Naltrexone Effects in Methamphetamine Users
Naltrexone significantly reduces methamphetamine cue-induced craving and attenuates the subjective "high" and rewarding effects of methamphetamine, but it is not FDA-approved for methamphetamine use disorder and evidence for sustained abstinence remains insufficient.
Mechanism and Acute Effects
Naltrexone blocks mu-opioid receptors, which indirectly modulates dopamine neurotransmission in the reward pathway, thereby reducing the reinforcing effects of methamphetamine. 1
Impact on Subjective Experience
In controlled laboratory studies, naltrexone 50 mg daily for 4 days significantly blunted cue-induced methamphetamine craving compared to placebo in individuals with methamphetamine use disorder. 2
During intravenous methamphetamine administration (30 mg), naltrexone decreased subjective ratings of "crave drug," "stimulated," "would like drug access," and "anxious" while increasing ratings of "bad drug effects" compared to placebo. 2
Naltrexone attenuated positive hedonic effects including "want more," "like effect," and overall stimulation from methamphetamine. 2, 3
The medication moderates the predictive relationship between cue-induced craving and positive subjective response to methamphetamine, meaning that even when cravings occur, the rewarding experience is diminished. 3
Neurobiological Changes
Extended-release naltrexone (380 mg monthly injection) significantly reduced resting-state functional connectivity between the ventral striatum, amygdala, hippocampus, and midbrain—regions hyperactive in methamphetamine use disorder. 4
Naltrexone decreased coupling between executive control networks and default mode networks, potentially enhancing attentional resources while suppressing self-referential emotional processing that drives drug-seeking. 5
Reductions in striatal connectivity were directly associated with reductions in methamphetamine use, suggesting a neurobiological mechanism of action. 4
Clinical Evidence for Treatment
Efficacy Data
A 2019 systematic review of randomized controlled trials found insufficient evidence to support naltrexone for methamphetamine use disorder, with only one of two studies showing increased abstinence rates and inconsistent effects on craving reduction. 6
In a preliminary clinical trial, extended-release naltrexone produced significant reductions in methamphetamine use over 4 weeks compared to placebo, along with decreased addiction severity scores. 4, 5
Laboratory studies consistently demonstrate that naltrexone reduces the reinforcing properties of methamphetamine, but translation to sustained real-world abstinence remains unproven. 2, 3
Current Regulatory Status
Naltrexone is FDA-approved only for opioid use disorder and alcohol use disorder—not for methamphetamine use disorder. 1, 7
The CDC guidelines recommend medication-assisted treatment with buprenorphine or methadone for opioid use disorder, with naltrexone as an alternative for motivated patients, but make no recommendations regarding methamphetamine. 8
Practical Clinical Algorithm
When to Consider Naltrexone Off-Label
Patient has methamphetamine use disorder with prominent cue-induced craving and difficulty resisting use despite motivation for abstinence. 2, 3
Patient is highly motivated and engaged in comprehensive behavioral therapy, as naltrexone alone is insufficient. 1, 7
Patient has no contraindications: active opioid use (must be opioid-free for 7-10 days), need for opioid pain medications, acute hepatitis, or decompensated liver disease. 1, 7
Dosing and Monitoring
Oral naltrexone 50 mg daily is the standard dose used in methamphetamine studies, or consider extended-release naltrexone 380 mg intramuscular monthly for improved adherence. 1, 2, 4
Obtain baseline liver function tests and repeat every 3-6 months due to potential hepatotoxicity at supratherapeutic doses. 1, 7
Screen for depression, anxiety, and insomnia before initiation, as naltrexone may worsen these conditions. 1
Combine with evidence-based behavioral therapies including cognitive behavioral therapy, contingency management, and mutual-help groups. 1, 7
Expected Outcomes
Primary benefit is reduction in the subjective rewarding effects and craving when exposed to methamphetamine cues or during use, not necessarily complete abstinence. 2, 3
Patients may continue to use methamphetamine but report less satisfaction and reduced compulsion to continue use. 2
Neurobiological changes in reward circuitry may take 4+ weeks to manifest. 4, 5
Critical Safety Considerations
Naltrexone does not alter methamphetamine metabolism or clearance—it only modulates the subjective experience through opioid receptor blockade. 2
Patients who discontinue naltrexone have markedly increased risk of opioid overdose if they subsequently use opioids, due to loss of tolerance during treatment. 1, 7
Naltrexone cannot be used in patients requiring opioid analgesics, as it blocks pain relief from opioid medications. 1, 7
For elective procedures requiring opioids, hold oral naltrexone 2-3 days prior or extended-release naltrexone 24-30 days after the last injection. 1, 7
Common Pitfalls
Do not prescribe naltrexone as monotherapy—it must be combined with intensive behavioral interventions to address the multifaceted nature of methamphetamine addiction. 1, 7
Do not expect complete abstinence—the evidence supports harm reduction through decreased rewarding effects rather than elimination of use. 6, 2
Do not initiate if patient has used opioids recently—verify opioid-free status for minimum 7-10 days to avoid precipitated withdrawal. 1, 7
Do not use in pregnancy—naltrexone is not recommended for pregnant women with substance use disorders. 8