Risks and
Mechanism of Action of Stimulants
Peter R. Breggin, M.D.
Table 1 summarizes the adverse drug reactions caused by
methylphenidate and amphetamine stimulant drugs. Table 2
provides estimated frequencies of these reactions and adds
those to pemoline. Younger children are especially
vulnerable to these harmful effects (Dulcan, Popper, 1991;
Schleifer, Weiss, Cohen, et al., 1975). Results of various
studies are as follows.
CNS Adverse Effects in Double-Blind Placebo-Controlled
Studies
Mayes and colleagues (1994) (partially controlled): 18.8
percent lethargy variously described by raters as
tired, withdrawn, listless, depressed, dopey, dazed, subdued
and inactive; 26.1 percent irritability; 7
percent severe adverse reactions including one manic-like
reaction with incessant talking, one
wild and out of control, and one
aggressive behavior.
Schachar and colleagues (1997): 10 percent of children
dropped out because of adverse drug reactions, including
serious behavioral aberrations, such as sadness and
behavioral deterioration, irritability, withdrawal,
lethargy, violent behavior, withdrawal and mild
mania, and withdrawal and dysphoria.
Barkley and colleagues (1990): the percentage of
children experiencing proneness to crying also increased by
at least 10 percent during the low-dose condition
(p<.05) (p. 187); 3.6 percent were unable to complete the
protocol because of serious adverse reactions including one
with manic-like symptoms (p. 186).
Gillberg and colleagues (1997): three children developed
hallucinations (4.8 percent).
These four controlled clinical trials found psychotic
symptoms in at least 2 percent (6 of 260) and higher rates
for other CNS effects.
Borcherding and colleagues (1990):
perseverative/compulsive behaviors in 51 percent
administered amphetamine and methylphenidate and one drop
out due to both the severity of the tic he developed
during his initial treatment phase (dextroamphetamine) and
exacerbated symptoms of separation anxiety. Solanto
and Wender (1989): 42 percent of completers
overarousedwith cognitive
perseveration(overfocused, obsessive/compulsive
reaction). Castellanos and colleagues (1997): 25 percent of
children (comorbid for ADHD and Tourettes) developed
largely transient obsessive/compulsive behavior
during a 3-week exposure to methylphenidate.
Table 1. Adverse effects caused by methylphenidate
and amphetamines
Cardiovascular
|
Central Nervous System
|
Gastrointestinal
|
Endocrine/ Metabolic
|
Other
|
Withdrawal and
Rebound
|
Palpitations
Tachycardia
Hypertension
[arrythmias]
[cardiac arrest]
|
Psychosis with hallucinations
(skin crawling or visions)
Excessive CNS stimulation
[convulsions]
Insomnia (nightmares)
Nervousness
Irritability
Anxiety
Emotional oversensitivity, easy crying
Dysphoria (especially at higher doses)
Impaired cognitive test performance (especially at
higher doses)
Dizziness
Headache
Attacks of Tourette's or other motor or vocal tic
syndromes
Nervous habits (e. g., picking at skin, pulling
hair)
Stereotyped activities or compulsions
Depression
Decreased social interest
Zombie- like constriction of affect and
spontaneity*
Amphetamine look (pinched, somber expression)
|
Anorexia
Nausea
Vomiting
Stomach pain, cramps
Dry mouth
|
Pituitary dysfunction
[including growth hormone and
prolactin]
Weight loss
Growth suppression
Growth retardation
|
Blurred vision
Hypersensitivity
reaction with rash, conjunctivitis, or hives
Anemia I
Leukopenia I
|
Insomnia
Evening crash
Depression
Overactivity and irritability
Rebound ADHD symptoms
|
Sources: Combination of Dulcan (1994, Table 35- 6, p.
1217), Arnold and Jensen (1995, Table 38- 5, p. 2306), and
Drug Enforcement Administration (1995, p. 23). Any
additional material indicated by brackets.
* Zombie references from Arnold and Jensen
(1995, Table 38- 5, p. 2306; Table 38- 7, p. 2307; and
column 2, p. 2307); Swanson, Cantwell, Lerner, et al. (1992,
p. 15); Fialkov and Hasley (1984, p. 328).
Arnold and Jensen (1995).
For methylphenidate only.
Table 2. Percentages of
children experiencing ADRs from stimulants
Side Effects
|
Dextroamphetamine
|
Methylphenidate
|
Pemoline
|
Central Nervous System Effects
|
|
|
|
Dyskinesias
|
< 1
|
3
|
5.5
|
Tourette's syndrome
|
< 1
|
< 1
|
<1
|
Tics
|
<1
|
--
|
--
|
Headache
|
18.3 (1-31)
|
9.3 (0-15)
|
13.8 (1-22)
|
Drowsiness, less alert
|
5.5
|
5.7 (0-17)
|
5.5
|
Psychosis (normal dose)
|
<1
|
<1
|
<1
|
Difficulty arousing
|
--
|
15 (11-19)
|
--
|
Insomnia
|
19 (5-43)
|
16.9 (0-52)
|
28.7 (<10-42)
|
Tremor
|
5.5
|
6.5
|
--
|
Confused, "dopey"
|
10.3 (8-12)
|
3.9 (2-10)
|
--
|
Mood changes
|
<1
|
>10
|
5.5
|
Agitation, restlessness (motoric)
|
39
|
8.7 (0-16)
|
--
|
Irritability, stimulation
|
25 (17-29)
|
17.3 (11-19.6)
|
13.3 (1-21)
|
Cardiovascular Effects
|
|
|
|
Dizziness, lightheadedness
|
11.5 (1-23)
|
7.7 (0-13)
|
5.5
|
Lower Blood Pressure
|
--
|
<1
|
<1
|
Higher Blood Pressure
|
>10
|
15.8 (1-26)
|
--
|
Tachycardia
|
5.5
|
15.8 (1-26)
|
5.5
|
Palpitations
|
5.5
|
4.4 (1-10)
|
5.5
|
Cardiac arrhythmias
|
<1
|
5.5
|
--
|
Chest pain
|
<1
|
4.4 (1-10)
|
--
|
Gastrointestinal Effects
|
|
|
|
Dry mouth and throat
|
>10
|
8.7 (0-17.4)
|
--
|
Anorexia, lower appetite
|
23.1 (1-56)
|
26.9 (0-72)
|
14.5 (1-34)
|
Nausea
|
5.5
|
5.1 (1-10)
|
5.5
|
Vomiting
|
5.5
|
--
|
5.5
|
Bad taste
|
5.5
|
--
|
--
|
Dyspepsia, upset stomach
|
5.5
|
9.7 (1-28)
|
5.5
|
Diarrhea
|
5.5
|
--
|
|
Constipation
|
5.5
|
6.5
|
--
|
Hepatotoxicity
|
--
|
--
|
2
|
Weight loss
|
29.5 (1-63)
|
13.5 (3-27)
|
5.5
|
Weight gain
|
--
|
4.3
|
--
|
Renal Effects
|
|
|
|
Enueresis
|
--
|
9 (3-20)
|
--
|
Endocrine and Sexual Effects
|
|
|
|
Impotence
|
5.5
|
--
|
--
|
Disturbed sexual function
|
5.5
|
--
|
--
|
Growth suppression
|
See text
|
See text
|
See text
|
Hematologic Effects
|
|
|
|
Easy bruising
|
--
|
5.5
|
--
|
Eye, Ear, Nose and Throat Effects
|
|
|
|
Blurred vision
|
5.5
|
<1
|
--
|
Nystagmus
|
--
|
--
|
5.5
|
Skin, Allergy, and Temperature
Effects
|
|
|
|
Unusual sweating
|
5.5
|
--
|
--
|
Rashes
|
<1
|
5.5
|
5.5
|
Hives
|
<1
|
5.5
|
--
|
Exfoliative dermatitis
|
--
|
5.5
|
--
|
Fever, unexplained
|
--
|
5.5
|
--
|
Joint pain
|
--
|
5.5
|
--
|
* These figures are based primarily on reports of
children and adolescents treated tbr ADHD.
-- Indicates nonexistence of information, not
nonexistence of adverse effects. All data taken from
Maxmen and Ward (1995, pp. 365-6).
Psychostimulant-Induced
Motor and Vocal Tics
Borcherding and colleagues (1990): approximately
59 percent abnormal movements. Barkley and colleagues
(1990): 10 percent increase in tics. Handen and
colleagues (1991): (mentally retarded with ADHD) 11
percent stopped methylphenidate because of motor tics.
Lipkin and colleagues (1994) (retrospective): 9
percent tics or dyskinesias, one severe, irreversible
case.
Psychostimulant
Addiction, Withdrawal, and Rebound
Rapoport and colleagues (1978) (controlled,
single amphetamine dose of 0.5 mg/kg): 71 percent of
normal children suffered marked behavioral
rebound, including excitability,
talkativeness, and, for three children, apparent
euphoria. Case reports of crashing with
depression (Dulcan, 1994; also see Porrino, Rapoport,
Behar, et al., 1983). The Drug Enforcement Administration
(1995) and International Narcotics Control Board (1996,
1997) express concern about clinical use encouraging
addiction and about abuse through illegal diversion.
Psychostimulant Growth
Suppression and Retardation
Methylphenidate disrupts growth hormone cycles
(Aarskog, Fevang, Klove, et al., 1977; Barter, Kammer,
1978; Brown, Williams, 1976; Joyce, Donald, Nicholls, et
al., 1986; Shaywitz, Hunt, Jatlow, et al., 1982; reviewed
in Dulcan, 1994, and Jacobvitz, Sroufe, Stewart, et al.,
1990). Stimulants inhibit growth (height and weight)
(Klein, Mannuzza, 1988; Safer, Allen, Barr, 1975).
Spencer and colleagues (1996) conclude that growth
deficits are related to ADHD, but the study is flawed,
including the use of only one measurement per child and a
control group that is 1 year older.
Methylphenidate
Cardiovascular Adverse Effects
FDAs Spontaneous Reporting System (SRS)
(1985 through March 3, 1997): 2,821 reports with 8
percent cardiovascular, including arrhythmias and
conduction problems (120) and heart arrests and failures
(13) (Breggin, 1998b). Psychostimulants have direct
cardiotoxic effects (Henderson, Fischer, 1994; Ishiguro,
Morgan, 1997).
Further Review of the
FDA Spontaneous Reporting System
FDA SRS reports indicate symptom clusters often
overlooked in reviews: drug dependency, addiction, and
withdrawal (117 reports); hair loss (250); various skin
disorders; various blood disorders, including leukopenia;
abnormal liver function tests (also see National
Toxicology Program, 1995, for cancer threat); and
convulsions (69). Adverse mental reactions: depression
(48); psychotic depression (11); combined categories of
overdose, overdose intentional, and suicide attempt (50);
personality disorders (89); agitation (55); hostility
(50); abnormal thinking (44); hallucinations (43);
psychosis (38); and emotional lability (33).
Methylphenidate-Induced
Abnormalities of Brain Function
Porrino and Lucignani (1987) (conscious rats):
alterations in glucose metabolism in the brain. Bell and
colleagues (1982) (rat brain tissue): glucose metabolic
rates reduced in the motor cortex and increased in the
substantia nigra and other deep structures.
Volkow and colleagues (1997) (PET in normals):
reduced relative metabolism of basal ganglia and varied
other effects. Wang and colleagues (1994) (PET in
normals): decreased overall flow of blood into brain by
23 to 30 percent. Nasrallah and colleagues (1986) (PET):
brain atrophy in more than 50 percent of 24 young adults
with stimulant-treated hyperactivity in childhood. They
conclude cortical atrophy may be a long-term
adverse effect of this treatment. Brain scan
studies that attempt to show pathology of ADHD (Lou,
Henriksen, Bruhn, 1984; Giedd, Castellanos, Casey, et
al., 1994; Hynd, Semrud-Clikeman, Lorys, et al., 1991)
are almost certainly measuring pathology caused by
psychostimulants.
Psychostimulant-Induced
Abnormalities of Brain Chemistry in Animals
Methamphetamine: chronic exposure can produce
irreversible CNS damage to dopamine receptors and
norepinephrine function (Wagner, Ricaurte, Johanson, et
al., 1980). Large chronic doses cause the death of
serotonergic nerves in animals (Battaglia, Yeh,
OHearn, et al., 1987). Melega and colleagues
(1997b) found persistent neurotoxic changes
in dopamine function (dopamine depletions of 55 to 85
percent) in vervet monkeys at 10 to 12 weeks (2 doses of
2 mg/kg). Sonsalla and colleagues (1996) found
dopaminergic cell death in the substantia nigra of mice
(approximate cell loss, 40 to 45 percent) (4 i.p.
injections at 10 mg/kg).
Amphetamine: in rhesus monkeys, demonstrated
long-lasting loss of dopamine and dopamine uptake sites
(receptors) (Wagner, Ricaurte, Johanson, et al., 1980);
down-regulation (subsensitivity) in the dopamine
neurotransmitter system (Barnett, Kuczenski, 1986).
Melega and colleagues (1997b) using PET in vervet monkeys
found marked decreases in dopamine synthesis (25 percent
at 10 to 12 weeks) with a 16 percent reduction in one
amphetamine-treated animal at 32 weeks (2 doses of 2
mg/kg). Melega and colleagues (1997a) recorded gradual
recovery from neurotoxicity in the striatum over 2 years
(4 to 18 mg/kg over 10 days).
Methylphenidate: down-regulation of dopamine receptors
(Barnett, Kuczenksi, 1986); reduction of the density of
the norepinephrine receptors (Mathieu, Ferron, Dewar, et
al., 1989); locus coeruleus loses responsiveness
(Lacroix, Ferron, 1988).
Fenfluramine: (chemically related to amphetamine)
causes death of serotonergic neurons (McCann, Seiden,
Rubin, et al., 1997).
Psychostimulant
Indirect Adverse Effects
Children lose their sense of responsibility for
their own behavior (Breggin, 1997, 1998a; Jensen, Bain,
Josephson, 1989) and experience many negative emotional
reactions that they may not report (Sroufe, Stewart,
1973).
Psychostimulant
Mechanism of Action
Spontaneous or self-generated
activities¾play, mastery, exploration, novelty
seeking, curiosity, and zestful socialization¾are
central to the growth and development of animals and
humans and necessary for the full elaboration of CNS
synaptic connections (Greenough, Black, 1992; Weiler,
Hawrylak, Greenough, 1995).
Psychostimulants consistently cause two specific,
related adverse drug effects in animals (and also
humans). First, stimulants suppress normal spontaneous or
self-generated activity and socialization (Arakawa, 1994;
Hughes, 1972; Randrup, Munkvad, 1967; Schiørring,
1979, 1981; Wallach, 1974). Second, stimulants promote
abnormal stereotyped, obsessive/compulsive, asocial
behaviors that are repetitive and meaningless
(Bhattacharyya, Ghosh, Aulakh, et al., 1980; Costall,
Naylor, 1974; Koek, Colpaert, 1993; Kuczenski, Segal,
1997; Mueller, 1993; Randrup, Munkvad, 1967; Rebec,
Bashore, 1984; Rebec, Segal, 1980; Segal, 1975; Segal,
Weinberger, Cahill, 1980; early studies reviewed in
Wallach, 1974, and Schiørring, 1979). The effects
occur in rats at doses as low as 0.63 mg/kg
methylphenidate (Koek, Colpaert, 1993) or 0.3 mg/kg
amphetamine (Rebec, Bashore, 1984).
The drugs suppress normal spontaneous,
self-generated behaviors and socialization; they promote
abnormal compulsive, asocial, compliant behaviors
deemed suitable to structured and often suppressive
situations, such as many classrooms (Breggin, 1997,
1998a; Breggin, Breggin, 1996, 1998; Ellinwood [in
Kramer, Lipton, Ellinwood, et al., 1970]; Fialkov,
Hasley, 1984; Rie, Rie, Stewart, et al., 1976; Rebec,
Bashore, 1984). This drug-induced suppression of behavior
and mental function is independent of the childs
mental state; it occurs in healthy animals and children.
When children seem to be overactive, impulsive, or
distractible, psychostimulants will also suppress these
behaviors regardless of the cause, including ADHD-like
behaviors that signal boredom, frustration, abuse,
conflict, lack of rational discipline or age-appropriate
attention, or inadequate educational interventions. This
mutes the childs distress or needs, allowing them
to be ignored.
Table 3 lists some of the ADRs that are mistakenly
seen as improvements when they reflect
suppressed, overfocused, asocial behavior.
Risk/Benefit
Ratio
There are no positive long-term psychostimulant
effects (beyond 7 to 18 weeks) and no improvement in
academic performance or learning (Swanson, 1993; also see
Breggin, 1998a; Jacobvitz, Sroufe, Stewart, et al., 1990;
Popper, Steingard, 1994; Richters, Arnold, Jensen, et
al., 1995; Whalen, Henker, 1997). Studies claiming that
ADHD leads to bad outcomes have studied children who have
been diagnosed and treated with drugs (Mannuzza, Klein,
Bessler, et al., 1993, 1998; Weis, Hechtman, Milroy, et
al., 1985). Diagnosis, treatment, and other non-ADHD
factors may contribute to any bad outcome. Meanwhile,
there are many common, severe stimulant hazards. The
therapeutic effects are in reality toxic
effects (Table 3). The use of psychostimulant drugs
for the control of behaviors labeled ADHD in children
should be stopped.
Future Research
Directions
Before the clinical use of psychostimulants for
ADHD is continued, large animal psychostimulant studies
are needed that focus on (1) the extent and potential
irreversibility of abnormalities in gross brain function
(blood flow and energy consumption), (2) the extent and
potential irreversibility of neurotransmitter
down-regulation and receptor loss, (3) neuronal death and
atrophy, (4) reduced brain plasticity (fewer synaptic
connections), (5) disruption of pituitary and hormonal
functions, (6) developmental retardation of growth and
behavior, and (7) cardiac toxicity.
Table 3. Adverse drug reactions
(ADRs) from stimulants mistakenly labelled beneficial
Obsessive Compulsive ADRs That Abnormally Focus
a Child
|
Social Withdrawal ADRs That Isolate a Child
|
Suppressive ADRs That Enforce Compliance,
Apathy, and Submissiveness
|
Stereotypical activities (2, 6, 23, 25)
Obsessive- compulsive behavior (2, 6, 12, 28)
Perseverative behavior (2, 14, 28)
Cognitive perseveration (12)
Inflexibility of thinking (14)
Overfocusing or excessive focusing (1, 12, 14,
25)
|
Social withdrawal and isolation (1, 3, 6, 19,
24, 25)
Reduced social interactions, talking, or
sociability (6, 13, 15*, 17, 21)
Decreased responsiveness to parents and other
children (15*)
Increased time spent alone (1, 21)
Increased solitary play (7, 13*)
Diminished play (26*)
Autism and schizophrenia (3, 23)
|
Compliance, especially in structured
environments (13*, 15*, 16*)
Fewer social interactions and diminished
responsiveness (26*)
Hypoactive, unusual stillness, too quiet, lost
sparkle (18, 25)
Reduced curiosity (12)
Somber (5), and somber, quiet, and still (1)
Subdued (6,10)
Apathetic; lethargic: tired, withdrawn,
listless, depressed, dopey, dazed, subdued and
inactive (6) (also 23, 25)
Bland, emotionally flat, affectless (9, 27)
Depressed, sad, easy or frequent crying (6, 7, 8,
18, 19, 20, 22)
Little or no initiative or spontaneity (9)
Diminished curiosity, surprise, or pleasure (9)
Humorless, not smiling (9, 22)
Drugged, spaced out (22, 25)
Social inhibition ¾ passive and submissive
behaviors (11)
Amphetamine look (pinched, somber expression) (1,
4)
Zombie effect ( zombie- like
constriction of affect and spontaneity) (1,
4, 25)
|
*Considered positive or therapeutic by the source.
cct = controlled clinical trial
1. Swanson, Cantwell, Lerner, et
al. (1992) [confirms many ADRs in list]
2. Borcherding, Keysor, Rapoport, et al. (1990)
[cct]
3. Schiørring (1981)
4. Arnold, Jensen (1995)
5. Tannock, Schachar, Carr, et al. (1989)
[cct]
6. Mayes, Crites, Bixler, et al. (1994)
[cct]
7. Schleifer, Weiss, Cohen, et al. (1975)
[cct]
8. Dulcan (1994) and Dulcan, Popper (1991)
[open trial]
9. Rie, Rie, Stewart, et al. (1976)
[cct]
|
10. Bradley (1937) [open
trial]
11. Granger, Whalen, Henker (1993)
[cct]
12. Solanto, Wender (1989) [cct]
13. Cunningham, Barkley (1978) [cct]
14. Dyme, Sahakian, Golinko, et al. (1982)
[cct]
15. Barkley, Karlsson, Pollard, et al. (1985)
[cct]
16. Cotton, Rothberg (1988) [cct]
17. Jacobvitz, Sroufe, Stewart, et al. (1990)
18. Davy, Rodgers (1989)
|
19. Schachar, Tannock,
Cunningham, et al. (1997) [cct]
20. Barkley, McMurray, Edelbrock, et al. (1990)
[cct]
21. Pelham (1989)
22. Sleator, Ullmann, von Neuwman (1982)
23. Ellinwood, Tong (1996)
24. Handen, Feldman, Gosling, et al. (1991)
[cct]
25. Fialkov, Hasley (1984)
26. Barkley, Cunningham (1979) [cct]
27. Whalen, Henker, Granger (1989)
[cct]
28. Castellanos, Giedd, Elia, et al. (1997)
[cct]
|
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