Swings and roundabouts

That is to say, the swings and roundabouts of medical and scientific fashion – it seeming that doctors and scientists are just as much prey to fashion as the rest of us. A post prompted by an email from Medscape advertising the piece at reference 1, from where I eventually jumped back to reference 5.

Back in 2018, I read Oliver Sacks’ book about his work around the end of the 1960’s with a group of people suffering from the effects of encephalitis lethargica (of reference 3), and his initial enthusiasm for treatment with L-dopa (of reference 4). A drug which promotes the production of dopamine in the body which, in turn, relieved some of the Parkinson’s like symptoms of these people. In this case, the drug mostly only worked for a limited period, and then only with very controlled dosing, but the drug is still important in the treatment of people who actually do have Parkinson’s disease. All this resulting in the post at reference 5.

So I was interested to read that since about the same time, lots of people have been working on the theory that poking the body’s dopamine machinery might help with addictions, that is to say to substances rather than to activities. Or perhaps to both sorts? In any event, people with, say, an addiction to gambling, can make useful experimental subjects because the chemistry of their bodies has not been disturbed by excessive consumption of recreational drugs.

[The main dopaminergic pathways of the human brain. Eyes left]

Wikipedia explains that ‘dopamine-producing nerve cells are comparatively few in number—a total of around 400,000 in the human brain—and their cell bodies are confined in groups to a few relatively small brain areas. However their axons project to many other brain areas, and they exert powerful effects on their targets…’. This is suggested in the graphic above, also taken from Wikipedia, with the two blue blobs being the production sites at the top of the brain stem. With the terminals of these nerve cells talking to yet more nerve cells, these being ones equipped with dopamine receptors, some of which excite, some of which inhibit.

With the ones of present interest being those in the ventral and dorsal striatum, right in the middle of the brain, partly because that was where you could see what was going on.

In the 1960’s, people started treating Parkinson’s with L-dopa. And it worked, although there were side effects which needed to be controlled.

Then, having scored a hit on Parkinson’s, work in the 1970’s with rats suggested that dopamine was also involved in addiction. First, the work with rats suggested that they liked to self-stimulate the bit of the brain where there was a lot of dopamine action: it was rewarding, it gave them pleasure – whatever that might mean for a rat. Second, further work showed that this self-stimulation was damped down by shutting down the dopamine action with drugs.

And so the dopamine theory of addiction came onto the scene. As reference 2 puts it: ‘this led to a general theory of addiction in which addictive drugs release dopamine but psychoactive, non-addictive drugs do not’. It was the dopamine which was both giving the rush and which was addictive and the inference which was made was ‘keep the dopamine down’. All suggested in the figure above. An inference which was, initially at least, plausible – but a theory which did not, despite a great deal of work over many years, lead to much in the way of useful treatments. A theory which had a longer life than perhaps it should have, given the evidence accumulating against it. The fact that, for example, the dopamine was doing good stuff as well as bad stuff and you couldn’t just shut it down. Maybe Sacks’ difficulty with dosing should have been a warning? 

The general theory had simplified what turned out to be a much more complicated story to the point of not being helpful at all. Reference 2 concludes with: ‘we propose that dopamine has a central role in addiction to stimulant drugs, which act directly via the dopamine system, but that it has a less important role, if any, in mediating addiction to other drugs, particularly opiates and cannabis’. Furthermore, it seems unlikely that tweaking the workings of a single, albeit important, neurotransmitter is going to sort out a disorder as complicated and as varied in its expression as addiction.

I associate to my GP who once explained to me how a new drug comes on the market for something or other, well puffed and hyped by the seller, so you try it out. You go a bit overboard prescribing it to all kinds of people with all kinds of ailments. Then, usually, after a year or two, it all settles down and the new drug finds a settled and sensible niche in the world. Until, perhaps, some new bit of research pushes it off in some new direction.

Oddments

Speaking for myself and nicotine addiction, I remember that when I first gave up pipe smoking many years ago now, one still craved the pipe, even when one was not really enjoying it any more. When the whole messy business of pipe smoking had become rather off-putting. So there is more than just pleasure involved here.

I believe that some people are more or less addicted to sweets and find it very hard to stop eating them if they are to hand. Think chocolates. While I find something of the sort with the half-cooked peanuts we are presently buying from Sainsbury’s, not quite those snapped above. If they are in front of one, put out in a bowl, one keeps going, but it is usually easy enough to put them away or move away, after which one forgets about them. Not addictions proper, but maybe they share some of their underlying machinery with addictions.

The drug called chlorpromazine (CPZ), marketed under the brand names Thorazine and Largactil, widely prescribed for psychotic disorders such as schizophrenia, is thought to work because it is a dopamine antagonist. To this layperson, some of the various side effects appear to mirror the use of L-dopa, that is to say dopamine promotion rather than demotion, with Parkinson’s.

These swings and roundabouts reminded me, rather unfairly, of the various nonsenses paraded by Mackay in his book about popular delusions, for which see reference 6. A book which I failed to turn up with Bing or blog and was reduced to finding it on the bookshelf – which, to be fair, took less than a minute. Probably less time than I had spent trying to find it on the computer.

Conclusions

The author of reference 1 sensibly concludes with the warning that ‘we should be careful how we handle such a delicate and still little-known system’ – that is to say the dopamine system. While the authors of reference 2 caution us against getting too carried away by attractive theories lacking solid evidential support. Give it a punt yes, but don’t bet your house on it.

From where I associate to the fad for ‘evidence based policy’ which has infested government. A fad which, to my mind, just rebadges what has gone before; a fad which is no more than a sexy label dished out by highly paid management consultants.

References

Reference 1: The truth about the 'happy hormone': Why we shouldn't mess with dopamine – Marta Zaraska, Medscape – 2022.

Reference 2: The dopamine theory of addiction: 40 years of highs and lows – David J. Nutt, Anne Lingford-Hughes, David Erritzoe, Paul R. A. Stokes – 2015. 

Reference 3: https://en.wikipedia.org/wiki/Encephalitis_lethargica. 

Reference 4: https://en.wikipedia.org/wiki/L-DOPA. 

Reference 5: http://psmv4.blogspot.com/2018/12/awakenings.html. 

Reference 6: https://psmv4.blogspot.com/2018/11/a-last-outing.html.

Additional information

Abstract of reference 2: For several decades, addiction has come to be viewed as a disorder of the dopamine neurotransmitter system; however, this view has not led to new treatments. In this opinion article, we review the origins of the dopamine theory of addiction and discuss the ability of addictive drugs to elicit the release of dopamine in the human striatum. There is robust evidence that stimulants increase striatal dopamine levels and some evidence that alcohol may have such an effect, but little evidence, if any, that cannabis and opiates increase dopamine levels. Moreover, there is good evidence that striatal dopamine receptor availability and dopamine release are diminished in individuals with stimulant or alcohol dependence but not in individuals with opiate, nicotine or cannabis dependence. These observations have implications for understanding reward and treatment responses in various addictions.