Drug-Drug Interactions of Amphetamines


Adrenergic neuron blocking drugs

Amphetamines and other stimulatory anorectic agents, apart from fenfluramine, would be expected to impair the hypotensive effects of adrenergic neuron blocking drugs such as guanethidine. Not only do they release noradrenaline from stores in adrenergic neurons and block the reuptake of released noradrenaline into the neuron, but they also impair re-entry of the antihypertensive drugs.


Alcohol increases blood concentrations of amphetamines.


Barbiturates can enhance amfetamine hyperactivity.


Benzodiazepines can enhance amfetamine hyperactivity.


Preclinical studies (as well as anecdotal clinical reports) have shown that estrogens, through effects on the central nervous system, can influence behavioral responses to psychoactive drugs. In an unusual crossover study, the subjective and physiological effects of oral D-amfetamine 10 mg were assessed after pretreatment with estradiol. One group of healthy young women used estradiol patches (Estraderm TTS, total dose 0.8 mg), which raised plasma estradiol concentrations to about 750 pg/ml, and a control group used placebo patches. Most of the subjective and physiological effects of amfetamine were not affected by acute estradiol treatment, but the estrogen did increase the magnitude of the effect of amfetamine on subjective ratings of “pleasant stimulation” and reduced ratings of “want more.” Estradiol also produced some subjective effects when used alone, raising ratings of “feel drug,” “energy and intellectual efficiency,” and “pleasant stimulation.” Some limitations of the study were:

(a) plasma amfetamine concentrations were not measured, so an effect of estradiol on the pharmacoki-netics of amfetamine cannot be ruled out;

(b) only single doses of amfetamine and estradiol were tested;

(c) the dose of amfetamine was relatively low and that of estradiol relatively high, maximizing the chances of detecting estradiol-dependent increases in two subjective effects of amfetamine.

Monoamine oxidase inhibitors

The amphetamines should not be used together with or within 14 days of any monoamine oxidase inhibitors; severe hypertensive reactions and on occasion confu-sional states (for example with fenfluramine) can occur.

Mood-stabilizing drugs

Amfetamine reduces regional brain activation during the performance of several cognitive tasks. The results of a double-blind, placebo-controlled study in healthy volunteers suggested that both lithium and valproate can significantly attenuate dexamfetamine-induced changes in brain activity in a task-dependent and region-specific manner. There is also good evidence that dexamfetamine stimulates the phosphatidylinositol (PI) cycle in vivo and in vitro, and this may be the mechanism responsible for its effect on brain activation; both lithium and valproate can attenuate the PI cycle, probably through different mechanisms.


A fatal interaction between ritonavir and metamfetamine has been described.

• A 49-year-old HIV-positive Caucasian man had taken ritonavir (400 mg bd), saquinavir (400 mg bd), and stavudine (40 mg bd) for 4 months. His CD4 cell count was 617 x 106 cells/1 and HIV-1 RNA less than 400 copies/ml. He had previously taken zidovudine for 7 months. He self-injected twice with metamfetamine and sniffed amyl nitrite and was found dead a few hours later. At autopsy, there was no obvious cause of death. Metamfetamine was detected in the bile (0.5 mg/l) and cannabinoids and traces of benzodiazepines were detected in the blood.

Nitric oxide formed from amyl nitrite inhibits cytochrome P450 and ritonavir inhibits CYP2D6, which has a major role in metamfetamine detoxification. This interaction could have led to fatal plasma concentrations of metamfetamine. It is therefore suggested that patients who take protease inhibitors are made aware of the potential risk of using any form of recreational drugs metabolized by CYP2D6, particularly metamfetamine.


A man taking long-term dexamfetamine had two episodes of serotonin syndrome while taking first venlafaxine and later citalopram.

• A 32-year-old man, who was taking dexamfetamine 5 mg tds for adult ADHD, developed marked agitation, anxiety, shivering, and tremor after taking venlafaxine for 2 weeks (75 mg/day increased after a week to 150 mg/day). His heart rate was 140/minute, blood pressure 142/93 mmHg, and temperature 37.3°C. His pupils were dilated but reactive. There was generalized hypertonia, hyper-reflexia, and frequent myoclonic jerking. Dexamfetamine and venlafaxine were withdrawn and cyproheptadine (in doses of 8 mg up to a total of 32 mg over 3 hours) was given. His symptoms completely resolved within a few hours.

Dexamfetamine was restarted 3 days later and citalopram was started a few days later. Two weeks later he reported similar symptoms and stopped taking citalopram. He was successfully treated again with cyproheptadine.


In 20 healthy adults who received a placebo, triazolam 0.25 mg/70 kg, amfetamine sulfate 20 mg/70 kg, and a combination of triazolam and amfetamine in a double-blind, crossover study the results supported the conclusion that triazolam-induced impairment of free recall is related to its sedative effects, whereas recognition, memory, and recall differ with respect to the contribution of sedation to the amnesic effect of triazolam. Thus, benzodiazepines have specific effects on memory that are not merely a by-product of their sedative effects, and the degree to which sedative effects contribute to their amnesic effects can vary as a function of the particular memory process being assessed. It is important to note that the generalizability of the conclusions of this study is limited by use of a single dose design for both drugs.

Tricyclic antidepressants

Tricyclic antidepressants increase blood concentrations of amfetamine.

Selections from the book: “Meyler’s Side Effects of Psychiatric Drugs” (2009)