A randomized clinical trial on the effects of bupropion and buprenorphine on the reduction of methamphetamine craving

Mental disorders have been growing problems around the world [1, 2]. Among psychiatric disorders, substance use disorders and substance-related disorders, involving mainly stimulants such as methamphetamines and cocaine, have been regarded as a developing problem worldwide. Currently, methamphetamine abuse and methamphetamine-induced psychiatric presentations to the hospitals and out-patient centers are growing problems [3‐16].

Methamphetamine abuse induces an elevated mood associated with increased wakefulness, physical activity, and energy [7]. Elongated use repeatedly ends to increase drug abuse, decreased weight, increased aggression, increased violence, poor impulse control, long-term health consequences, unstable mood, unstable affect, severe dependency, memory deficits, poor concentration, delusions, and hallucinations [12, 13].

Methamphetamine is abused globally. In the US, 18 million people over age 12 have used methamphetamine during their life [12]. Similar to other addictions, methamphetamine addiction is a chronic relapsing disorder requiring effective pharmacotherapies to help the prevention of relapse.

Previously in Iran, methamphetamine was illegally smuggled in from other regions of the globe, mostly the West [10], but currently it is illegally synthesized and prepared here in “underground” laboratories. It should be mentioned that the methamphetamine illegally synthesized in Iran is much more powerful and is frequently associated with psychosis [10]. A single episode of methamphetamine abuse may induce visual or auditory hallucinations and also persecutory delusions. We have visited and interviewed patients who became psychotic after smoking methamphetamine on only one occasion [10].

Buprenorphine administration is for the treatment of opioid withdrawal symptoms, and bupropion is for the treatment of nicotine dependence [7]. Now we are administering buprenorphine as a new application for the treatment of severe methamphetamine withdrawal cravings because we theorize that (our rationale) the biochemistries involved in methamphetamine and buprenorphine are more or less the same (both medications involve the endogenous opioid system) [7, 9‐11].

Buprenorphine, a semi-synthetic partial agonist at mu-opioid receptors and antagonist at delta- and kappa-opioid receptors, has been investigated largely for the treatment of opioid use disorder [7]. It is considered safer than methadone [7, 9], and 8 mg of buprenorphine is as effective as 60 mg of methadone [9]. Buprenorphine is well absorbed after sublingual administration [7]. In animals, buprenorphine shows a flattened or inverted U-shaped curve, and there are dose-correlated rises in anti-nociceptive effect at lower doses and either no greater anti-nociception or a decrease in effect at larger doses [7‐11]. Buprenorphine has typical mu-opioid agonist effects, such as sedation, analgesia, and euphoria, and also its partial agonist action at mu-opioid receptors has favored the usage of buprenorphine over methadone; particularly, the minimal respiratory depressant effects of buprenorphine produce greater safety [9‐11].

Substances such as alcohol, methamphetamine, and cocaine stimulate release of dopamine from cells originating in the brain’s ventral tegmental area (VTA) region, which is a component of a neuronal circuit called the mesolimbic dopamine system and is connected with behavioral reward and motivation. After exposure to alcohol, methamphetamine, or cocaine, dopamine released into the nucleus accumbens and prefrontal cortex reinforces alcohol-, methamphetamine-, and cocaine-seeking behaviors [17‐20].

To the best of our knowledge, based in part on a review of the literature, few studies on this matter (comparing the effects of buprenorphine with those of bupropion for the treatment of severe methamphetamine cravings) have been published [9, 10].

Furthermore, we are administering bupropion as a new approach for the treatment of methamphetamine withdrawal craving because we hypothesize that (our rationale) the biochemistries engaged in methamphetamine and bupropion use are more or less alike (both medications boost the level of dopamine) [7, 9, 11].

This study is a clinical trial that presents data obtained from comparing sublingual buprenorphine with oral bupropion in the treatment of severe methamphetamine withdrawal craving. The primary goal of the present research was to appraise the efficacy of 8 mg of sublingual buprenorphine and 300 mg of oral bupropion per day in the treatment of methamphetamine withdrawal cravings. Craving is a major feature of substance use disorders, including stimulant use disorders, as evidenced by its recent addition to the diagnostic criteria for these disorders in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) (American Psychiatric Association) [7], and it continues even after detoxification to promote relapse [7].

The CONSORT (Consolidated Standards of Reporting Trials) flow and checklist of patients in the trial are shown in Figs. 1 and 2. Seventy-one patients were screened to enter this trial. Of the 69 patients who were randomly allocated to one of the two groups, 34 patients were in the bupropion group and 35 patients were allocated to the buprenorphine group. Four patients of the bupropion group refused to receive the medication at the beginning of the trial.

All 65 subjects completed the 2-week period. Therefore, the data were collected from 65 methamphetamine-dependent men whose mean age was 32.98 years (standard deviation (SD) = 7.9, range = 17 to 59). Of the 65 subjects, 35 (53.8%) received buprenorphine and 30 (46.2%) received bupropion. The mean ages were 32.8 years (SD = 7.56, range = 22 to 59) for the buprenorphine group and 32.21 years (SD = 8.45, range = 17 to 51) for the bupropion group (t test = −0.205, degrees of freedom (df) = 1, P = 0.838). The mean durations of education were 9.12 years (SD = 2.84) for the buprenorphine group and 9.97 years (SD = 3.11) for the bupropion group (t test = −1.118, df = 1, P = 0.268). The mean durations of methamphetamine dependency were 9.69 years (SD = 6.28) for the buprenorphine group and 7.48 years (SD = 4.65) for the bupropion group (t test = 1.523, df = 1, P = 0.133).

There were no statistically significant differences between the two groups in regard to age, education, and duration of methamphetamine dependency.

Table 1 indicates t tests and ANOVA with repeated measures for craving scores of both groups during 14 days of treatment. As we observe in the buprenorphine group, there are significant differences in craving scores from days 1 to 14 (P <0.001). Furthermore, in the bupropion group, there are significant differences in craving scores from days 1 to 14 (P <0.001).

In the mean of craving between the buprenorphine and bupropion groups, there is a significant difference (F = 6.811, df = 13, power = 0.729, P = 0.011) (Table 2).

Overall, a significant main effect of day (P <0.001) and group (P = 0.011) and a non-significant group-by-day interaction (P >0.05) were detected.

All patients had a positive urine drug test for methamphetamine at the beginning of the study. Furthermore, all patients had a negative urine drug test for methamphetamine carried out twice a week during the 14-day interval.

Opioid receptor, mainly mu-opioid receptor, a member of the opioid neuromodulatory system and of the large family of G protein–coupled receptors, is the prominent pharmacological target for the treatment of moderate to severe pain and is of therapeutic value for the management of abuse of amphetamines, opioids, cannabis, alcohol, and other drugs [21‐33].

The mechanism of action by which opioids such as buprenorphine prevent methamphetamine craving and dependence is not fully understood; however, there are basic and essential interactions between dopamine and the endogenous opioid neuropeptide systems. Naltrexone (an opioid antagonist) decreases and interrupts the interactions between dopamine and the endogenous opioid neuropeptide systems [19‐21]. We theorized that opioid medications such as buprenorphine could enhance the interactions between dopamine and the endogenous opioid neuropeptide systems.

The results of this study are supportive of the effect of buprenorphine and bupropion for the treatment of methamphetamine craving. There was superiority of buprenorphine compared with bupropion. We recommend these two medications as short-term and in-patient treatments to enhance retention or even as longer-term maintenance treatment to reduce relapse.

It can be considered that buprenorphine is a practical and safe medication for the cessation or reduction of methamphetamine withdrawal craving and is better than bupropion. Use of buprenorphine could be considered for the treatment of methamphetamine craving.