One good thing about Trump’s election (maybe two)

Two comments on the election then back to some neuropharmacology and neuropsychiatry which will likely affect many of you (because of some state ballot initiatives).

First: Over the years I’ve thought the mainstream press has become increasingly biased toward the left (not on the editorial page which is fine) but in supposedly objective reporting. Here are just two post election examples

#1 Front page of the New York Times 9 Nov — the first sentence from something they characterize as ‘News Analysis’

““Donald John Trump was elected the 45th president of the United States on Tuesday in a stunning culmination of an explosive, populist and polarizing campaign that took relentless aim at the institutions and long-held ideals of American democracy.”

#2 Front page of the New York Times 10 Nov — more ‘News Analysis’ — Here’s the lead “Populist Fury may Backfire”. Don’t they wish.

I’ll never complain about this sort of thing again (well at least not for four years). Why? Because I’ve been reading the Wall Street Journal, The New York Times, The Nation and the National Review for probably 50 years, and Trump as the antiChrist is the first thing I’ve ever seen all four agree on. This biased coverage simply no longer matters. If it did, Trump would have lost and lost big. This just confirms the marked loss of credibility that the mainstream media has suffered.  People aren’t as dumb as the elites think they are.

Second: Political correctness and attempts to control speech so as not to offend lost big. That’s very good for us all right and left (although the impetus for speech control has switched to the left from the right over the past 56 years) — see https://luysii.wordpress.com/2015/11/22/from-banned-in-boston-to-banned-in-berkeley-in-55-years/

What do the state ballot initiatives have to do with neuropharmacology? Just this. Voters in California, Massachusetts and Nevada approved recreational marijuana initiatives Tuesday night, and several other states passed medical marijuana provisions.

I don’t think this is good. One of the arguments in its favor is that marihuana isn’t as bad as alcohol, which may be true, but if marihuana isn’t all good why add it to the mix? We don’t have a good handle on marihuana use, but it is likely to increase if it’s legal.

Why do I think this is bad (particularly for adolescents)? It is likely that inhibiting synaptic feedback isn’t a good thing for a brain which is pruning a lot of them (which happens in normal adolescence as the thickness of the cerebral cortex shrinks).

There have been many explanations for the decline in College Board Scores over the years. This has led to their normalization (so all our children are above average). If you’re a correlation equals causation fan, plot the decline vs. time of atmospheric lead. It is similar to the board scores decline. Or you can plot 1/adolescent marihuana use vs. time and get a similar curve. The problem, of course, is that we have no accurate figures for use.

Here’s the science — it’s an old post, but little has happened since it was written to change the science behind it

Why marihuana scares me

There’s an editorial in the current Science concerning how very little we know about the effects of marihuana on the developing adolescent brain [ Science vol. 344 p. 557 ’14 ]. We know all sorts of wonderful neuropharmacology and neurophysiology about delta-9 tetrahydrocannabinol (d9-THC) — http://en.wikipedia.org/wiki/Tetrahydrocannabinol The point of the authors (the current head of the Amnerican Psychiatric Association, and the first director of the National (US) Institute of Drug Abuse), is that there are no significant studies of what happens to adolescent humans (as opposed to rodents) taking the stuff.

Marihuana would the first mind-alteraing substance NOT to have serious side effects in a subpopulation of people using the drug — or just about any drug in medical use for that matter.

Any organic chemist looking at the structure of d9-THC (see the link) has to be impressed with what a lipid it is — 21 carbons, only 1 hydroxyl group, and an ether moiety. Everything else is hydrogen. Like most neuroactive drugs produced by plants, it is quite potent. A joint has only 9 milliGrams, and smoking undoubtedly destroys some of it. Consider alcohol, another lipid soluble drug. A 12 ounce beer with 3.2% alcohol content has 12 * 28.3 *.032 10.8 grams of alcohol — molecular mass 62 grams — so the dose is 11/62 moles. To get drunk you need more than one beer. Compare that to a dose of .009/300 moles of d9-THC.

As we’ve found out — d9-THC is so potent because it binds to receptors for it. Unlike ethanol which can be a product of intermediary metabolism, there aren’t enzymes specifically devoted to breaking down d9-THC. In contrast, fatty acid amide hydrolase (FAAH) is devoted to breaking down anandamide, one of the endogenous compounds d9-THC is mimicking.

What really concerns me about this class of drugs, is how long they must hang around. Teaching neuropharmacology in the 70s and 80s was great fun. Every year a new receptor for neurotransmitters seemed to be found. In some cases mind benders bound to them (e.g. LSD and a serotonin receptor). In other cases the endogenous transmitters being mimicked by a plant substance were found (the endogenous opiates and their receptors). Years passed, but the receptor for d9-thc wasn’t found. The reason it wasn’t is exactly why I’m scared of the drug.

How were the various receptors for mind benders found? You throw a radioactively labelled drug (say morphine) at a brain homogenate, and purify what it is binding to. That’s how the opiate receptors etc. etc. were found. Why did it take so long to find the cannabinoid receptors? Because they bind strongly to all the fats in the brain being so incredibly lipid soluble. So the vast majority of stuff bound wasn’t protein at all, but fat. The brain has the highest percentage of fat of any organ in the body — 60%, unless you considered dispersed fatty tissue an organ (which it actually is from an endocrine point of view).

This has to mean that the stuff hangs around for a long time, without any specific enzymes to clear it.

It’s obvious to all that cognitive capacity changes from childhood to adult life. All sorts of studies with large numbers of people have done serial MRIs children and adolescents as the develop and age. Here are a few references to get you started [ Neuron vol. 72 pp. 873 – 884, 11, Proc. Natl. Acad. Sci. vol. 107 pp. 16988 – 16993 ’10, vol. 111 pp. 6774 -= 6779 ’14 ]. If you don’t know the answer, think about the change thickness of the cerebral cortex from age 9 to 20. Surprisingly, it get thinner, not thicker. The effect happens later in the association areas thought to be important in higher cognitive function, than the primary motor or sensory areas. Paradoxical isn’t it? Based on animal work this is thought to be due pruning of synapses.

So throw a long-lasting retrograde neurotransmitter mimic like d9-THC at the dynamically changing adolescent brain and hope for the best. That’s what the cited editorialists are concerned about. We simply don’t know and we should.

Addendum 11 Nov ’16:  From an emerita nonscientific professor friend of my wife. “Much of the chemistry/pharmacology etc. is way beyond me, but I did get the drift of the conversation about marihuana and am glad to now have even a simplified concept of what it does to the brain. Having spent the last 20 years working with undergraduate and graduate students, I’ve seen first hand the decline in cognitive ability.” 

Scary ! ! ! !

Having been in Cambridge when Leary was just getting started in the early 60’s, I must say that the idea of tune in turn on and drop out never appealed to me. Most of the heavy marihuana users I’ve known (and treated for other things) were happy, but rather vague and frankly rather dull.

Unfortunately as a neurologist, I had to evaluate physician colleagues who got in trouble with drugs (mostly with alcohol). One very intelligent polydrug user MD, put it to me this way — “The problem is that you like reality, and I don’t”.

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Comments

  • YoYo  On November 11, 2016 at 2:09 am

    Marijuana legalization is a good thing. The ideological pimps who push prohibition are so venal and stupid that they punish drugs by weight. Weight! The gray market responds by marketing ever more potent drugs, and distributing them as the pure product. If more than, say, one gram is a life-ending felony, better make your 0.9 gram stash be a pure drug with picomolar potency. This has resulted in clueless young people discovering that there are, in fact, maiming and lethal doses of cannabinoids.

    It’s far safer to have them using low-grade plants from supervised growers.

    One thing to look at for young people and cannabinoid receptors is acetaminophen/paracetamol. It is apparently metabolized into an active product that is a cannabinoid reuptake inhibitor. Several studies show it to have significant psychological effects when compared to placebo. The effects of acetaminophen use in youth might show up in brain development. I doubt any twin adoption studies have recorded it though.

    Have you been following the suspected dementia-inducing effects of the antimuscarinic anticholinergics? The association is strong and scary. I no longer use them for anything. Causation has not been proven, but the odds ratios are so large I would take LSD once before I took diphenhydramine for a year.

  • andyextance  On November 11, 2016 at 3:55 am

    I freely admit to not having the full picture on marijuana, but I’m thinking about related issues for a project I’m working on, and it’s there’s a good argument that criminalising users and forcing them to go to illegal suppliers isn’t a good thing. Even though it’s illegal many people use it and see no problem in doing so, and there’s a not-entirely-evenly-weighted lottery of whether you get caught, and the resulting punishment and criminal record harms the rest of your life. I also feel that legalising it to get some legitimate funds to help work out the best way to fit it into our society is presumably a good thing. I also remembered coming across the striking graph in this article this week: http://www.vox.com/2015/2/24/8094759/alcohol-marijuana The article itself indicates that it’s probably flawed, but it does stick in the mind.

  • luysii  On November 11, 2016 at 5:15 am

    These are certainly valid concerns. The world’s largest uncontrolled drug evaluation experiment has likely just gotten larger. Good luck to us all.

    https://www.bostonglobe.com/metro/2016/10/09/five-people-killed-wrong-way-driver-vermont/RprOWz7uppPhyiD4iBkU4H/story.html. The guy had marihuana in his system and was driving the wrong way on an interstate. The dead were teenagers coming back from a concert.

    • Santa  On November 15, 2016 at 1:14 pm

      There is no statement in the article you link to about marijuana.
      I expected better from a former neurologist.

  • John Wayne  On November 11, 2016 at 11:17 am

    In my age group, not dosing yourself with cannabinoids puts you solidly in the minority. I’ve decided to embrace this idiosyncrasy, and I don’t make excuses for my choice. When people challenge my decision (happens occasionally, but regularly), I say three things:
    (1) it is still smoking, and that is generally bad for you
    (2) you don’t really know what you dosing yourself with (criminals, terrible at QC)
    (3) the long term effects of all of this are both not understood and probably bad.

    All that being said, I voted for legalization.
    – Hopefully regulations will address dose and composition of what you are buying
    – Easier research in the field will start to get at the real health effects
    – Start to tax the hell out of it, because we are probably going to need the money to pay for the health problems my generation are already inflicting on themselves.

  • francini  On November 13, 2016 at 7:57 pm

    Aren’t there other ways to ingest Marijuana than just smoking it? And as to the accident caused by the wrong-way driver–no different than if they guy was drunk. Driving impaired is driving impared — drunk, stoned, or under the influence of a legally-prescribed or legal OTC medication.

    We are never, repeat never ever going to get people to stop putting things into their bodies that change their mental state and disconnect them from reality. No amount of temperance movements, ‘wars on drugs’, or other attempts at interdiction or prohibition. It simply will not happen for H. sapiens.

    However, when people under the influence perform actions that directly threaten the lives or welfare of others, there should be strong consequences.

    • luysii  On November 13, 2016 at 8:04 pm

      Agree (particularly the second paragraph) — “Unfortunately as a neurologist, I had to evaluate physician colleagues who got in trouble with drugs (mostly with alcohol). One very intelligent polydrug user MD, put it to me this way — “The problem is that you like reality, and I don’t”.

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