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Ketamine and Naltrexone: Dissociation and Potentiation

Discussion in 'Ketamine' started by Forthesevenlakes, Jul 18, 2006.

  1. Forthesevenlakes

    Forthesevenlakes Platinum Member

    Reputation Points:
    Feb 26, 2006
    I used the search engine and didnt see this article posted, so he is putting this up as an interesting use for ketamine: helping to break addictive cycles. It's known to many that this dissociative can be used to help treat addictions, such as opiates and alcohol, but he figured some may find it interesting to read a study that supports this idea. Just the abstract is posted now, but the full article can be found here!

    Potentiation of Low Dose Ketamine Effects by Naltrexone: Potential Implications for the Pharmacotherapy of Alcoholism

    John H Krystal1,2,3, Steven Madonick1,2,3,4, Edward Perry1,2,3, Ralitza Gueorguieva3,5, Laura Brush1,2, Yola Wray1,2, Aysenil Belger1,2,6 and Deepak Cyril D'Souza1,2,3

    awww.nature.com_npp_images_spacer.gif The interplay of opiate and NMDA glutamate receptors may contribute to psychosis, cognitive function, alcoholism, and substance dependence. Ketamine and ethanol block the NMDA glutamate receptor. The purpose of this randomized double-blind, placebo-controlled human laboratory study was to evaluate whether the interactive effects of drugs acting at opiate and NMDA glutamate receptors might partially explain the efficacy of naltrexone for the treatment of alcoholism, that is, whether naltrexone 25 mg pretreatment would modulate ketamine effects in healthy human subjects. Two groups of healthy subjects were studied. An initial group (n=31) received a perception-altering subanesthetic dose of ketamine (bolus of 0.23 mg/kg over 1 min followed by a 60-min infusion of 0.58 mg/kg or saline bolus and infusion). A second group (n=24) completed the same testing procedures, but received a subperceptual ketamine dose (bolus 0.081 mg/kg over 10 min followed by an infusion of 0.4 mg/kg/h). Ketamine produced positive symptoms, negative symptoms, emotional discomfort, and cognitive effects as measured by the Positive and Negative Syndrome Scale (PANSS) in a dose-related fashion. The lower ketamine dose produced subjective effects similar to two standard ethanol drinks, whereas the higher ketamine dose produced effects similar to five standard drinks. Although naltrexone produced no significant behavioral effects, it significantly magnified the increase in the total PANSS score produced by the lower subperceptual dose of ketamine, but not the higher perception-altering dose of ketamine. These data suggest that the interplay of opiate receptor antagonism and NMDA receptor antagonism may be relevant to the protective effects of naltrexone on alcohol consumption via potentiation of dysphoric effects associated with the NMDA receptor antagonist effects of ethanol. However, these data suggest that at levels of NMDA receptor antagonism associated with heavy drinking, this protective effect of naltrexone on drinking is no longer present.
    So, to simplify a bit, ketamine's action as an NMDA antagonist may counteract certain addictive potentials of many drugs. Alcohol is also an NMDA antagonist, but has the added effect of causing reinforcement through the mu-opioid receptors. Opiates are mu-opioid receptors as well, which explains why addiction to them can be treated with an opioid antagonist like naltrexone.

    What I find intriguing is the interaction between the NMDA and mu-opioid neurons that allows ketamine and naltrexone to have a potentiated effect when they are administered together. No pleasure is felt when drugs are administered following a dose of ketamine+naltrexone, and in some cases, dysphoria will actually increase. I think this would allow people to "un-learn" that drugs will cause a pleasurable effect when administered, making it that much easier to quit.

    Following with this idea, I found in this article that mu-opioid and NMDA receptors are often found together on the same neurons in some areas of the brain, particularly the periaqueductal grey which mediates the pain response. Perhaps it is here that reward and addiction could also be partially mediated, or it could be a pleasure center that it happens. I would like to know if anyone has found any information on other areas where these receptor types overlap.

    Along with ketamine, DXM and nitrous oxide, which at least in part are NMDA antagonists, can play a role in addiction treatment. After reading these articles, I understand a bit better why this might be. I am wondering if any NMDA antagonist could serve the same purpose. Does anyone know of any articles which support this idea?
    Last edited by a moderator: Apr 30, 2017