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Comorbidity of mental disorders and substance use: a brief guide for the primary care clinician

5.6 Major clinical issues with depression and stimulant (including methamphetamine) use

Table of contents

Depression is common amongst stimulant users, both in the days following heavy use and during withdrawal.
Tolerance develops quickly to the positive effects of stimulant drugs when used to self medicate for depression, leaving the person at risk of dose escalation and dependence.
Stimulant effects on sleep may worsen sleep-wake cycle disturbances associated with depression.
Monoamine Oxidase Inhibitors (MAO-I) (either irreversible or reversible) are contraindicated in people using amphetamines or MDM^xxx.
Reductions in stimulant use improve symptoms of depression.
If depression persists despite adequate withdrawal from stimulants, then treat as for primary depression.

5.6.1 Effects of stimulants on depression

Depression is common amongst stimulant users^{(40, 41, 43, 45, 49-51, 53, 54)}.
In the days following use of stimulants, users report rebound depression, most likely due to monamine depletion^{(39, 47, 48)}.
Depression is also present during the withdrawal phase from stimulants as well as for a significant period of time following abstinence^{(42, 44, 46)}.
There is an association between depression and severity of stimulant use and dependence, with higher levels of use being more indicative of greater severity of depression^{(41, 44, 50, 52, 53, 56, 167, 168)}.
Evidence suggests that depression precedes MDMA use in particular in most instances, supporting the self medication hypothesis in this case^{(40, 53, 55, 169-171)}.
Evidence from animal studies suggests that serotonin producing neurons are damaged by heavy MDMA use⁽¹⁷²⁾ and that it is likely that at least some of these levels are achieved in humans who use MDMA(^173-177).
Tolerance develops quickly to the positive effects of these stimulant drugs⁽¹⁷⁸⁾ leaving the person at risk of dose escalation and dependence.
Stimulant effects on sleep⁽¹⁷¹⁾ may worsen sleep-wake cycle disturbances associated with depression.

Stimulant drugs are likely to exacerbate the effects of SSRI and SNRI antidepressants in particular (and vice versa) and may result in serotonin syndrome (Appendix 1)^{x(127, 179, 180)}. Patients should be warned of signs of serotonin syndrome and be monitored.
MAO-Is (either irreversible or reversible) are contraindicated in people using amphetamines or MDMA. Deaths have been associated with concurrent use of moclobemide and MDMA^{xxx(181, 182)}.
Fluoxetine, norfluoxetine, paroxetine and sertraline are potential inhibitors of CYP 2D6 which metabolises MDMA and methamphetamine. This may result in elevated plasma concentrations leading to toxicity^x.

Reductions in stimulant use improve symptoms of depression⁽¹⁸³⁾. Therefore, reductions and cessation of stimulant use should be encouraged.
Treatment for depression should be commenced if use of stimulants is only occasional and there is established coexisting depression.
If depression persists despite adequate withdrawal from stimulants, then treat as for primary depression.
Formal drug detoxification should be considered if the person is dependent.
There is little consistent evidence that antidepressants are beneficial in management of stimulant withdrawal⁽¹⁸⁴⁾.
CBT can be used to address stimulant use and is effective***^{(49, 183)}.
Care should be taken to select an appropriate antidepressant in order to minimise chances of drug interactions.