Effects of Acute Oral Naltrexone on the Subjective and Physiological Effects of Oral D-Amphetamine and Smoked Cocaine in Cocaine Abusers

Abstract

Despite the prevalent worldwide abuse of stimulants, such as amphetamines and cocaine, no medications are currently approved for treating this serious public health problem. Both preclinical and clinical studies suggest that the opioid antagonist naltrexone (NTX) is effective in reducing the abuse liability of amphetamine, raising the question of whether similar positive findings would be obtained for cocaine. The purpose of this study was to evaluate the ability of oral NTX to alter the cardiovascular and subjective effects of D-amphetamine (D-AMPH) and cocaine (COC). Non-treatment-seeking COC users (N=12) completed this 3-week inpatient, randomized, crossover study. Participants received 0, 12.5, or 50 mg oral NTX 60 min before active or placebo stimulant administration during 10 separate laboratory sessions. Oral AMPH (0, 10, and 20 mg; or all placebo) was administered in ascending order within a laboratory session using a 60-min interdose interval. Smoked COC (0, 12.5, 25, and 50 mg; or all placebo) was administered in ascending order within a laboratory session using a 14-min interdose interval. Active COC and AMPH produced dose-related increases in cardiovascular function that were of comparable magnitude. In contrast, COC, but not AMPH, produced dose-related increases in several subjective measures of positive drug effect (eg, high, liking, and willingness to pay for the drug). NTX did not alter the cardiovascular effects of AMPH or COC. NTX also did not alter positive subjective ratings after COC administration, but it did significantly reduce ratings of craving for COC and tobacco during COC sessions. These results show that (1) oral AMPH produces minimal abuse-related subjective responses in COC smokers, and (2) NTX reduces craving for COC and tobacco during COC sessions. Future studies should continue to evaluate NTX as a potential anti-craving medication for COC dependence.

The Effects of Naltrexone on Subjective Response to Methamphetamine in a Clinical Sample: a Double-Blind, Placebo-Controlled Laboratory Study

“…Notably, NTX attenuated the cue-induced elevation of heart rate and diastolic blood pressure. On balance, these results are consistent with previous work on amphetamines (Jayaram-Lindstrom et al, 2008b;Jayaram-Lindstrom et al, 2004) and cocaine (Comer et al, 2013), suggesting that NTX may have anti-craving properties and may alter subjective respones to stimulants. This is the first study of NTX and MA and combines several strengths, such as a sample comprised of individuals with clinically Figure 2 Subjective response scores (drug effects questionnaire (DEQ)), presented with standard errors, at baseline (BA) and change from baseline at 5,10,15,20,30,60,90, and 120 min following methamphetamine (MA) administration, during both placebo and naltrexone (NTX) conditions.…”

“…A clinical trial of a NTX depot implant demonstrated significant benefit over placebo on measures of treatment retention, drug-free urines, and global assessments of functioning in a hard-totreat sample of heroin and amphetamine polydrugdependent individuals (Tiihonen et al, 2012). Further, a recent behavioral pharmacology study found that acute oral NTX significantly reduced craving during cocaine administration in a sample of non-treatment-seeking cocaine users (n = 12) (Comer et al, 2013). However, in the aforementioned study, NTX did not alter the cardiovascular or subjective effects of smoked cocaine (0, 12.5, 25, and 50 mg), and as oral amphetamine (0, 10, and 20 mg) produced no discernable subjective effects, NTX effects on subjective response to amphetamine could not be assessed in this sample.…”

Methamphetamine: An update on epidemiology, pharmacology, clinical phenomenology, and treatment literature

“…Clinical and preclinical laboratory models have also found support for reduced ATS use with naltrexone treatment. Specifically, clinical laboratory studies of naltrexone found reductions of both heroin and amphetamine use in a sample of individuals dependent on both substances (Tiihonen et al., 2012), and decreases in quality/liking ratings of administered amphetamine in a sample comprised of predominant cocaine users (Comer et al, 2013). Preclinical studies have observed naltrexone-related decreases in d-amphetamine and alcohol self-administration in adult rhesus monkeys (Jimenez-Gomez et al, 2011), and attenuated amphetamine-induced reinstatement with no effect on food taking behavior in the rat (Haggkvist et al, 2009).…”

Agonist Medications for the Treatment of Cocaine Use Disorder

“…A final important caveat with agonist medications is concern over side effects that include abuse liability and cardiovascular effects. Prevailing data suggest that agonist medications such as amphetamine produce surprisingly weak evidence for abuse potential or cardiovascular risk in cocaine abusers (Comer et al, 2013;Grabowski et al, 2004;Lane et al, 2014;Rush et al, 2009), but it remains important to weigh therapeutic effectiveness against risk factors and to also consider risks associated with medication diversion to nonpatients.…”