*Never Enough: the neuroscience and experience of addiction*

That is the new and fascinating book by Judith Grisel, unlike most neuroscientists on these topics she has been addicted to many of the drugs she writes about, or at least has tried them “for real,” furthermore her book integrates her personal and scientific knowledge in a consistently interesting manner.

Here is one bit from early on:

The very definition of an addictive drug is one that stimulates the mesolimbic pathway, but there are three general axioms in psychopharmacology that also apply to all drugs:

1. All drugs act by changing the rate of what is already going on.

2. All drugs have side effects.

3. The brain adapts to all drugs that affect it by counteracting the drug’s effects.

And a tiny bit from the middle:

Excessive use of alcohol now results in about 3.3 million deaths around the world each year.  In Russia and its former satellite states, one in five male deaths is caused by drinking.  And in the United States during the period 2006 and 2010, excessive alcohol use was responsible for close to 90,000 deaths a year…

And finally:

…primates given ecstasy twice a day for four days (eight total doses) show reduction in the number of serotonergic neurons seven years later.

Definitely recommended, this will make my list for the year’s best non-fiction.


"…primates given ecstasy twice a day for four days (eight total doses) show reduction in the number of serotonergic neurons seven years later."

Sounds like it was sufficient to kick the brain into a new equilibrium. This could be good, bad, different, or have no noticeable effect. (The later 3 are more likely.)

Sounds really hard to believe.

Lower down in the comments people say the study is flawed. But I had noticed hominids seem much the same as they were after a dozen musical festivals of E use so if their brains were changed it didn't seem to result in much effect.

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They're very convincing and can definitely work.
Still, the posts are very short for novices.
May you please extend them a little from subsequent time?
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Whatever happened to neuroeconomics or econophysics? I remember it used to be all the rage a while back. Have these subfields made any fundamental discovery or have they petered out?

So. how is gambling handled? Or does the author just gently glide over that addiction, as it does not fit into the highlighted 3 step drug model?

Points 1 - 3 are interesting and useful bits of information.

The 3.3 million world wide alcohol deaths constitute a mere ca. 5.8% of annual deaths [https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death]. Hell, we gotta die of something!

My sincere worry is that this sort of stuff plays into the hands of those who do not wish us to have any fun. :-)

Many want to ban firearms yet they cause far fewer deaths than alcohol. When you add the economic costs and social capital destruction due to alcohol it looks even worse.

Auto accidents top all preventable deaths and when you add up its costs and destruction it dwarfs everything else. With phone driving on the rise, expect even more future carnage.

Actually no. Globally tobacco, and mostly cigarettes at that, is still the leading cause of preventable deaths. Other major culprits include obesity, drinking, hyperglycemia, hyperlipidemia, hypertension, STIs, malnutrition, solid fuel smoke exposure, and physical inactivity.

Obviously, there is some overlap. But there just are not enough people in cars in the world to make this work out. In enough wealthy countries there are people who rarely drive (e.g. NYC, Tokyo, London) and there are plenty of poor people who also never drive in the back country and slums of poor countries.

In the US. The big causes of preventable death are Obesity (which per some research has just risen to #1), Tobacco, and Alcohol. Depending on your thoughts about anti-coagulation, you can throw in medical errors and toxin ingestions. Last I checked, we were still estimating STIs as more risky for your death than driving.

Truth is driving is obnoxiously safe, we have to measure the death toll in deaths per billion miles driven. And frankly the single biggest thing keeping traffic deaths up is DWI. Most of that is alcohol, though I am seeing more patients coming through with marijuana intoxication and, of course, heroin.

'Truth is driving is obnoxiously safe, we have to measure the death toll in deaths per billion miles driven.'

Motorcycle riding on the other hand ...

Information as PDF here - https://www.nhtsa.gov/sites/nhtsa.dot.gov/files/810887.pdf

The offset of that is that motorcycling is an excellent source of organ donations. We are currently something around saving a net one life per two motorcycle deaths (useable donations can save over five lives when the organs come in good); we may soon reach the point where motorcycle deaths save lives.

So yeah, motorcycling is dangerous, but at a societal level its costs are far less than alcohol or most other public health issues.

Interesting, though motorcycles have been called organ donor machines for decades. On the other hand, how does that organ donation equation work out with gun shot fatalities?

And to be something along the lines of cynical, since the rapid rise in motorcycle fatalities seems in major part based on older men riding motorcycles, how do they work out as organ donors? Especially as the crossover between older men, alcohol use, and motorcycling riding fatality is not trivial.

Not so well. Motorcycles deaths are much more likely to have the mechanism of death be brain trauma. As long as the damage is mostly supratentorial the mind dies, but the organs stay well perfused and oxygenated.

GSWs are most likely to die from CV failure (e.g. exsanguination, traumatic heart failure, reactive ischemia). The organs endure much longer periods ischemic time before harvest and take a much heavier battering in other ways. Kidneys and liver very commonly get destroyed by reactive ischemia as the epinephrine shunts blood to the brain.

GSWs to the head can make for good donors, but the mechanics of injury are much more likely to disrupt the carotids. This again can lead to ischemia and damaged organs remote from the trauma. One of the big things with motorcycle deaths is that they are often not obviously dead in the field. Sure GCS is 3, but coma vs death is not all that obvious for crushing head injuries. So they ship off to the hospital stat and hope. GSW to the brain are very obviously not survivable, this may prevent rapid transport and harvesting.

Older organ donors work out okay until they hit ~70. You only need the organ to last as long as the recipient. Typically they are very sick with underlying disease so 20 years is more than enough. A 65 year old without specific organ disease often has another 30 years in his kidneys. Similarly, livers that are not dealing with something like cirrhosis or NAFLD typically are good for a few more decades. Highest I have heard about are some organs that have made 120 years.

The other thing to remember is that in medical terms riding a motorcycle is hard. If you have too much damage to anything, you simply cannot ride. Liver damage leads to ascites and encephalopathy both of which make the physical task of riding difficult (pain and balance). Kidney failure leads to malignant hypertension which destroys the eyes and harms propioception. Lung disease makes it harder to breath at highways speeds in open air. Heart failure makes the legs swell and makings riding gear uncomfortable.

In general, motorcycle riders are not that unhealthy when it comes to end organ function.

We probably could make the world a better place by banning alcohol.

For a lot of measures it has done so every time it has been tried.

For instance, last go round we had a massive drop in liver disease and associated fatalities. There were also drops in spousal killings, child abandonment, and arguably petty crime. We saw lifelong changes in the drinking habits of people socialized by the prohibition era (roughly became teenagers during prohibition/born within 10 years of national prohibition's end). As those generations have died off we have seen reversion to previous alcohol consumption patterns with a dramatic rise in all sorts of traditionally negative outcome indicators.

Virtually all of the costs were confined to a small number of urban areas, and even there they tended to be concentrated among those involved in organized crime.

"Better" is one of those slippery constructs though. Even though the documented externalities of alcohol consumption dwarf the entire gross revenue of the alcohol industry, many people believe that their right unfettered access to intoxicating substances is more important than the lives lost on the other side.

They have a point, banning everything that negatively impacts public health is very wide ranging. But my experience does show me that people tend to not know the real costs and to be highly classist about people who "bring things on themselves" with their inability to moderate their alcohol consumption.

The issue is that the unintended nd negative consequences of Prohibition outweighed the benefits. Deal with it.

Great, point me to your cost/benefit analysis. I would love to see a robust quantitative analysis that weights the negative consequences against the benefits.

As a fellow doc, Sure is 100% correct. Prohibition gets remembered because gang violence is emotional. A few hundred gang deaths is a drop in the bucket compared to the lives saved from cancer, cirrhosis, violence directly attributable to prohibition. In my own practice (middle/upper middle class suburbs), I'd estimate about 30% of my patients will have a shortened life due to alcohol. >50% of all the rape, murder, and child abuse cases I've been involved with featured the assailant or victim being under the influence of alcohol.

....we can hope the public increasingly substitutes cannabis for alcohol. Cannabis isn't good for you of course, but seems less bad to both yourself and those around you than alcohol.

Unfortunately, preliminary data does not support this hope. In CO, for instance, marijuana legalization was followed with more alcohol consumption. We can verify this by looking at excise tax receipts which, last I looked, had risen every year in CO since legalizing marijuana.

The most recent trendline is 142, 147, 150, 153 million gallons of ethanol purchased and taxed in Colorado in the last 4 years. The Colorado Department of Revenue has shown increases in alcohol consumption every year since marijuana was legalized; it has shown larger increases in alcohol excise growth.

To the best of my knowledge, none of the states that have legalized marijuana have seen a decrease in ethanol volumes. This suggests that in practice any substitution effect is very weak at best.

Similarly, I have not seen anything suggesting a dramatic drop in DWI ED visits in any of these states. As I recall, Colorado saw a nice drop the year before legalization and much smaller ups and downs since.

I just have not seen a whole lot of data that suggest actual population level substitution. My suspicion is that there is some substitution by lighter users of both vices, but that there is complementation among heaviest users (this all makes sense of the otherwise confusing numbers coming out of CO where bulk marijuana sales continue to grow while there is some reduction in marijuana use rates in the population).

And legitimately, if you have some real world data about substitution, preferably anything other than asking stoners for recall data, I would be all ears.

Dingo bites kill hardly anyone when compared to alcohol. That's why when someone gets mauled by dingos we just let them die.

"Excessive use of alcohol now results in about 3.3 million deaths around the world each year": my suspicion is that these sort of data are essentially just made up.

I have no doubt that boozing is a dangerous game, I have no doubt that taken to excess it kills. What I doubt is the honesty and verifiability of the numbers.

I also wonder about a usage such as "results in". Does it mean that it causes? If so why not say "causes"? If it doesn't mean "causes" what the devil does it mean?

If anything, those numbers are low.

Around 700,000 die each year just from hepatocellular carcinoma. Alcohol is the leading risk factor and because it typically is part of a long cascade of liver issues we can trace alcohol throughout. This is the 3rd most deadly cancer globally (helps that China has an alcohol problem, high incidence of poor alcohol metabolism genes, and crappy screening/treatment for liver disease).

After all hepatic mortality follows a common trajectory: alcoholic steatohepatitis (which has unique biomarkers and pathology from NAFLD) to cirrhosis (which again can typically be differentiated if due to alcohol) to terminal liver problems.

Other things are also pretty easy to trace. The overwhelming majority of pancreatitis is quite predictable with alcohol consumption, rising in a nice dose dependent fashion. Similarly, beer potomania, thiamine deficiency, and the like all have profiles that are pretty specific for alcohol and less so for other causes.

Alcohol has a unique chemistry and it shows up in a lot of ways (ALT:AST ratios, non-anion gap metabolic derangements).

I have the same level of confidence that alcohol contributes a high proportion of these causes of deaths that I do for cigarettes and lung cancer.

It's no use saying "risk factor" to me because unlike most of the population I know it is just a way of weaselling, of pretending that a positive correlate is a demonstrated cause.

"those numbers are low": it must be many decades since I saw a number advanced by an interest group that seemed to err on the conservative side. Exaggerating or downright lying is now the norm. Can you suggest a reason why this particular topic should involve a cautious estimate rather than the usual bluster?

'of pretending that a positive correlate is a demonstrated cause'

So, riding a motorcycle without a helmet increases the fatality risk factor three times. Is that a positive correlate, or it is actually based on the fact that helmets offer protection in the event of a motorcycle rider's head coming into contact with a hard surface?

To put it differently, would you dismiss the idea that riding without a helmet is a risk factor for dying in an accident is weaselly?

Don't get me wrong, risk factor can be defined as anything, of course. On the other hand, the Hurt Report did an excellent job actually investigating motorcycle accidents, and determined that not having eye protection (googles or face shield) is a distinct risk factor in motorcycles accidents. This is not merely positive correlation, because anyone who has ever had something strike their eye at 60mph is quite aware that it is more than a sufficient cause to lose control of a piece of machinery temporarily.

It is how to draw the line between cause and effect that is important, though I fully agree about the point concerning interest groups in general.

Well here is what we do know. All of the causes of death I discussed dropped, dramatically, following prohibition. They all increased following prohibitions repeal. And the timing depended on when prohibition and repeal happened. Oh, and the correlation held in international context (e.g. Finland).

At a population level you need to have an awfully special correlation with some other cause to drop when you ban alcohol, rise when you legalize it, and show up with differing time periods in international data.

At the patient level, there is a very nice dose response curve. HCC rates rise with alcohol consumption and track that better than other proxies for poor health outcomes (e.g. IV drug use).

For the earlier parts of the disease progression, we have can just track by the ALT:AST ratio. For the middle parts we can see the difference on pathology sections. For both we can reverse some of the disease process by stopping ethanol consumption.

Again we have this weird thing where stopping the alcohol consumption actually halts or even reverses the steatohepatitis.

As far as why I think they would be higher, there is not quite as robust data suggesting that a lot of metabolic disorders are driven in part by drinking habits (lots of calories that biochemically bypass a number of the sugar homeostasis checkpoints). Even a small fraction of the mortality associated with diabetes, obesity, and the like is going to bump the numbers substantially. Likewise, the STI burden is heavily dependent on alcohol fueled poor sexual choices (e.g. lack of protection, sexual relations with people you would otherwise refuse). These are all hard to quantify and pretty much anytime you relate the dangers of alcohol consumption you get lambasted a moral scold.

I'm guessing, but your sort of disbelief is exactly what people may be attempting to avoid without just running every mortality bloc through an odds ratio with alcohol consumption.

"sexual relations with people you would otherwise refuse"

Your solution means that these people may never get laid. Dying from alcohol-related disease in old age might not seem bad in comparison.

Everything you do in life has risks of dying. In a system such as ours where we all pay into government healthcare programs like Medicaid and Medicare, it is appropriate to ask how much any given activity impacts outcomes and ask that the partakers offset their bills.

Maybe being laid by something with active penile discharge is worth a lot to you, well okay, why should the rest of us have to pay for your joint aspiration or replacement?

If it is that valuable then a marginal increase in alcohol taxation should not be an imposition.

Personally, I always advocate for using the same methodology for alcohol and tobacco taxation. The fact that the rich and powerful like to drink more than they like to smoke, however, seems to always result in alcohol being taxed less than its externalities.

+1 that is how I undestand it.

Here is some data on impaired driving:

"In 2016, 10,497 people died in alcohol-impaired driving crashes, accounting for 28% of all traffic-related deaths in the United States."

Then there is domestic abuse and other crimes.

They're coming for your guns. After that your booze. The US military will roll over when they realize that you and other patriots and sovereign citizens are armed and deadly serious about protecting your constitutional rights to keep and bear arms and be a member of a militia and own slaves.

The US government took away our booze before with a constitutional amendment. Decided it was a bad idea and rolled it back. I don't think Tyler wants to ban alcohol but he is doing the equivalent of a public service announcement.

From 2006 to 2010, 18,000 Americans or 0.006% of the population died from excessive alcohol.

Tyler forgot to mention another addictive substance: each year over 500,000 Americans die from tobacco, almost 30 times as many as die from alcohol, although they are older when the die.

(18,000 died from excessive alcohol per year.)

The problem with the 18th Amendment was it had too many exceptions. Next time they won't make that same mistake. All intoxicating beverages will be banned for everyone for every purpose. And the law will be rigidly enforced this time! Yes, even at the cost of your so-called precious "privacy". Desperate times call for desperate measures.
As I often do, I will recommend a book: Last Call, by Daniel Okrent (2010, Simon & Schuster)

That's an excellent book. I especially liked the chapter about how supplying the nation with communion wine during Prohibition supercharged the California wine industry.

Okrent was on EconTalk when his book came out. Great episode.


"All drugs have side effects"

There's a sense in which that is true, but it's also banal. A "side effect" is just an effect of the drug that isn't desired. Often people think that "side effects" are more substantive than that - that there are the "real" effects, and then the "side effects", but that's not right. I think it would have been more accurate, and more informative, to say that all drugs have undesired effects.

On the drinking deaths in Russia, the toll is really high, but it's important to note that this number includes people who die because of accidents while drinking. Those are real deaths, of course, and should be addressed, but it might be addressed in somewhat different ways than, say, deaths due to pure excess consumption. (Russia is a place where there are _lots_ of accidents. Some of this is _directly_ tied to lots of people being drunk, but not all - some of it is tied to a culture of very lax safety standards, bribes paid to people who are meant to enforce those standards, etc. If that was changed, this number would change - being drunk would be less dangerous.)

Over-all, on topics like this, Tyler tends to do bad cost-benefit analysis (as do most people, but in a different direction.) He counts the costs very clearly, but not the benefits, because he, himself, doesn't see them or hasn't experienced them. That's just as much a mistake as counting the benefits, but not the costs. It's one of his consistent blind spots.

"primates given ecstasy twice a day for four days (eight total doses) show reduction in the number of serotonergic neurons seven years later."

Any idea what the reduction in neurons was? 100 million? 1 million? Did the reduction reduce cognitive function? (The obvious answer is "no.")


How can a monoamine in a 50-100 milligram dosage 'kill' neurons?

Is there a putative mechanism?

Colour me skeptical.

More on MDMA neurotoxicity:

"Under this model, three things need to happen in order for you to suffer neurotoxicity. First, you need to take a fairly large dose of MDMA (how much is needed isn’t clear.) Then, you need to run a very high body temperature for an extended period of time. And finally, the axon’s supply of antioxidants must be largely exhausted". [SNIP]


primates given ecstasy twice a day for four days (eight total doses)"

That doesn't really match how people use the drug, though, does it? Ecstasy is mainly a party drug; not many parties last for four days, except I guess there are those weird EDM festivals that go on for 2-3 days, but I think you're already part brain-damaged if that seems like a good use of your time.

John Hopkins is now pouring serious effort into the study of psychedelics. Who says science is complacent?


The research about MDMA effects in primates is flawed and shouldn't be trusted.


Mislabeled? Even some recreational drug users use test kits on their MDMA before taking it. Even if it was really accidental, it shows sloppiness and incompetence on the researcher's part.
The book is probably not talking about the retracted study but a previous one, however this guy (Ricaurte) is known to use questionable methods in his work.


The MDMA serotonin scare was faked by some drug crusade types. Nobody could reproduce their findings.
That and MDMA is not addictive. Essentially nobody would take so much every day for four days.

> Essentially nobody would take so much every day for four days

I just got back from burning man, gotta tell you you're wrong about that one

Drugs alter reality. That's the point of using them. For most people, the altered reality is uncomfortable, but for some, it's closer to "normal" than sobriety. That's a difficult concept for "normal" people to understand. Virtual reality might work for people who are not "normal". By "work" I mean create an artificial environment that is "normal" for the user. Consider that many who are prone to drug use (i.e., those with higher levels of dopamine) are also drawn to sensation seeking behavior such as riding a roller coaster. Also consider that older people are less inclined to engage in such behaviors.

A common expression among alcoholics is: one drink is too many, a thousand not enough. Thus, the title of Cowen's blog post.

Steven Gubster died last week in a rock climbing accident in the French Alps when his rope broke and he fell 800 feet to his death. Dr. Gubster was an experienced and passionate rock climber, as was his father. What's fascinating is that many physicists share the same passion for rock climbing. From Dr. Gubster's obituary in the NYT:

'“Over a hundred years ago, a mathematician named Arthur Cayley said that climbing a mountain and proving a theorem gave him the same sort of satisfaction,” the article quoted Dr. Gubser as saying when he was at Caltech. “I think that captures one of the motivations of climbing physicists today.” But the dangers were always inherent. Indeed, the day after Dr. Gubser plunged to his death, Ann Nelson, another prizewinning theoretical physicist and mountaineer, died while hiking in Washington State when she slipped and fell into a gully.' https://www.nytimes.com/2019/09/06/science/steven-gubser-dead.html

Gubser, not Gubster. Gubser is known for his work on string theory.

What is it about the brains of physicists that draws them to rock climbing? What is it about the brains of Grand Prix racers that draws them to Grand Prix racing? What is it about the brains of drug users that draws them to drugs? Rock climbing and Grand Prix racing are inherently risky behaviors, very risky behaviors. Why do they do it? Isn't it irrational? Using drugs is inherently risky behavior, very risky behavior. Why do they do it? Isn't it irrational?

"her book integrates her personal and scientific knowledge in a consistently interesting manner": so does Theodore Dalrymple's 'Junk Medicine: Doctors, Lies and the Addiction Bureaucracy'. From the blurb on Amazon:

Almost everything you know about heroin addiction is wrong. Not only is it wrong, but it is obviously wrong. Heroin is not highly addictive; withdrawal from it is not medically serious; addicts do not become criminals to feed their habit; addicts do not need any medical assistance to stop taking heroin; and contrary to received wisdom, heroin addiction most certainly IS a moral or spiritual problem. Based on his experience as a prison doctor and as a psychiatrist in a large general hospital in Birmingham, Dr. Dalrymple argues that addiction to heroin is not an illness at all, and that doctors only make it worse.

'and contrary to received wisdom, heroin addiction most certainly IS a moral or spiritual problem'

Rare to see you be so overtly anti-American in quoting someone, as the continuing growth of opioid addiction in the U.S. is normally considered to be based on opioid's addictive qualities, and not deep failings in American society.

'and that doctors only make it worse'

Well, as court cases in the U.S. have clearly shown, though it might not be doctors precisely, there is no question that America's problem with opioid addiction can be traced to large extent to medical sources, such as pharma companies, who relied on doctors to write the prescriptions.

Anti-American? What are you drivelling about? Facts is facts, insofar as you can establish them.

'Facts is facts'

So America's growing problems with opioid addiction actually most certainly IS a moral or spiritual problem.

Fair enough, just wanted to make sure that you wanted to point out America's moral or spiritual problem as reflected through growing opioid addiction.

Admittedly, that moral or spiritual failing may be centered in the sort of thing that Prof. Cowen has written a love letter to, with court documents providing evidence.

…primates given ecstasy twice a day for four days (eight total doses) show reduction in the number of serotonergic neurons seven years later.

Doesn't surprise me, but nobody uses ecstasy that way. For one thing Ecstasy will tend to not work if you try to do it even one dose two days in a row, because the serotonin stores in the brain have been depleted. Ecstasy users will often take 5-HTP to try to help replenish serotonin levels, to avoid the well known period of depression that tends to follow Ecstasy use. If you try to use it again before your brain's serotonin level are resotred it will not work and make the depression worse.

So it doesn't surprise me that taking TWO doses per day for FOUR days would trigger some serious neurological trauma. But nobody would voluntarily do that - they wouldn't get a "high" off of 7 of the 8 doses, and it would send them into a pit of horrifying depression for days, if not longer. What's probably happening is that that high of a dose causes a permanent depression, thus the lower serotonergic neurons.

You would think that, but I get a last one of these every few months. Typically they are young, not the most experienced, and disproportionately likely to opt for combined use.

To be fair I see a lot of dumb use. Personal favorites include: (long ago) a kid who had stolen a relative's Antabuse and swallowed "a few" and then had chased them with vodka, a guy who swore by mixing anabolic steroids and estrogen for body building, and a bulimic girl who would ingest molly only to vomit it up.

Drug users are not the sharpest knives in the drawer and many of them just use simple heuristics when trying to get high. Eventually trial and error either kills them, incarcerates them, bankrupts them, sobers them up, or they figure out typical use patterns.

Typical use patterns by you or any of your friends are light-years away from the idiots holding down the far end of the bell curve.

"So it doesn't surprise me that taking TWO doses per day for FOUR days would trigger some serious neurological trauma."

But the study didn't say it triggered some serious neurological trauma.

As I feared, the fun has been forgotten.

Drugs are for sick people. When will we learn.

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