother on his father's sde has been in and out of hospitals where she's been admitted for psychological disorders.

My mother-in-law was also on psychiatric meds her whole adult life. All three of my wife's sisters take antidepressants, including my nephew's mother, as does one of my nieces.

My wife, by contrast, has never evinced depression or psychotic disorders; one of my sons struggled a bit in high school, but he muscled through it by teaching himself neurophysiology apparently.

I do believe that genetics can and do influence mood disorders; although again, I'm not a genetic reductionist. I believe we have to work to handle our genes; not that our genes determine us.

My nephew's a very nice kid, generally, and he will talk freely with me about his state, but we live about 200 miles away and as an uncle, I'm not sure if or how I can help.

I don't think there's any kind of magic wand.

As far as "chicken and egg," though I'd go with egg. He's had problems for some time. His parents divorce did not help, even though the divorce was fairly civil.

The pot thing however is not helping; it's making things worse. It is definitely creating an inability to form stable friendships.

As for the root cause of his inability to do without pot - understanding the extreme unpopularity of this view here - it has the hallmarks to me of physiological addiction, and I'm not fond of the glib objections to this claim, particularly when they are rote and dismissive without even a shred of intellectual integrity, for instance calling the paper in the OP "garbage" without clearly offering a shred of specific evidence to support the claim. (This has happened elsewhere in this thread.)

I, of course, come from a generation in which pot was presented as some kind of wonderful and marvelous substance that was "good for people." I don't agree, and my lack of agreement does not stem from naivete. Overall, I think pot use is a negative.

(I live in a world dominated by molecular biology and my world view is very much connected to it.)

We have in the past, and do now, worry about my nephew's potential for suicide. He was smoking pot the last time he was hospitalized for a suicide watch, so I really don't want to hear that pot is keeping him from it. Right now insurance problems have him on a wait list for an evaluation.

I'm worried that his mother, my sister-in-law, is giving up on him. I understand it's hard on her, and again, I wish there was something, anything, I could do.

All this said, I don't think it's a problem that OTC substances can address, although I do thank you for your concern and advice.

[Warpy]

12. My problem with that study is the consistent cart-horse mismatch

one finds so often in these studies, the conclusion that cannabis caused a problem when its use was actually an attempt to treat a serious underlying problem. It's bad science and smells very strongly of confirmation bias.

Case in point: my own family runs to bipolar disease, and the first thing the people who have it tend to do is start using alcohol. Drinking works to numb the depression and blunt the mania, and they might even get a few years of decent treatment that way, but alcohol also produces tolerance, meaning they need to drink more to get the same effect, and a withdrawal process that's 50% fatal if done suddenly and with no medical supervision. Mostly, they hit the 5 or so year mark as bipolar alcoholics. If they detox, does that mean detoxing from alcohol made them bipolar? No, it means they were undiagnosed and medicating with a substance that only worked short term while producing physical dependency..

Try asking your nephew if he can remember what he felt like before he started using cannabis. You might find the answer very enlightening.