Doping with the Amphetamines

We’ll start off our discussions on sports doping with the classic psychomotor stimulants, the amphetamines. You know, good old “speed”. A class of drugs primarily considered indirect dopamine agonists because they bind to the dopamine transporter with good affinity (dopamine reuptake inhibitor) and also act to facilitate dopamine release from the terminal. As with similar compounds they also tend to have some affinity for other monoaminergic transporters and will thus modulate norepinephrine and serotonin. Nevertheless, the major action usually under discussion is to increase dopamine levels in the synapse.

Most usually we’re talking amphetamine or methamphetamine, not least because they have been available in prescription formulations for ages (for you casual readers, that’s technical blogger phrasing for “I’m not gonna look that one up, go ‘head and Google it if you want”). According to Monitoring the Future, prescription amphetamines remain one of the most popular illicit drugs; see incidence rates and attitudes and compare to other drug use in 12th graders. Interestingly I was in high school, running XC and track just before that circa-1984 JustSayNo decline in annual amphetamine incidence and yep, we had a guy who was on speed for more than one race. A couple of others tried it here and there. Perhaps even more interestingly this was the beginning and end of my direct experience with sports-doping. I never ran into any experiences after that in which I was positive through the evidence of my own eyes, and an admission, that someone was doping. Go figure. Anyway, the amphetamines have a long history in cycling, including one nasty and transforming incident…

The most famous event in cycling’s amphetamine story was the death of Tom Simpson during the 1967 Tour de France (ghouls can YouTube the collapse on Mt. Ventoux here). Astute readers will note that it was the 40th anniversary this summer- there has been an explosion of readily-Googleable media on the topic, some of which is relevant to the science.

Go see a post on the 1950s-1960s racers’ perspective on “benzedrine” (i.e., amphetamine) doping and the Simpson fatality from Dave Moulton (yes, that Dave Moulton, the great frame builder) in his blog. Gems include:

Every year we followed the Tour de France; it was an “open secret” that riders in the Tour took dope.

The subject was openly talked about amongst cyclists, but never written about or criticized in the cycling press. The general media could care less, and it seemed the UCI and other cycling governing bodies turned a blind eye.

All this changed on July 13, 1967 when British cyclist Tom Simpson died on the slopes Mt. Ventoux in Southern France. This was a mountain stage of that year’s Tour, and a brutally hot day. Tom Simpson died of heat exhaustion but would not have done so if amphetamines had not caused him to push his body beyond the limits of human endurance.

from John Wilcockson over at VeloSnooze:

It was so blazingly hot up on the exposed limestone flanks of the Ventoux that perhaps Tom had fallen victim to heat stroke, which he suffered from as a boy. (emphasis added)

…The newspapers said a couple of amphetamine ampoules were found in his back pocket. But that was no surprise. I’d seen empty amphetamine ampoules in the changing rooms after amateur criterium races in Brittany. There were no medical controls in 1967 and no rules against using drugs. That was the way.

another quote from the Daily Peloton:

A post mortum confirmed that a certain quantity of amphetamine and methylamphetamine had been discovered in his blood. The same experts confirmed that the dosage would not have been enough, by itself, to kill him but would have permitted him to pass the limit of his endurance and therefore allow him to fall victim of to excessive exhaustion.

The Guardian comments:

1967
Tom Simpson, England’s best ever rider, dies of heart failure on the ascent of Mont Ventoux. Amphetamines and alcohol are detected in his blood and amphetamine pills found in his shirt. The Tour begins drug testing.

So the stage is set: A guy, perhaps with a history of hyperthermia sensitivity, takes some speed, maybe continually through the race, maybe drinks some alcohol, rides beastly hard in the heat and may not drink enough. What killed him? The unique set of circumstances, clearly. Every evidence he’d 1) ridden hard before and 2) on amphetamines. Every evidence other riders were doing the same, under similarly adverse conditions. The lay media sort of get the idea that it must have been a unique confluence of factors but still leave things pretty murky. Scientifically, there is all kinds of stuff in here to investigate.

The biggest problem with the usual lay-media analyses (and by now the confirmed “lore”) is that they seem to overlook the fact that amphetamines have specific pharmacological effects which dysregulate body temperature. This has been known for a loooong time: A quick Pubmed search pulls some 255 references dating back to 1957. You will note most lay reports focus on the stimulant properties, i.e., that amphetamine let Simpson ride harder.

In animal models, under at thermoneutral or higher ambient temperature conditions, the amphetamines elevate body temperature which can be a proximal cause of amphetamine-related fatality. In rodents, if you push the ambient temperature up, alter bedding, social housing, humidity, etc in ways that counter heat shedding you increase the drug lethality (meaning a greater fraction dying at the same dose or the same fraction at a lower dose). Ethanol seems to be protective in MDMA-induced hyperthermia in rats but of course, MDMA is not really a typical psychomotor stimulant amphetamine as it has a greater preponderance of serotonergic activity over dopaminergic activity. I haven’t found much on ethanol/amphetamine interactions yet but I’ll keep looking.