Topic 3: Pharmacological management of methamphetamine dependence

MODAFINIL

Rationale to use

Evidence- 

A pilot randomised controlled trial by Lee et al, 2013, concluded that 67 % of the patients in the modafinil group and 50 % of the patients in the control group completed the course of treatment, although this difference was not statistically significant.

Preliminary evidence suggested by Karila et al, 2010, found that Modafinil was an effective medication to reduce craving and to increase the percentage of negative urine tests in terms of MA.

Common side effects-

Serious side effects- 

METHYLPHENIDATE

Rationale to use- 

MPH is a nor-adrenaline and dopamine re-uptake inhibitor with agonist-like activity. Act as an agonist substitution treatment for methamphetamine use.

The DA uptake inhibitors like MPH may therefore prevent methamphetamine from interacting with the DAT to release DA, and such an effect would antagonize effects of methamphetamine (Linda D Simmler et al, 2013).

Evidence-

A review of treatment of methamphetamine use disorder by Chan et al, 2017, two RCTs found a positive effect of methylphenidate on reduction in use, one trial reporting 6.5% versus 2.8% mean proportion amphetamine-negative urine samples in an intent-to-treat analysis (adjusted odds of positive urine sample 0.46, 95% CI 0.26, 0.81, p = 0.008), and another reporting 23% versus 16% amphetamine-negative urines (n = 54, p 0.047).

Found that MPH was associated with reduced methamphetamine use in some studies, but the effects were small and not consistent across all studies.

Conclusion

Overall, studies have shown mixed results, although further investigation is required for more definitive clinical evidence. It warrants further investigation. Good option in co-occurring ADHD.

Side effects

Common side effects- Dry mouth, insomnia, irritability, dysphoria, diminished appetite, weight loss, and headaches, exacerbation of existing motor and vocal tics.

Cardiovascular- elevations in systolic and diastolic blood pressure and heart rate 

Priapism is a rare complication.

Can worsen psychosis

AMPHETAMINE SALTS

Rationale to use

Increases the release and blocks the reuptake of dopamine, a neurotransmitter associated with the brain’s reward system.

Amphetamine may help regulate the dysregulated reward pathways in addiction, potentially reducing cravings and drug-seeking behaviors. 

Evidence

A randomized controlled trial by G P Galloway et al, 2011 reported that he methamphetamine-negative scores in the d-AMP group (3.1 ± SD 4.6) were no higher than those in the placebo group (3.3 ± SD 5.3; P > 0.05). However, withdrawal and craving scores were significantly lower in the d-AMP group (P < 0.05 for both). 

A phase-2, dose-escalating, open-label, single-group study of oral Lis-dexamphetamine daily in Methamphetamine use disorder by Nadine Ezard et al, 2021. In this, supervised LDX of 100-250 mg was given. Found MA use decreased from a median of 21 days (IQR: 16-23) to 13 days (IQR: 11-17) over the 4-week escalation period (p=0.013).

Conclusion

The evidence supporting the effectiveness of amphetamine in treating methamphetamine use disorder are limited (GP Galloway et al, 2010; Chen et al, 2019)

Side-effects

Common side effects- Dry mouth, insomnia, irritability, dysphoria, diminished appetite, weight loss, and headaches, exacerbation of existing motor and vocal tics.

Cardiovascular- elevations in systolic and diastolic blood pressure and heart rate 

Priapism is a rare complication.

Can worsen psychosis

ANTI-PSYCHOTICS

Methamphetamine releases dopamine (DA) via the DA transporter (DAT). DA is thought to mediate the reinforcing effects of psychostimulants, which lead to drug dependence. 

Blocking the pronounced release of DA by methamphetamine may therefore be an interesting therapeutic option for the treatment of methamphetamine dependence

RISPERIDONE

Tentative evidence to discount use of antipsychotics for stimulant use disorder (Indave et al. 2016; Chan et al. 2019). Needs further study.

In general, they are not recommended to use, however required to use if patient had developed psychotic episode (stimulant induced). 

ARIPIPRAZOLE

HALOPERIDOL

GABAERGIC AGENTS

GABAergic properties may have anxiolytic effects, potentially reducing anxiety symptoms associated with MDMA addiction.

GABAergic signaling is involved in the reward pathways and addiction processes. By modulating GABAergic transmission, these medicines may potentially reduce cravings and drug-seeking behaviors associated with MDMA addiction.

GABAPENTIN

Rationale to use

Enhance the activity of GABA, an inhibitory neurotransmitter in the brain.

By promoting better sleep, and improvement in overall mood during addiction recovery.

Evidence

A randomized placebo-controlled trial by Keith G. Heinzerling et al, 2006, found no statistically significant main effects for baclofen or gabapentin in reducing methamphetamine use were observed using a generalized estimating equation (GEE). 

Conclusion

Sufficient evidence from reviews to discount the

effectiveness of anticonvulsants for stimulant use for cocaine use (Chen et al, 2019).

Side effects

CNS- Dizziness, Sedation, fatigue, Unsteadiness or clumsiness, Memory problems, Headache

GIT- Nausea, Vomiting, Diarrhoea, Dry mouth, Constipation, Increased appetite and weight gain.

Potential for misuse.

TOPIRAMATE

Rationale to use

Na+ and Ca++ channel blockade; GABA potentiation; glutamate antagonism

By modulating glutamatergic transmission, topiramate may potentially reduce cravings and drug-seeking behaviors associated with MDMA addiction.

It has some mood-stabilizing effects, which may promote recovery in its addiction.

Evidence

A systematic review and meta-analysis by Chan et al, 2019 (2 RCTs, N=227). Reported reduction in use with topiramate for the treatment of amphetamine or methamphetamine use disorder.

A systematic review and meta-analysis of randomized controlled trials by Singh M et al, 2016, found no significant difference was reported for retention in treatment between topiramate-treated and control groups. However, reported improvement in continuous abstinence and reduction in craving in some studies.

More study in this area may be of benefit.

Conclusion

Potential effects are small, the committee agreed that topiramate could be considered to reduce use of ATS, as well as alcohol consumption.

Common s/e- 

drowsiness, Difficulty concentrating, nausea, Changes in taste sensation, weight loss, Tingling or numbness in the extremities, kidney stones.

Note- monitor for any changes in mood or mental health

ANTI-DEPRESSANTS-

Sufficient evidence from reviews to discount the effectiveness of antidepressants for cocaine use (Chen et al, 2019).

Patients who have emotional dysregulation, co-morbid anxiety or depressive symptoms, which are some of the reasons to perpetuate stimulant use. In those patient, anti-depressants might help as an adjuvant medication.

BUPROPION

Rationale to use

Evidence

A systematic review by Lee et al (2018), included 7 studies (n=699), of which 3 studies and 1 secondary analysis showed benefit, and reported mixed evidence.

Conclusion

Data from systematic review and meta-analysis suggest that bupropion is not effective for all individuals with ATS use disorder. 

However, in individuals with less-than-daily use and adherence with medication, evidence suggests that bupropion may reduce stimulant use. 

Additionally, data suggest bupropion may reduce comorbid cigarette smoking.

Side-effects

Common side-effects- 

GIT side effects- dry mouth, nausea, Constipation, headache, insomnia, tremors/ Sweating, agitation, dizziness, Weight loss or gain.

Less common- Seizures, suicidal thoughts or behaviours, allergic reactions, mania or psychosis.

ATOMOXETINE Selective norepinephrine transporter (NET) inhibitor.

Rationale to use

Potent inhibitor of presynaptic NET, moderate inhibitor of serotonin reuptake and weak inhibitor of dopamine uptake, moderate affinity for 5HT2 and GABA-A receptors but poor affinity for most other receptors

Evidence

Its efficacy in methamphetamine disorder patients who were on methadone maintenance therapy was evaluated in a double blind RCT by Alie RAabiey et al, 2019. concluded Atomoxetine significantly reduced METH craving (P < 0.001). Negative METH urine test increased significantly in the drug group compared to the placebo group (P = 0.007). 

Conclusion

More studies are required which would assess its efficacy exclusively.

Side-effects

Side effects

Dry mouth, insomnia, nausea, decreased appetite, constipation.

Decreased libido, erectile dysfunction, urinary hesitancy,

Dizziness, and sweating; QTc prolongation.

Aggressive behaviour or hostility, and the emergence of psychosis or mania.

MIRTAZAPINE

Rationale to use

Methamphetamine abuse can disrupt sleep patterns and lead to sleep disturbances. Mirtazapine has sedative properties and can improve sleep quality also would improve appetite.

Mirtazapine is an antidepressant with anxiolytic properties, and its use can help address these co-occurring mental health conditions, which may contribute to methamphetamine abuse.

Evidence

Two randomized, placebo-controlled trials showed a small benefit of Mirtazapine (30 mg/d) in reducing amphetamine users among MSM compared to placebo (Coffin et al, 2020; Colfax et al 2011). 

Colfax et al, (2011) reported the number needed to treat to achieve a negative weekly urine test result was 3.1.

Conclusion

As per ASAM guidelines, evidence is relatively weak, concluded that mirtazapine may be preferable to no treatment at all, particularly in MSM population. 

Side-effects

Sedation, increased appetite, weight gain, constipation, 

GLUTAMATERGIC AGENTS- It has been hypothesized that glutamatergic agents may exert its effects on substance use disorders by reducing cravings, restoring glutamate homeostasis, and improving executive functions.

N-ACETYL CYSTEINE

Amino acid. Reduces the release of glutamate from the synapse by stimulation of inhibitory glutamate receptors

A randomized, double-blind, placebo-controlled trial by Rebecca McKetin et al, 2021; included 116 participants who received either NAC (2400 mg/day) or placebo for 12 weeks. 

Study found no significant difference between the NAC and placebo groups regarding methamphetamine use or treatment retention.

Side effects-

Nausea, vomiting, diarrhoea,

abdominal discomfort, headache, dizziness, allergic reaction, insomnia, bleeding

RILUZOLE

Glutamate regulatory effects in the CNS- 

Inhibition of Glutamate Release, Enhancement of Glutamate Uptake, block glutamate receptors. Can potentially decrease excitotoxicity of neurons.

Also, has neuroprotective effects via calcium channel modulation.

A randomized, double-blind, placebo-controlled clinical trial received either 50 mg riluzole (N=34) twice daily for 12 weeks or placebo. 

Patients in the riluzole arm experienced significantly greater improvement on all the craving, withdrawal, and depression measures regarding mean score changes from baseline to endpoint. Results cannot be generalised.

Need further study. 

Common side effects- Dizziness, headache, Fatigue, sleep disturbances (insomnia or drowsiness) 

Rare serious side effects- Elevated liver enzymes (detected through blood tests)

Hepatotoxicity (rare but potentially serious)

OPIOID BASED MEDICATIONS- Opioid receptor agonists can modulate the activity of dopamine neurons and can therefore modify the pharmacodynamic effects of METH on the dopaminergic system.

BUPRENORPHINE

Opioid agonism 

A few clinical trials have shown that buprenorphine maintenance decreases craving for METH in METH users (Ahmadi J et al, 2017)

The evidence specifically for the opioids in amphetamine use disorder is limited.

Needs further research trials.

In individuals with co-occurring opioid and MDMA addiction may benefit from the appropriate use of buprenorphine or methadone to address their opioid dependence while also receiving comprehensive addiction treatment for their MDMA use.

BUPRENORPHINE

Vs METHADONE

Opioid agonism and N-methyl-d-aspartate (NMDA) antagonism.

a randomized clinical trial Comparing the effect of buprenorphine and methadone in the reduction of methamphetamine craving in 40 patients. Both drugs were effective in decreasing methamphetamine craving during methamphetamine withdrawal. Reduction of craving in the buprenorphine group was significantly more than in the methadone group (P < 0.05) (Ahmadi J et al, 2017).