It's Like Cocaine, But No Fun

In a very interesting paper, Dutch pharmaceutical company NeuroSearch, in conjunction with Canadian research corporation Kendle Early Stage, report on Subjective and Objective Effects of the Novel Triple Reuptake Inhibitor Tesofensine in Recreational Stimulant Users.

Tesofensine is a drug NeuroSearch are developing for obesity, and they report that it's shown excellent weight-loss-inducing properties in early clinical trials, although of course they would say that. What makes "tes-fens" so interesting is how it works: it's a triple reuptake inhibitor or SNDRI, acting on three neurotransmitters: serotonin, dopamine, and noradrenaline. The only drug of this class in widespread use is, er, cocaine. As you can see, the two drugs are chemically pretty similar.

Experimental SNDRIs are hot right now. It's hoped that they could be effective treatments for obesity, depression, and who knows what else. SNRIs, that inhibit the reuptake of serotonin and noradrenaline but not dopamine, are well known as antidepressants (e.g. venlafaxine aka Effexor) and weight-loss drugs (sibutramine). The thinking goes that if two monoamines are good, three's got to be even better.

But the problem is that drugs that inhibit the reuptake of dopamine are powerful stimulants with the ability to get you as high as a kite. Or to put it technically they "have a strong abuse potential". The best known are amphetamine, methamphetamine, and, yes, cocaine. Here's a Mickey Mouse comic from 1951 showing what amphetamine does...

This is why this new paper is so interesting. The authors gave tesofensine, at a variety of doses, to 52 volunteers, all of whom were recreational users of illegal stimulants: the idea being that such experienced people are best placed to be able to tell you whether a certain drug is an abusable stimulant or not. Which seems like an excellent idea.

What happened? Not much: in the opinion of the expert judges, a single dose of tesofensine at 1, 6 or 9 mg, is a complete washout, man. 1 mg had no noticeable effects at all above placebo. 6 mg and 9 mg did but they were not perceived as enjoyable or as amphetamine-like; if anything, they were slightly unpleasant.

By contrast, the volunteers really liked 30 mg of d-amphetamine - no surprise there - but they did not like the antidepressant bupropion, or the ADHD drug atomoxetine. Everything was double-blind, by the way, and the fact that there was not one but three comparator drugs, as well as inert placebo, means that this study will have avoided active placebo effects.

No serious adverse events occurred, but the higher doses of tesofensine raised blood pressure and caused insomnia. Bear in mind that for obesity the lowest dose 1 mg is looking to be the most promising and this dose didn't cause many side effects. Overall, these results seem pretty convincing: tesofensine is no fun.

Why not, given that it's so similar to cocaine? The answer is almost certainly that it's just too slow. After taking it orally, it takes 5 to 8 h for blood levels to peak, and it persists in the body for weeks (halflife of ~220 h.) With cocaine, if you snort it, peak blood levels are achieved in minutes and the halflife is less than one hour.

In general, the faster a drug gets into the blood the more pleasurable it is: this is why people tend to snort, smoke, and inject recreational drugs, rather than swallowing them. Crack is the same drug as normal cocaine, but it can be smoked, which is even faster than snorting. Compared to drugs of abuse tesofensine is ridiculously slow to enter and leave the body.

But this does raise the question of whether, with repeated use, levels might build up and produce effects very different to those seen in this study, which only used a single dose. It has a half-life of 220 hours which means that 9 days after you take some, half of it is still in your bloodstream! In the obesity trials, it was given at a dose of up to 1 mg per day. This is unlikely to give it an abuse potential per se but it could cause a lot of side effects down the line. We'll just have to wait and see...

Schoedel, K., Meier, D., Chakraborty, B., Manniche, P., & Sellers, E. (2010). Subjective and Objective Effects of the Novel Triple Reuptake Inhibitor Tesofensine in Recreational Stimulant Users Clinical Pharmacology & Therapeutics, 88 (1), 69-78 DOI: 10.1038/clpt.2010.67