It’s Like Cocaine, But No Fun

By Neuroskeptic | July 2, 2010 9:00 pm

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…

ResearchBlogging.orgSchoedel, 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

CATEGORIZED UNDER: antidepressants, drugs, papers
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  • http://www.blogger.com/profile/15204392479942503797 kufilefunsho

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  • http://synthesis.williamgunn.org Mr. Gunn

    I think the half-life is a big reason for concern. I wonder why they only went up to 9 mg, whereas they used 30 for cocaine? I mean, what an abuser will do, if a given dose doesn't do anything for then, is take more. With the slow-half life here, you'd better hope that higher doses don't become recreationally-compelling, or it's going to be a problem. Cocaine's short half-life is actually a good thing in that respect.

  • http://www.blogger.com/profile/17860606393347567512 Helen Krummenacker

    Sounds like maybe it would be best as a take-once-a-week type drug, to slow it's potential to build up (which it would still do over time, but one could break off after 3 months and 'coast' on the residuals for a while?) With obeisity and depression, I think that could be really useful, With luck, overeaters would get used to smaller portions, and some depressives just need the cycle broken to get back on track, so having it slowly taper out of the system might be ideal.
    I'm also thinking it might help sufferers of some chronic pain disorders, like fibromyalgia.

    Some people with depression & obeisity work changing shifts, and a weekly medicine would be much more effective. Good luck to the researchers, I have many friends who might find this more helpful than current medications.

  • Anonymous

    Sounds interesting. Wonder if this one drug could replace 2 drugs I take (among others): Effexor XR (bipolar w/tendency toward depression) and Adderall (ADD diagnosed in adulthood). That would be nice, except for the insomnia bit.

  • Beth

    My first thought is, “And I thought finding I was allergic to a drug with a two-day half-life was bad..” I realize that long half-lives could be a good thing in some respects, but I shudder to think of people that would be allergic to the drug or experience severe adverse effects.

  • http://www.blogger.com/profile/07650701412022872445 Mike Mike

    It's known that low doses of psychostimulants are often aversive, and it's only at high doses that they are rewarding (ie. see Cabib et al 1996: http://www.springerlink.com/content/y273752l4325235q/ ). This might change with experience, so that experienced stimulant users need more drug than newbies to feel the good effects (this has been hard to show in rat models of drug addiction, but is a reliably self-reported phenomenon in human drug addicts.) If they didn't inject both substances, as well as do a wide dose-response curve, then it's unlikely that the effect of the two doses are comparable. This is complicated by the use of experienced stimulant users, as it's hard to say what effect their (abnormal) experience has had on how they perceive the drugs.

    I can find no evidence (using pubmed and google) that this drug has ever been systematically tested for its rewarding (or unrewarding) properties at various doses and in a variety of routes of administration. As such, it seems like saying anything about it's abuse potential is premature.

    Also, strictly speaking, the half-life isn't at all an issue in terms of getting people high – methampetamine's halflife is around 12 hours, and it gets people pretty high – for about a day at a time. If this drug ends up “working” as a recreational drug, then it might just get people high for a really long time (at least until neuroadaptations start to take place to reverse the effect.)

    I haven't read the paper (no access at home,) but I wonder how they deal with the possibility that 30 mg of tesofensine might feel good enough to get people to divert and abuse it. Distributing it in low doses is a poor solution. Do we honestly think that a drug addict wouldn't grind up and inject some pills if it would get him off?

    One more thing – a short editorial: it's disturbing to me how excited we get about pills to “cure” obesity, and how much money we're willing to dump into them. It seems to me that developing generally healthy lifestyles is going to be a lot easier, cheaper, and more enjoyable than tinkering with brain chemistry (although it affects a different group of people, leaving out those with strongly genetic weight problems.) It's not that I don't want people with genetic weight problems to be healthy, I'm just afraid that what is really driving this research is the idea that we'll all be able to pop a pill and get thin with no ill effects, which is highly unlikely (although it would make for great marketing.) I guess the market is never wrong, but damn is it frustrating some times.

  • http://www.blogger.com/profile/06647064768789308157 Neuroskeptic

    Beth: Good point. I assume you'd start out by giving a tiny dose and ramp it up slowly. The long half life means that you could give a very small dose each day and wait till it builds up. But that probably wouldn't help against allergic reactions per se.

  • http://www.blogger.com/profile/06647064768789308157 Neuroskeptic

    Mike Mike: All good points. Also, I just realized, that if the lack of abuse potential is a product of the slow absorption after oral use, people are going to crush the pills and snort them, or something. Although I believe there are anti-crushing formulations of oxycodone for that reason, I don't know how effective they are…

  • http://www.blogger.com/profile/06832177812057826894 pj

    Hmm, would be interestimng to try that in depression.

  • Anonymous

    This is the stranges and WORST written article ever. NOTHING here is of ANY value WHAT-SO-EVER.

  • MikeS

    Obesity is not caused by chemical imbalances in the brain, and now we have a drug that works on 3 neurotransmitter systems? This is not the right way to treat it, I'm sure this drug will have awful side effects and withdrawal symptoms, because it is not fixing any chemical problems, rather it is creating them. There is no psychotropic magic bullet to treat obesity and it is quite alarming how willing drug companies are to disrupt 3 chemical pathways.

  • http://www.blogger.com/profile/06837467954881003505 Ian Smith

    I suspect all frequent bloggers of being on something. How 'bout you?

  • http://www.blogger.com/profile/06647064768789308157 Neuroskeptic

    Well I'm on venlafaxine which is an SNRI. So it's got 2 out of the 3 monoamines covered. Not dopamine though :(

  • http://www.blogger.com/profile/07429793255785560043 Dirk Hanson

    From now on it's Tesofensine for me.

  • http://www.blogger.com/profile/06647064768789308157 Neuroskeptic

    I think we need to invent a street name for this stuff.

    “Tezzies”
    “Fence”
    “Sophie”
    “Triple X” (for the pharmacologically-minded drug user)

  • http://www.myviagrarx.com generic viagra

    Cool Article I like it so much thanks a lot for this awesome post keep working and posting variety of articles.

    Smith Alan

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Neuroskeptic is a British neuroscientist who takes a skeptical look at his own field, and beyond. His blog offers a look at the latest developments in neuroscience, psychiatry and psychology through a critical lens.

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