Monday, 1 January 2018

Drug for a cocktail before bedtime?

Melatonin, agomelatin, imipramine, amitriptyline or something different?

As I can see, many patients take 20mg of melatonin before bedtime.

However, as written in CUSPND
"Agomelatine’s circulating half-life in humans is ~2hours versus 30 to 40 minutes for melatonin. This is a significant advantage of agomelatine. Further complicating the use of melatonin would be the variable and generally poor absorption after oral administration. Agomelatine penetrates the blood-brain barrier."

This study ( compared agomelatine and other drugs and concluded that the most effective for glioblastoma - imipramine or amitriptyline.

However, here ( on the contrary it is reported "that imipramine and tranylcypromine reduced the cytotoxic efficacy of temozolomide under some oxygen conditions while fluoxetine did not demonstrate such effects".

So which of these drugs should be added to the cocktail before bedtime?


  1. Richard Kast (author of the CUSP9 protocols) first introduced agomelatine into CUSP-ND. I agree with his assessment that it is likely superior to melatonin for the reasons listed. The main advantage of melatonin is that it can be purchased without a prescription.

    The study you linked to comparing the effects of various antidepressants is one that I would glance at, check which drug concentrations were being used, and then probably not even bother reading once I've seen they are testing these drugs at 10 micromolar, unless they can back up the observations in vivo. Plasma concentrations of these drugs is in the hundreds of nanomolar range, with free plasma concentrations in the single digit or tens of nanomolar range. While micromolar levels of these drugs have been achieved in human or animal brains, the unbound fraction of these drugs in the brain is typically well under 1%. This is the same problem with most in vitro work: the drug concentrations showing effects in vitro are often far from achievable in vivo. In vitro work usually has to be taken with some huge boulders of salt.

    There is some in vivo evidence for imipramine in a genetically engineered mouse model:

    And a mouse model showing efficacy of fluoxetine:

    CUSP-ND includes both agomelatine and fluoxetine, but this cocktail hasn't been tried in humans.

    1. Stephen, would you advise against agomelatine then?
      My dad is currently taking 10 mg of melatonin at bedtime but I've been considering agomelatine lately and wondering if it would be a smart and better choice.

    2. My mother began taking agomelatine 25mg to sleep. Now she drinks 50mg before bed.

    3. I would not advise against agomelatine. As I mentioned, agomelatine may be superior to melatonin for the reasons quoted in the post.

      The description of agomelatine within the CUSP-ND document can be found here: (click on the "Science" tab)

    4. I know, I know, I’ve read the CUSP-ND protocol and it’s what made me consider agomelatine. I was just asking because of your last “warning” about not have been tested in humans.
      So... should I dump melatonin and go for agomelatine? It makes perfect sense from a theoretical point of view and I’m really tempted...

    5. I wasn't trying to warn anyone off agomelatine, I was just noting that the entire CUSP-ND protocol has not been tried in humans before, the way CUSP-9 has.

      Agomelatine is worth a try if you can get the prescription.

    6. Thank you Stephen, I'm sorry if I misunderstood what you said.
      I guess what I really wanted to know was if I would be losing any advantage of melatonin by giving agomelatine instead. And since we're talking about this, how much should I start with? TIA

    7. Both melatonin and agomelatine are potent agonists of both MT1 and MT2 receptors, and molecule for molecule, agomelatine looks like it is a somewhat more potent agonist especially at MT2. Agomelatine also has superior pharmacokinetics versus melatonin, although there may be special formulations of melatonin (prolonged-release melatonin) with better bioavilability and longer half-life versus agomelatine. I don't have a strong opinion on using agomelatine versus a prolonged-release form of melatonin. Agomelatine also has 5-HT2C serotonin receptor antagonist activity, but I don't know if that has any implications on glioma biology.

      For agomelatine dosing I would follow the guidelines given by the EMA, starting with 25 mg once daily at bedtime and increasing to 50 mg once daily after a week or two. (see under "posology and method of administration"

    8. Once again, thank you very much for your answer Stephen!