NIH Consensus Development Conference
on Diagnosis and Treatment
of Attention Deficit Hyperactivity Disorder
November 1618, 1998
National Institutes of Health
The following is an abstract of the presentation of Peter R. Breggin, M.D. on risks and mechanism of action of stimulants. The abstract is designed for the use of panelists and participants in the conference and as a reference document for anyone interested in the conference deliberations. We are grateful to the author, who has summarized his materials and made them available in a timely fashion.
It is intended that this be a text-only version. Much of the information in the original is in tables which are not reproduced here. E-mail me if you need the tables sent to you. (I can send them as a Microsoft Word 6.0 document.) (A page using both tables and graphics is also available.)
Book by Peter R. Breggin, M.D.: Talking Back to Ritalin
Webmaster's note: This presentation was made before the announcement of results at Stanford showing the efficacy of Ritalin and the brain differences in boys with ADHD - both in function and in the way the brain responds to Ritalin. Breggin's views are considered controversial by many who have studied and worked with ADHD patients.
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Mayes and colleagues (1994) (partially controlled): 18.8 percent lethargy variously described by raters as tired, withdrawn, listless, depressed, dopey, dazed, subdued and inactive; 26.1 percent irritability; 7 percent severe adverse reactions including one manic-like reaction with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
(table omitted from text-only version)
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
* 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
(table omitted from text-only version)
* 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.
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
(omitted from text-only version)
*Considered positive or therapeutic by the source. cct = controlled clinical trial
- Swanson, Cantwell, Lerner, et al. (1992) [confirms many ADRs in list]
- Borcherding, Keysor, Rapoport, et al. (1990) [cct]
- Schiørring (1981)
- Arnold, Jensen (1995)
- Tannock, Schachar, Carr, et al. (1989) [cct]
- Mayes, Crites, Bixler, et al. (1994) [cct]
- Schleifer, Weiss, Cohen, et al. (1975) [cct]
- Dulcan (1994) and Dulcan, Popper (1991) [open trial]
- Rie, Rie, Stewart, et al. (1976) [cct]
- Bradley (1937) [open trial]
- Granger, Whalen, Henker (1993) [cct]
- Solanto, Wender (1989) [cct]
- Cunningham, Barkley (1978) [cct]
- Dyme, Sahakian, Golinko, et al. (1982) [cct]
- Barkley, Karlsson, Pollard, et al. (1985) [cct]
- Cotton, Rothberg (1988) [cct]
- Jacobvitz, Sroufe, Stewart, et al. (1990)
- Davy, Rodgers (1989)
- Schachar, Tannock, Cunningham, et al. (1997) [cct]
- Barkley, McMurray, Edelbrock, et al. (1990) [cct]
- Pelham (1989)
- Sleator, Ullmann, von Neuwman (1982)
- Ellinwood, Tong (1996)
- Handen, Feldman, Gosling, et al. (1991) [cct]
- Fialkov, Hasley (1984)
- Barkley, Cunningham (1979) [cct]
- Whalen, Henker, Granger (1989) [cct]
- Castellanos, Giedd, Elia, et al. (1997) [cct]
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