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

Abstract

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, placebocontrolled 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 ¼ 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 ¼ 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 doserelated 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.

Update on neuropharmacological treatments for alcoholism: Scientific basis and clinical findings

“…1). Obviously, opioid receptors also have interactions with other neurotransmitters, including those in the glutamate [15], GABA [16], 5-HT [17], cannabinoid [18] and perhaps glycine [19] systems, that contribute to its effects on ethanol intake.…”

Effects of haloperidol on the behavioral, subjective, cognitive, motor, and neuroendocrine effects of Δ-9-tetrahydrocannabinol in humans

“…Nevertheless, the peak increases in PANSS positive symptoms scores induced by this Δ-9-THC dosing paradigm were comparable to the peak increases in positive symptom scores induced by (1) amphetamine 0.25 mg/kg administered i.v. over 1 min , (2) low-dose ketamine (bolus 0.081 mg/kg over 10 min followed by an infusion of 0.4 mg kg −1 h −1 ; Krystal et al 2006), and m-chlorphenyl-piperazine (D 'Souza et al 2006). As discussed earlier, we attempted a shorter infusion and higher dose of Δ-9-THC in combination with haloperidol, but this was poorly tolerated.…”

The safety of studies with intravenous Δ9-tetrahydrocannabinol in humans, with case histories

“…Screening procedures were identical to those used in other studies at this center with psychoactive agents such as ketamine, amphetamine, and m-CPP Krystal et al 1999;Krystal et al 2005a;Krystal et al 1998a;Krystal et al 2006;Krystal et al 2005b;Krystal et al 1998b). Excluded were subjects with a current or past psychiatric diagnosis (except a cannabis use disorder in selected protocols), a history of any DSM-IV Axis I psychotic disorder in a first-degree relative, a history of counseling (other than for a life circumstance disorder), any recent significant psychosocial stressor, or clinical instability (recent or current hospitalization, homicidality, suicidality, or grave disability).…”