BACKGROUND: Daily ingestion of amphetamines is common, as they are widely prescribed for attention-deficit hyperactivity disorder (ADHD) and other diagnoses. People also use amphetamines recreationally or in an attempt to boost cognitive or athletic performance. Amphetamines have the potential to increase blood pressure, and we do not know if the long-term benefits of daily amphetamine use outweigh the potential harms.
OBJECTIVES: Primary: to quantify the changes in systolic and diastolic blood pressure in children and adults taking amphetamines, compared to placebo. Secondary: to quantify the changes in heart rate in children and adults taking amphetamines, compared to placebo; to quantify the number of withdrawals due to adverse effects of amphetamine, compared to placebo.
SEARCH METHODS: We used the Cochrane Hypertension Specialized Register, CENTRAL, MEDLINE, Embase and two clinical trial registers, together with reference checking and contact with study authors to identify the studies included in the review. We imposed no restrictions on language, publication year or publication status. The latest search date was March 2023.
SELECTION CRITERIA: Randomized controlled trials (RCTs) that compared the effects of daily oral amphetamines versus placebo on blood pressure. There were no restrictions on participants' age or gender.
DATA COLLECTION AND ANALYSIS: We used standard methods expected by Cochrane. Primary outcomes were change in systolic and diastolic blood pressure (measured in millimeters of mercury (mmHg) above atmospheric pressure; continuous outcomes). Secondary outcomes were heart rate (measured as beats per minute; continuous outcome) and withdrawals due to adverse effects (dichotomous outcome). We calculated continuous outcomes as mean differences (MD) with 95% confidence intervals (CI). We expressed withdrawals due to adverse effects as a risk ratio with 95% CI. We used a fixed-effect model to pool effect sizes from all studies.
MAIN RESULTS: We included 56 RCTs with a total of 10,583 participants, both adults and children. Most studies were conducted in North America (mainly the USA), followed by Europe. A few studies took place in Asia (Japan) and Australia. The studies tested racemic amphetamine, dextroamphetamine, mixed amphetamine salts, lisdexamfetamine dimesylate, methylenedioxymethamphetamine (MDMA) and methylphenidate. The amphetamines were prescribed for ADHD, weight loss and other indications. In 48 RCTs, blood pressure was measured within 24 hours of the last dose. Based on data from all included studies, amphetamines increased systolic blood pressure (SBP) by 1.93 mmHg (95% CI 1.54 to 2.31) and diastolic blood pressure (DBP) by 1.84 mmHg (95% CI 1.51 to 2.16) (56 studies, 10,583 participants; high-certainty evidence for both). Amphetamines increased heart rate by 3.71 beats per minute (95% CI 3.27 to 4.14; 47 studies, 10,075 participants; high-certainty evidence). In a subgroup analysis limited to studies that gave participants amphetamines for at least eight weeks, the effects were similar, suggesting that these are sustained effects. These findings suggest that people taking daily oral amphetamines are at increased risk of adverse cardiovascular events. Participants in the amphetamine group were also more likely to withdraw from the study due to adverse effects compared to those given placebo (risk ratio 2.69, 95% CI 2.13 to 3.40; absolute risk increase of 4.3% over an average duration of 1 month; 42 studies, 8952 participants; high-certainty evidence). In general, the studies were well-executed, and the methodology was sound. We judged most studies to have a low risk of bias across most domains. Selection bias (random sequence generation and allocation concealment) was the domain most often rated as at unclear risk of bias, because the methods used were not reported. We judged 13 studies (23%) to have a high risk of bias in at least one of the seven domains, primarily due to high dropout rates, leading to a high risk of attrition bias.
AUTHORS' CONCLUSIONS: Daily oral amphetamines increase blood pressure, heart rate, and withdrawals due to adverse effects, with these effects observed across all time points, including shorter (= four weeks) and longer durations (> four weeks to < eight weeks; = eight weeks) of use. Future trials should measure blood pressure using 24-hour ambulatory monitoring and assess the effect of long-term use.
| Discipline Area | Score |
|---|---|
| Special Interest - Obesity -- Physician |  |
| Family Medicine (FM)/General Practice (GP) | |
| General Internal Medicine-Primary Care(US) | |
| Psychiatry | |
| Pediatrics (General) | |
| Cardiology |  |
Amphetamines are increasingly frequently used in connection with AHDH. In this respect, the question of whether their use leads to an increase in blood pressure is relevant. The measured increase in blood pressure of 1.93/1.84 mm Hg appears to be clinically relevant. Unlike blood glucose, blood pressure is a surrogate parameter, the increase of which is also likely to lead to an increase in clinical endpoints. However, methylphenidate and similar substances are mostly used in children and adolescents in whom possible cardiovascular consequences of increased blood pressure values can hardly be assumed. Also, the prescription is usually limited to a few years. So, it remains somewhat unclear what the consequences of the slight increase in blood pressure values are. A completely different topic would be the question of the effects of illegal consumption of such stimulating substances.
I don't see how an increase of <2mmHG for SBP and DBP can be said to demonstrate increased cardiovascular event risk. Normal human BP varies more than this throughout the day.
Useful information in Paediatrics especially because more adolescents are experimenting with amphetamines since they are easier to source in most countries. ADHD diagnoses seem to be on the rise due to greater awareness amongst parents and higher index of suspicion from healthcare providers. This will likely result in an increase in prescribed amphetamines.
Stimulants have had a long confusing history of safety versus harm. At one point, the American Heart Association wanted EKGs on all kids who were to be placed on stimulants. The findings are interesting in that the average changes would not be considered clinically significant. This does highlight the importance of checking vital signs. The authors noted that in most of the RCTs, blood pressure was checked within 24 hours of the last dose. That is a weakness, as stimulants have short half-lives. In clinical practice, it would seem important to measure vital signs at peak stimulant levels. Now I wonder whether a study doing that would show more robust changes, although I was not impressed with robust changes in the majority of kids I treated.
