Some Research on Stimulant Medication
and Heart Disease
Research Menu Page ||| Last update 05/02/2010
Listed in reverse date order:
READ THE STUDIES LISTED IN RED FIRST
|Negrao 2009 ||The effect of sympathomimetic medication on cardiovascular functioning of children with attention-deficit/hyperactivity disorder (stimulant medications)|
|Gracious 1999 ||Atrioventricular nodal re-entrant tachycardia [fast heartbeat] associated with stimulant treatment.|
|Volkow 1999||Methylphenidate and cocaine have a similar in vivo potency to block dopamine transporters in the human brain. |
|Wilens 1999||Absence of cardiovascular adverse effects of sertraline in children and adolescents.
|Brumaghim 1998 ||Methylphenidate's effects on paired-associate learning and event-related potentials of young adults.|
|Ishiguro 1997||Biphasic inotropic effects [changing strength of muscle contractions] of methamphetamine and methylphenidate on ferret papillary muscles.|
|Findling 1996||Open-label treatment of comorbid depression and attentional disorders with co-administration of
serotonin reuptake inhibitors and psychostimulants in children, adolescents, and adults: a case series.|
|Henderson 1995 ||Effects of methylphenidate (Ritalin) on mammalian myocardial ultrastructure.|
|Lazarus 1994||Methylphenidate and nortriptyline in the treatment of poststroke depression: a retrospective comparison.|
|Wang 1994||Methylphenidate decreases regional cerebral blood flow in normal human subjects.|
|Knuepfer 1993||Cocaine-induced myocardial ultrastructural alterations and cardiac output responses in rats.|
|Knuepfer 1991||Mechanisms of cardiac and vascular responses to cocaine.|
|Pelham 1991||Effects of background anger, provocation, and methylphenidate on emotional arousal and aggressive responding in attention-deficit hyperactivity disordered boys with and without concurrent aggressiveness.|
|Brown 1989||Effects of methylphenidate on cardiovascular responses in [Black] attention deficit hyperactivity disordered adolescents.|
|Brown 1988||A controlled trial of methylphenidate in black adolescents. Attentional, behavioral, and physiological effects.|
|Kelly 1988||Attention deficit disorder and methylphenidate: a multi-step analysis of dose-response effects on children's cardiovascular functioning. |
|Brown 1984||Attention deficit disorder and the effect of methylphenidate on attention, behavioral, and cardiovascular functioning.|
|Coons 1981||Effect of methylphenidate on young adult's vigilance and event-related potentials.|
|Ballard 1976||Cardiovascular responses of hyperactive children to methylphenidate.|
Cardiovascular responses of hyperactive children to methylphenidate.
Ballard JE et al.,
JAMA 1976 Dec 20;236(25):2870-4
Heart rate, blood pressure, and oxygen consumption were measured in 27 hyperactive children during rest, exercise, and recovery,
once taking placebo and again taking methylphenidate hydrochloride. ... Oxygen consumption did not change (P = .40), but heart rate (P = .001) and blood pressure (P =
.003) increased significantly with methylphenidate therapy. There was a significant correlation between size of dose in milligrams per
kilogram and increase in heart rate (.38, P less than .05) and blood pressure (.50, P less than .05 systolic) (.46, P less than .05
diastolic). No evidence of the development of tolerance to these drug effects was found in children who had been taking
methylphenidate from two months to more than a year. No ECG changes other than tachycardia were seen."
A controlled trial of methylphenidate in black adolescents. Attentional, behavioral, and physiological effects.
Brown RT, Sexson SB,
Clin Pediatr (Phila) 1988 Feb;27(2):74-81
The short-term effects of methylphenidate were examined on behavioral, laboratory, academic, and physiological measures in 11 black
male adolescents diagnosed as having attention deficit disorder (ADD). . . Significant drug effects were found for the majority of measures. . . . However, a significant
linear increase occurred in diastolic blood pressure. . . ."
Effects of methylphenidate on cardiovascular responses in attention deficit hyperactivity disordered adolescents.
Brown RT, Sexson SB,
J Adolesc Health Care 1989 May;10(3):179-83
The short-term dose effects of methylphenidate were examined on cardiovascular measures in 11 black male adolescents diagnosed as
having attention deficit hyperactivity disorder (ADHD). In a double-blind, cross-over design with randomized order, the subjects
received placebo and each of three methylphenidate doses (0.15, 0.3, and 0.5 mg/kg) for a period of 2 weeks per medication dosage.
Significant main effects were found for diastolic and systolic blood pressure; however, pairwise comparisons revealed a significant
linear increase in diastolic blood pressure only. Because of the unexpected increase in diastolic blood pressure, careful monitoring of
black adolescents who are receiving methylphenidate is recommended."
Attention deficit disorder and the effect of methylphenidate on attention, behavioral, and cardiovascular functioning.
Brown RT, Wynne ME, Slimmer LW,
J Clin Psychiatry 1984 Nov;45(11):473-6
The effect of a 0.3 mg/kg dose ... Consistent with previous research,
cardiovascular functioning did not significantly increase as a function of methylphenidate. Due to the large intraindividual variability in
cardiovascular response, careful monitoring of each patient's response is recommended."
Methylphenidate's effects on paired-associate learning and event-related potentials of young adults.
Brumaghim JT, Klorman R,
Psychophysiology 1998 Jan;35(1):73-85,
The effects of methylphenidate (0.3 mg/kg) on young adults paired-associate learning (PAL) of consonant-vowel-consonant (CVC) pairs and concomitant event-related potentials were assessed. The stimulant elevated mood and heart rate but did not affect PAL
performance. . . ."
Effect of methylphenidate on young adult's vigilance and event-related potentials.
Coons HW et al,
Electroencephalogr Clin Neurophysiol 1981 Apr;51(4):373-87
... In study 2, although heart rate was again elevated by the 20 mg dose of methylphenidate,
... increases in LPC amplitude by methylphenidate are obtained only in tasks in which the subject may
profit from the recruitment of additional attentional resources."
Open-label treatment of comorbid depression and attentional disorders with co-administration of
serotonin reuptake inhibitors and psychostimulants in children, adolescents, and adults: a case series.
J Child Adolesc Psychopharmacol 1996 Fall;6(3):165-75
... This case series describes 7 pediatric patients ... and 4 adults ... whose ADHD and comorbid major depression were treated in a naturalistic open clinical
fashion. . . . With the exception of one adult who had a 20 mm Hg
increase in diastolic pressure on methylphenidate monotherapy at 22.5 mg daily, the administration and coadministration of these
agents were not associated with significant changes in blood pressure or heart rate. . . . These cases support previous suggestions that adjunctive treatment with
psychostimulants might be a safe and effective intervention . . ."
NOTE: A 20 mm Hg increase in diastolic (the lower number) blood pressure can be very significant. Depending on the starting point, it can bring the blood pressure into the "stroke range." And 22.5 mg Ritalin is not a high dose for an adult - or even a child. "Monotherapy" means he was on Ritalin alone, not the combination. Although it was one man, it is almost 10% of this sample. If 10% of a sample risks heart attack or stroke in a short trial, how can this be considered safe?
Atrioventricular nodal re-entrant tachycardia associated with stimulant treatment.
Journal of Child Adolescent Psychopharmacology 1999;9(2):125-8
"A 13-year-old African-American female taking sertraline [Zoloft] for obsessive compulsive disorder was diagnosed with her first episode of atrioventricular (AV) nodal re-entrant tachycardia [irregular heartbeat and shortness of breath or fainting] five days after beginning Mixed Salts of a Single-Entity Amphetamine Product (Adderall) for treatment of attention-deficit hyperactivity disorder (ADHD). She received successful cardioversion [they stabilized her heart rhythm] ... but [she] developed a second episode ... twelve days after Adderall was reinitiated at half the previous dose. The patient had clinically similar cardiac episodes five and six months after treatment was changed to slow-release methylphenidate [Ritalin]. Stimulant medication may evoke onset of AV nodal tachyarrhythmias in patients who have the potential to develop them, possibly in combination with a selective serotonergic reuptake inhibitor (SSRI) [like Zoloft or Prozac].
NOTE: Tachycardia = excessive rapidity of heart rate, usually over 100 beats per minute.
Effects of methylphenidate (Ritalin) on mammalian myocardial ultrastructure.
Henderson TA, Fischer VW,
Am J Cardiovasc Pathol 1995;5(1):68-78
Previous observations have indicated lamellated ultrastructural [small] lesions in the myocardium [muscle of the heart wall] of a patient treated with methylphenidate (Ritalin) hydrochloride (MPH). A causal relationship between MPH exposure and these membranous changes was tested in the myocardium of rats and mice. Following injection of varying doses of MPH for different periods, myocardial ultrastructure was
examined . . . MPH induced membrane
accumulations and lamellations [damage]. . . Lamellations were evident
at the earliest timepoints examined and appeared to occur without lysosomal involvement. Lesions were still apparent 12 weeks after
terminating MPH. These data suggest that MPH may have persistent, cumulative effects on the myocardium."
A lysosome is a small package of strong enzymes in a cell, so small you have to use an electron microscope to see it. If the lysosome is injured, the enzymes are released and can cause damage to the cell or surrounding tissue. Here there was no lysosomal involvement - so the damage was not made by injury to lysosomes.
Biphasic inotropic effects of methamphetamine and methylphenidate on ferret papillary muscles.
Ishiguro Y, Morgan JP,
J Cardiovasc Pharmacol 1997 Dec;30(6):744-9
Methamphetamine and methylphenidate are structurally related agents that have direct negative inotropic (NIEs) [making muscle contractions weaker] and indirect positive
inotropic effects (PIEs) [making muscle contractions stronger] in cardiac tissues. ...The direct NIE of methylphenidate was more prominent. Our results suggest that the
negative inotropic effects [making contractions weaker] of methamphetamine and methylphenidate may be important with clinically used and abused concentrations of
these drugs and may be difficult to reverse with beta-adrenergic inotropic agents in cases of toxicity."
Attention deficit disorder and methylphenidate: a multi-step analysis of dose-response effects on children's cardiovascular functioning.
Kelly KL, Rapport MD, DuPaul GJ,
Int Clin Psychopharmacol 1988 Apr;3(2):167-81
The present study investigated the effects of methylphenidate (MPH) on the resting heart rate of 47 children with Attention Deficit
Disorder/Hyperactivity. Children ...received each
of 5 doses of MPH in a counterbalanced sequence. ...
Results indicated that higher dosages are linearly related to increasing levels of HR [heart rate] and that these effects are dependent upon both the
initial HR value and the time course of the medication."
NOTE: Only 5 doses were used, counterbalanced with placebo. Rebound effect seems to be ignored in most of these studies. Has anyone seen a study on the cardiac effect of stopping the meds?
Mechanisms of cardiac and vascular responses to cocaine.
Knuepfer MM, Branch CA, Fischer VW,
NIDA Res Monogr 1991;108:55-73
Department of Pharmacological and Physiological Science, St. Louis University School of Medicine, MO 63104.
Cocaine-induced myocardial ultrastructural alterations and cardiac output responses in rats.
Knuepfer MM, Branch CA, Gan Q, Fischer VW,
Exp Mol Pathol 1993 Oct;59(2):155-68
. . . freely moving rats were treated with
cocaine (5 mg/kg) or saline intravenously twice daily for 14 days before removing the myocardium [heart muscle] for analysis. . . While little change was evident at low magnification, electron microscopy revealed diffusely
distributed myocardial lesions . . . The incidence of these alterations was greater in rats with a decrease in
cardiac output. . . These
data represent the first evidence that there is a relationship between cocaine-induced functional and pathological alterations and that
rats, like humans, may be differentially sensitive to these effects."
NOTE: These lesions are similar to the ones seen by Henderson & Fischer in 1995 when giving Ritalin to rats.
Methylphenidate and nortriptyline in the treatment of poststroke depression: a retrospective
Lazarus LW, Moberg PJ, Langsley PR, Lingam VR,
Arch Phys Med Rehabil 1994 Apr;75(4):403-6
"The hospital charts of elderly stroke patients with major depression, ... who were treated with
either methylphenidate [Ritalin](n = 28) or nortriptyline [a tricyclic antidepressant or TCA] (n = 30) were retrospectively reviewed. ... Adverse side effects, such as cardiac changes, did
not differ between groups, generally falling in the mild range of severity. ..."
The effect of sympathomimetic medication on cardiovascular functioning of children with attention-deficit/hyperactivity disorder.
Negrao BL, Crafford D, Viljoen M.,
Cardiovascular Journal of Africa, 2009 Sep-Oct;20(5):296-9.
... CONCLUSION: Methylphenidate causes an increase in HR [heart rate] as well as increases in both systolic and diastolic BP [blood pressure], but no change in cardiac depolarisation and repolarisation duration or homogeneity."
Effects of background anger, provocation, and methylphenidate on emotional arousal and aggressive responding in attention-deficit hyperactivity disordered boys with and without concurrent aggressiveness.
J Abnorm Child Psychol 1991 Aug;19(4):407-26
... Our study
revealed that ADHD boys showed more emotional and physiological distress when exposed to an interaction in which an administrator
chastised each boy's favorite counselor, compared to a friendly interaction between the two adults. ... High-aggressive (HA)
ADHD boys were more likely to respond to provocation with aggression than low-aggressive (LA) ADHD boys, but only LA boys
showed increased physiological reactivity with increasing provocation. Methylphenidate resulted in increased heart rates under all
conditions and did not interact with any of the other findings."
NOTE: Yes, you read this right. They spent money to study whether boys are more upset to see their friend yelled at than they are when their friend is not yelled at. And boys labeled "high aggression" had higher aggression than boys labeled "low aggression." I hope it wasn't taxpayers' money.
Methylphenidate and cocaine have a similar in vivo potency to block dopamine transporters in the
Volkow ND et al,
Life Sci 1999;65(1):PL7-12
The reinforcing effects of cocaine and methylphenidate have been linked to their ability to block dopamine transporters (DAT). . . Parallel measures were obtained to assess the cardiovascular effects of
these two drugs. Methylphenidate and cocaine produced comparable dose-dependent blockade of DAT with an estimated ED50
(dose required to block 50% of the DAT) for methylphenidate of 0.07 mg/kg and for cocaine of 0.13 mg/kg. Both drugs induced
similar increases in heart rate and blood pressure but the duration of the effects were significantly longer for methylphenidate than for
cocaine. . . . Thus, differences in the in vivo potency of these two drugs at the
DAT cannot be responsible for the differences in their rate of abuse in humans. Other variables i.e. longer duration of
methylphenidate's side effects may counterbalance its reinforcing effects."
Methylphenidate decreases regional cerebral blood flow in normal human subjects.
Wang GJ, et al.,
Life Sci 1994;54(9):PL143-6
To assess the effects of methylphenidate (MP) on cerebral blood flow (CBF), 5 healthy males were studied . . . MP significantly decreased whole brain CBF at 5-10 minutes (25 +/- 11%) and at 30 minutes (20 +/- 10%) after its administration. Decrements in CBF were homogeneous throughout the brain (regional decrements 23-30%) and probably reflect the vasoactive [having an effect on the caliber of blood vessels] properties of MP. The vasoactive properties of MP should be considered when prescribing this drug chronically and/or when giving it to subjects with cerebrovascular compromise."
Absence of cardiovascular adverse effects of sertraline in children and adolescents.
Wilens TE, Biederman J et al,
J Am Acad Child Adolesc Psychiatry 1999 May;38(5):573-7
In a 12 week, placebo-controlled, parallel-design, multicenter study of sertraline [Zoloft] for obsessive-compulsive disorder in
107 children and 80 adolescents, the authors prospectively assessed cardiovascular effects ... RESULTS: There were no clinically significant cardiovascular adverse events in
any of the subjects enrolled in the study. Moreover, compared with baseline and placebo, sertraline treatment at an average dose of
167 mg did not result in any clinically meaningful changes in any ECG indices (PR, QRS, and QTc intervals), cardiac rhythm, blood
pressure, or heart rate. CONCLUSIONS: These prospectively derived results support the cardiovascular safety of sertraline at doses
up to 200 mg in children and adolescents."
NOTE: The adverse effects were not really ABSENT, in spite of the title. They were considered "not significant." So the drug is safe for 12 weeks. Is it safe for 12 years?