Psychostimulants in the treatment of children diagnosed with ADHD

62 Pages·1999·1.08 MB·English

InternationalJournalofRisk&SafetyinMedicine12(1999)3–35 3
IOSPress
Psychostimulants in the treatment of children
diagnosed with ADHD: Risks and
(cid:3)
mechanism of action
Peter R.Breggin(cid:3)(cid:3)
Director,International CenterfortheStudyofPsychiatryandPsychology(ICSPP)
Abstract.MillionsofchildreninNorthAmericaarediagnosedwithattentiondeficit/hyperactivitydisorder andtreatedwith
psychostimulants such as methylphenidate, dextroamphetamine, and methamphetamine. These drugs produce a continuum
of central nervous system toxicity that begins with increased energy, hyperalertness, and overfocusing on rote activities. It
progresses toward obsessive/compulsive or perseverative activities, insomnia, agitation, hypomania, mania, and sometimes
seizures.Theyalsocommonly resultinapathy,socialwithdrawal,emotionaldepression, anddocility.Psychostimulantsalso
causephysicalwithdrawal,includingreboundanddependence.Theyinhibitgrowth,andproducevariouscerebraldysfunctions,
someofwhichcanbecomeirreversible.
The“therapeutic”effectsofstimulantsareadirectexpressionof theirtoxicity.Animalandhumanresearchindicatesthat
thesedrugsoftensuppressspontaneousandsocialbehaviorswhilepromotingobsessive/compulsivebehaviors.Theseadverse
drugeffectsmakethepsychostimulantsseeminglyusefulforcontrollingthebehaviorofchildren,especiallyinhighlystructured
environmentsthatdonotattendtotheirgenuineneeds.
1. Introduction
Thediagnosis ofAttention Deficit/Hyperactivity Disorder (ADHD)inchildren, andtheuseofstimu-
lantmedication forbehavioral control, hasbecome verycommoninNorthAmerica, andisspreading to
Europe and Australia. In 1995, the International Narcotics Control Board (INCB) showed concern that
“10 to 12 percent of all boys between the ages of 6 and 14 in the United States have been diagnosed
as having ADD and are being treated with methylphenidate” (p. 2). Recently, the US Drug Enforce-
mentAdministration (DEA)announced aneight-fold increase inproduction quotasformethylphenidate
(MPH) from 1,768 kg in 1990 to 14,442 kg in 1998 (Feussner, 1998). In addition, the use of stimulant
medicationhasfurtherescalatedwiththevigorousmarketingofamphetamines.Noofficialdataareavail-
able,butprobably4–5millionchildrenreceivepsychostimulantsintheUnitedStateseachyear(Breggin,
1998a).
Drawinglargelyondouble-blindplacebo-controlled trials,thisreportexaminesadversedrugreactions
(ADRs) associated with dextroamphetamine (AMPH) (Dexedrine(cid:226) , Adderall(cid:226) ),1 methamphetamine
*ThepresentpaperappearssimultaneouslyinEthicalHumanSciencesandServices,JournaloftheInternationalCenterfor
theStudyofPsychiatryandPsychology,andiscopyrightedbySpringerPublishingCompany,NewYork,NY.
A much shorter, modified version of this paper (Breggin, 1998d, for the abstract) was given as a scientific presentation at
theNationalInstitutesofHealth(1998)ConsensusDevelopmentConferenceonDiagnosisandTreatmentofAttentionDeficit
HyperactivityDisorderandwillbepublishedintheproceedingsofthatconference.
**Correspondence:P.R.Breggin,MD,4628ChestnutStreet,Bethesda,MD20814,USA.
1SincethepresentpaperisdevotedalmostexclusivelytothesituationintheUnitedStates,thetradenamescitedwillbethose
mostcommonlyusedinthatcountry.
0924-6479/99/$8.00(cid:211) 1999–IOSPress.Allrightsreserved
4 P.R.Breggin/PsychostimulantsinthetreatmentofADHD
(M-AMPH) (Desoxyn(cid:226) , Gradumet(cid:226) ), and MPH (Ritalin(cid:226) ). Special attention will be given to ADRs
affecting the central nervous system (CNS).The report also examines the mechanism ofstimulant drug
action. The behavioral or clinical effects of stimulants may be understood as a continuum of CNS tox-
icity. The drugs suppress spontaneous and social behaviors while promoting obsessive/compulsive or
perseverative behaviors. These adverse drug effects make children more manageable in structured or
controlled situations, especially thosethatlacksufficientadultsupervision andattention. Theeffectsare
independent ofanydiagnosable disorder andoccurinentirelynormalanimalsandchildren.
2. Overviewofstimulant-inducedadversedrugreactions(ADR’s)
2.1. Thecontinuum ofpsychostimulant toxicity
Psychostimulants produce a continuum of toxicity based on generalized CNS excitation with direct
effects on various neurotransmitter systems, including dopamine, norepinephrine, and serotonin. The
continuum begins with feelings of increased energy, hyper-alertness, and an intensified focus on rote
activities. Itprogresses towardinsomnia, obsessive/compulsive orperseverative activities, agitation, hy-
pomania,mania,andsometimesseizures.
Other psychostimulant ADRs–such as somnolence, fatigue, lethargy, social withdrawal, and mental
depression – probably result from a combination of direct drug actions and the brain’s compensatory
reactions to these effects. Compensatory reactions became especially apparent during reductions in the
blood concentration ofthedrug during withdrawal or between doses. Rebound isaworsening ofsymp-
toms above baseline as direct drug effects wear off and compensatory CNS reactions become more
dominant.
Table1summarizestheADRscausedbyMPHandAMPHascompiledfromseveralwell-recognized
sources. In addition to familiar psychiatric ADRs such as nervousness, irritability, anxiety, depression,
and increased emotional sensitivity or easy crying, there are infrequently emphasized ADRs such as
impairedcognitiveperformance, compulsions, decreased socialinterest,and,intheextreme,a“zombie-
like” constriction of affect and spontaneity mentioned by name and described by Arnold and Jensen
(1995), Swanson,Cantwell,Lerner,McBurnett, Pfiffneretal.(1992), andFialkovandHasley(1984).
3. ADRsineightdouble-blindplacebo-controlled clinicaltrials
The eight studies listed in Table 2 were double-blind and (with one partial exception) placebo-
controlled, and were selected because they are relatively recent and make an attempt to evaluate ADRs
(Table2).
3.1. OnerecentstudyofADRsinpre-school children
Firestone,Musten,Pisterman,Mercer,andBennett(1998)foundstatisticallysignificantMPH-induced
ADRsinyoungerchildrenacrosstreatmentconditions onthebroadcategories of“SomaticComplaints”
and “Sociability”, including inhibition or suppression of behavior such as Sad/unhappy, Drowsiness,
Talks less with others, and Uninterested in others, as well as Nightmares, and Decreased appetite. Ob-
sessive/compulsive ADRswerenotincludedinthelistofpotential ADRs.
P.R.Breggin/PsychostimulantsinthetreatmentofADHD 5
Table1
Summaryofadversedrugreactions(ADRs)causedbymethylphenidateandamphetamines
Cardio- Centralnervoussystem Gastro- Endocrine/ Other Withdrawal
vascular intestinal metabolic andrebound
Palpitations Psychosiswithhallucinations Anorexia Pituitary Blurredvision Insomnia
Tachycardia (skincrawlingorvisions) Nausea dysfunction, Headache Eveningcrash
Hypertension [psychoticdepressionand Vomiting including Dizziness Depression
Arrythmias mania] Stomach growth Hypersensitivity Overactivity
Chestpain Excessivebrainstimulation ache, hormoneand reactionwith and
[Cardiacarrest] [convulsions] cramps prolactin rash, irritability
Drowsiness,“dopey”,lessalert Drymouth disruption conjunctivitis, Rebound
Confusion Constipation Weightloss orhives worsening
Insomnia [Abnormal Growth [Hairloss]*** ofADHD-
Agitation,anxiety,irritability, liver suppression Exfoliative like
nervousness function Growth dermatitis*** symptoms
[Hostility] tests] retardation Anemia***
Dysphoria Badtaste**** Disturbedsexual Leukopenia***
Impairedcognitivetest Diarrhea**** function**** Enuresis***
performance Fever***
Dyskinesias,tics,Tourette’s (unexplained)
Nervoushabits(e.g.,picking Jointpain***
atskin,pullinghair) Unusual
Stereotypyandcompulsions sweating***
Depression,emotional
oversensitivity,easycrying
Decreasedsocialinterest
Zombielikeconstrictionof
affectandspontaneity*
Amphetaminelook(pinched,
somberexpression)**
Note:DatadrawnfromArnoldandJensen(1995,Table38-5,p.2306),DrugEnforcementAdministration(1995,p.23),Dulcan
(1994, Table 35-6, p. 1217), and Maxman and Ward(1995, pp. 365–6). Additional material taken from the Food and Drug
Administration(1997,March)andindicatedbybrackets.*ArnoldandJensen(1995,Table38-5,p.2306,Table38-7,p.2307,
andcolumn2,p.2307).**ArnoldandJensen(1995).***Formethylphenidateonly.****Fordextroamphetamineonly.
Incomparing placebo tothehigher dosethere werestriking findings inregardtoADRsthatsuppress
behavior: “Talks less with others” increased from 21.9 to 50% with a rise in severe cases from 3.1
to 9.4%; “Uninterested in others” increased from 31.2 to 75% with a rise in severe cases from 0 to
12.5%;“Sad/unhappy”rosefrom47to84%withariseinseverecasesfrom9to19%;and“Drowsiness”
increased from12.5to66%withariseinseverecasesfrom3.1to15.6%.“Nightmares” increased from
28 to 62% with an increase in severity from 0 to 6%. “Tics or nervous movements” increased from 3.1
to12.5%withariseinseverecasesfrom0to3.3%.
Theauthorsalsomadeaseparatecalculationofthepercentageofchildrenwho“deteriorated”inregard
to various symptoms when comparing the 0.5 mg/kg dose to placebo: Sad/unhappy – 69% (p = 0.01);
Drowsiness – 62% (p = 0.001); Uninterested in others – 62% (p = 0.0002). In addition, there was a
deterioration ofappetitein75%(p = 0.001)ofthechildren on0.5mg/kgcomparedtoplacebo.
Fourof41children(10%)withdrewfromtreatment(reasonsunspecifiedinreport). Asaconservative
estimate,atleast4children hadsevereADRs.
Table2
6
Methylphenidate(MPH)andD-amphetamine(AMPH)adversedrugreactions(ADRs)in8double-blindplacebo-controlledstudiesofchildrendiagnosedwith
ADHD
Study Group* Dosemg/kg Duration SalientADRs
1.Firestoneetal. 41,age4–6 MPH0.3and0.5BID 7–10days Markeddeteriorationfromplaceboto0.5mginSad/unhappy(69%of
(1998) children),Drowsiness(62%),Uninterestedinothers(62%).Lossofap-
petite in 75%. Severe symptoms increased 12% for “Uninterested in
others”(0–12%)and28%for“Talkslesswithothers”(22–50%).Night-
maresincreased35%(28–62%);ticsornervousmovementsincreased
9%(3to12%).
2.Mayesetal. 69,age2–13 MPH most commonly mean8 6 discontinued because of ADRs. 13 “significantly worse” on drug.
(1994)** 0.3TID days 5.8% increase or emergence of “stereotypical behaviors, including P
.R
hand-wringing, arm-waving, teeth-grinding and foot-tapping”. 7% se- .
B
verereactionswithonemanic-like.18.8%experiencelethargy:“Chil- r
e
dren with lethargy were variously described by raters as tired, with- gg
drawn, listless, depressed, dopey, dazed, subdued and inactive”. 26% in
/
“irritability”. P
s
3.Barkleyetal. 83,age5–13 MPH0.3and0.5BID 14–20days Decreasedappetite,insomnia,stomachaches,andheadaches.Proneness y
c
(1990) tocryingincreasedatleast10%duringlowdose.Tics/nervousmove- ho
s
mentsincreased10%atthehighdose.Decreasedappetiteandinsomnia tim
“serious” in13%and 18% atboth dosescompared to1% and7% on u
placebo.3.6%droppedoutdueto“serious”ADRs.Onecaseof“exces- la
n
sivespeechanddisjointedthinking”. ts
4.Schacharetal. 46,age6–12 MPHapproximately 4months >10%dropout duetoADRs,3dueto“sadness andbehavioral dete- in
(1997) 0.5–0.6BID rioration, irritability, withdrawal, lethargy, violent behavior, or rash”; the
1dueto“withdrawalandmildmania”;1dueto“withdrawalanddys- tr
e
phoria”.45%experiencedanincreaseinatleast1ADR(p<0.005).In- atm
creasedseverityofaffectiveADRs(mostlywithdrawal,sadness,crying) e
n
(p<0.01).IncreasedseverityofphysiologicalADRs(mostlyanorexia t
o
andstomachaches)(p<0.005). f
A
5.Gillbergetal. 62,age6–11 AMPHvaryingdoses 4–15 3casesofhallucination,1withseveretics.32%abdominalpainocca- D
H
(1997) months sionallyoroften.56%poorappetite. D
6.Borcherding 46boys,age6– Average weekly dose: 3weeks StudiedcompulsiveandticADRs.58%developabnormalmovements.
etal.(1990) 12 MPH 0.5, 0.8, and 1.3 51%developobsessive/compulsiveorperseverativeADRs.1persistent
BID. AMPH 0.2, 0.5, tic.ManysevereOCDADRs.SeeTable3.
and0.7BID
7.Solantoand 19,age6–10 MPH 0.3, 0.6 and 1.0 3separate Studiedcognitivefunctions.42%“overaroused”with“cognitiveperse-
Wender(1989) QD days veration”(overfocused,OCDreaction).
8.Castellanosetal. 20,age6–13; AMPHmeans0.2, 3weeks 25%developobsessiveADRsonMPH.3stoppedmedicationatcom-
(1997) allcomorbid 0.41, 0.64 BID. MPH pletionduetoincreasedtics.Onethirdexperiencedworsenedtics.
forTourette’s means 0.43, 0.67, and
1.20BID
Note:QD=oncedaily;BID=2(cid:2)daily;TID=3(cid:2)daily;*Placebosubjectswerenotincludedintotals;**Onlythepreschoolersweredouble-blind placebo-
controlled.
P.R.Breggin/PsychostimulantsinthetreatmentofADHD 7
Theauthors raised thepossibility that observers might unintentionally consider thesocial dampening
ADRs as improvements in the children’s behaviors. However, they also noted: “This social dampening
effectreportedbyparentsisofsomeconcern,especiallyconsideringclaimsthatmethylphenidateisused
as a ‘chemical billy club’ or ‘straightjacket’” (p. 20). These findings, indicating severe ADRs among
veryyoungchildren,areconsistentwithanearlierstudybySchleifer,Weiss,Cohen,Elman,Crejicetal.
(1975) who reported “less social behavior and interaction”, as well as “sadness, irritability, excessive
hugging andclinging, andincreased solitary play, aswellasthemoreusualsideeffectsofpoorappetite
anddifficulty getting tosleep:::”(p.49). Thetreating physician andthe parents discontinued treatment
in25of28children becauseofADRs.
3.2. Fourrecentstudies thatevaluateaspectrum ofpsychiatric ADRs
Mayes, Crites, Bixler, Humphrey, and Mattison (1994) conducted double-blind placebo-controlled
MPH trials involving preschoolers but trials involving older children were single blind. There was a
substantial rateofbehavior-suppressing ADRs:18.8%ofthechildren suffered from lethargy. “Children
with lethargy were variously described by raters as tired, withdrawn, listless, depressed, dopey, dazed,
subduedandinactive”(p.1104).In5.8%therewasanincreaseoremergenceof“stereotypicalbehaviors,
includinghand-wringing,arm-waving,teeth-grindingandfoot-tapping”(p.1104).Obsessive-compulsive
activities (stereotypy) werealsoobserved.
Mayesetal.reportedthat26.1%ofthechildrensufferedfrom“irritability”duringtreatment.Fivechil-
dren (7%) displayed disturbing ADRs, including one manic-like reaction with “incessant talking”, one
“wild” and “out of control”, and one “aggressive behavior” (p. 1105). Twoof these fivealso developed
abnormalmovements.Mayesetal.alsodescribedmoretypicalMPHadverseeffects,includinginsomnia
(13%);stomachache, nauseaorvomiting(11.6%);lossofappetite(20.3%);andheadache (4.3%).
Allowing for overlapping reports of morethan one ADRper child in study, probably more than 50%
of the children suffered from lethargy and other adverse CNS reactions. Six were discontinued due to
ADRsandthatnumberwillbeusedtomakeaconservative estimateofsevereADRs.
Schachar,Tannock,CunninghamandCorkum(1997)foundthat5of46children(>10%)droppedout
due to ADRs in a 24-week long MPH study. These 5 children will be used to calculate the number of
severe ADRs. Their drug-induced symptoms included behavioral aberrations such as “sadness and be-
havioraldeterioration,irritability, withdrawal,lethargy,violentbehavior”,“withdrawalandmildmania”,
and “withdrawal and dysphoria” (p. 760). Parental ratings by phone indicated a statistically significant
overallincreaseinphysiologicalsymptoms(commonly,anorexiaandstomachaches)andaffectivesymp-
toms(commonly, withdrawal,sadness, andcrying).
Theauthorsconcluded,“AffectivesymptomsweresignificantlyassociatedwithMPH,buttheytended
todevelop laterinthecourse oftreatment” (p.761). Thesedelayed ADRswillbemissed intypical drug
studieswhichlastonlyafewweeks.
Barkley, McMurray, Edelbrock, and Robbins (1990) studied ADRs associated with MPH by using a
predeterminedlistof17potentialADRs.Thelistdidnotincludeobsessive/compulsive andperseverative
symptoms. There were significant differences between MPH and placebo in decreased appetite, insom-
nia, stomachaches (all p < 0.01), and headaches (p < 0.05). The first two were rated as “serious” in
13%and18%ofchildren onthetwoMPHdosescomparedto1%and7%onplacebo.
Barkley et al. also found that “the percentage of children experiencing proneness to crying also in-
creased by at least 10% during the low-dose condition” (p < 0.05) and that “the percentage reporting
tics/nervous movements increased by10% atthehigh dose ofmedication” (p < 0.05) (p. 187). Finally,
8 P.R.Breggin/PsychostimulantsinthetreatmentofADHD
Barkley et al. reported that three children (3.6%) “were unable to complete the protocol because of se-
rious adverse reactions to medication::: One child had a nervous facial tic, dizziness, and headache;
a second had dizziness, headache, and increased hyperactivity; and the third had excessive speech and
disjointed thinking” (p. 186). Even in this brief, relatively low dose study, one child developed manic-
likesymptomswith“excessivespeechanddisjointedthinking”.Againchoosingarelativelyconservative
estimate,Barkleyetal.studyhadthreechildren withsevereADRs.
Gillberg, Melander, von Knorring, Janols, Thernlund et al. (1997) reported that three children devel-
opedhallucinations onroutinedosesofAMPH.Twosubsidedondiscontinuation ofthedrugandoneon
reduction. The total number of subjects in the pool is unclear but did not exceed 62 (minimum rate of
4.8%).Overall,thestudydoesnotappeartobewell-focused onADRs.
3.3. Threestudiesthatfocusonobsessive/compulsive ADRs
Borcherding, Keysor, Rapoport, Elia, and Amass (1990) focused on perseverative, obsessive-
compulsive or overfocused ADRs (for details, see Table 3). The treatment included both MPH and
AMPH. Observations were made on the day hospital ward, in school, and by the families. This close
scrutiny probably accounts for the “extraordinarily high rate of obsessive-compulsive behaviors, move-
ment abnormalities, or both” (p. 92). Most of these ADRs “were seen only by staff sensitive to these
possible effects”(p.92).
Borcherdingetal.foundastrongconnectionbetweenabnormalmovementsandobsessive/compulsive
behaviors in association with MPH (p = 0.009). Tics, overfocusing, and other compulsive behaviors
were observed in 34 (76%) of the 45 participants who completed the study, plus one subject with se-
vere tics who was dropped. Abnormal movements were observed in 26 of 45 children (58%). Obses-
sive/compulsive or perseverative ADRs (summarized in Table 3) were observed in 23 of 45 children
(51%).Theauthorsreported,“Whencomparedtoplacebo,bothdrugsincreasedthelikelihood(p < 0.01)
ofrepetitious, perfectionistic, overfocused behaviors” (p.90).Ofthese23children, 14(60.8%)suffered
one or more of the following abnormal movements: orofacial, stereotypy, or other tics. Twelve of the
23 had orofacial tics and 6 had stereotypy, including 4 who had both. At least three children developed
severe drug-induced obsessive/compulsive symptoms (one on MPH, two on AMPH), including a child
whoplayedLegosfora36-hourperiod withoutbreaking toeatorsleepandanother who“became com-
pulsiveaboutrakingleavesanddidsofor7consecutive hours,afterwhichhestillfeltcompelledtorake
individual leavesastheyfell”(p.87).
One child had to stop the trial “due to both the severity of the tic he developed during his initial
treatmentphase(AMPH)andexacerbatedsymptomsofseparation anxiety.Thischildalsolost2pounds
during treatment” (p. 85). Atone point thetics “increased tooccur over10 timesperhour” (p. 87). The
ticsdidnotfullyclear.Conservatively, atleast4children inthistrialhadsevereADRs.
SolantoandWender (1989) studied cognitive function usingonedaily doseofMPHfor3days. They
found that 42%ofthechildren became “overaroused” with“cognitive perseveration”. Compulsive, per-
severativebehaviorsthusbeginwiththefirstdosesofstimulantmedication,accountingforitsimmediate
“therapeutic” effect.
Castellanos, Giedd, Elia,Marsh, Ritchieetal.(1997) studied theeffects ofAMPHandMPHonchil-
drencomorbidforADHDandTourette’ssyndrome.Whiletheinvestigatorsfocusedonticsratherthanon
perseverative/obsessive ADRs, they reported: “Largely transient obsessive-compulsive symptoms were
also noted (n = 5onMPH,1on AMPH)including retracing letters, excessive erasing, rearranging and
collectingcompulsions,andobsessionalsexualthoughts”(p.593).TherateofobsessiveADRsforMPH
was25%during athree-weekexposure.
P.R.Breggin/PsychostimulantsinthetreatmentofADHD 9
Table3
Obsessive-compulsive adversedrugreactionsin23of45hyperactiveboys treatedwithmethylphenidate (MPH)anddextro-
amphetamine(AMPH)
Subject Age Perseverative/compulsivebehaviors
MPH AMPH
1 6 Perseverative drawing and writing at home; counting puzzle
pieces
2 6 PerseverativeplaywithLegosandpuzzles
3 6 Perseverativeplayingofpiano
4 6 Perseverativespeech
5 7 Rewriting work; overerasing; repetitive checking of work;
overlyneatandorganizedathome
6 7 Rewritingwork Compulsivelyliningupcrayons
7 8 Overlydetailoriented
8 8 Coloringoverandoverthesamearea Repetitivecheckingofwork;franticallygoal-directed;solitary
activities
9 8 Perseverativeplayingofvideogames Cleaningroomcompulsively;buttoningandthenfoldingdirty
laundry
10 8 Repetitivecheckingofwork:perseverativewithworkinschool
11 8 Overerasing;redrawing;excessive Overerasing
pressureonpencil
12 8 Markedlydetailorientedindrawings
13 9 Overerasing;makinglists(TVshows,modelcars)
14 9 Cleaningroomcompulsively;overlyorderlyathome
15 9 Perseverativeatschool
16 9 Overerasing;rewriting;excessive Overlymeticulous;inabilitytoterminateschoolandplayactiv-
pressureonpencilandcrayons; ities;perseverativespeech
perseverativespeech
17 9 Inabilitytoterminateschoolandplay
activities;repetitiveerasingandredo-
ingprojects;overlydetailoriented
18 10 Cleaningroomcompulsively;foldingdirtylaundry
19 10 Repetitivecheckingbehavior;liningthingsup;excessivepres-
sureonpencil;repetitiveerasingandrewriting
20 11 Overly meticulous work; overly neat and organized; cleaning
roomcompulsively;rakingleavesastheyfallindividually
21 11 Liningupcrayons;repetitiveerasingandredrawing
22 11 Repetitiveerasing;“perfectionist”;
excessivepressureonpencil
23 12 Overlydetailoriented;excessivepressureonpencilandcrayons
Note:AdaptedfromBorcherdingetal.(1990,pp.88–89).
Castellanos et al. (1997) reported that one child on AMPH dropped out due to vomiting and another
due to worsened behavior. Three more had “greater tic severity scores on all doses of both stimulants
than at baseline” and were discontinued from stimulants at the conclusion of the study. This leads to a
conservative estimateof5severeADRs.
Stimulant-induced obsessions and compulsions havebeen reported aslongas4years afterthe begin-
ningofdrugtreatment (Kouris,1998). Therefore, eventhehighratesfound inthesestudies arelikely to
underestimate theseADRsforlong-term treatment.
10 P.R.Breggin/PsychostimulantsinthetreatmentofADHD
3.4. Stimulant-induced abnormalmovements
Firestoneetal.foundanincreasein“Ticsornervousmovements”from3.1%onplaceboto12.5%on
0.5mg/kgMPH,withanincreaseinseverecasesfrom0%onplaceboto3.1%on0.5mg/kg.Borcherding
et al. (1990), as noted, reported the appearance of abnormal movements in approximately 58% of their
children, including one seemingly irreversible case. Barkley et al. (1990) found a 10% increase in tics
in children treated with the higher dose ofMPH.With both MPH and AMPH,Castellanos et al. (1997)
found a dose-dependent worsening of tics in a “substantial minority” of patients comorbid for ADHD
andTourette’s syndrome. Asalready noted,threediscontinued medication attheconclusion ofthetrials
due to increased tic severity on both MPH and Amph. They observed, “a substantial proportion of our
smallsample(onethird)continuedtohavestimulant-associated exacerbationsoftheirticdisorderwhich
outweighed theclinicalbenefitsofstimulants” (p.594).
Lipkin, Goldstein and Adesman (1994) (not 1 of the 8 controlled trials) found a 9% rate of abnor-
mal movements in a retrospective evaluation of 122 children diagnosed with ADHD currently or re-
cently treated with stimulants. One child developed a very severe and irreversible Tourette’s syndrome
involving “facial twitching, head turning, lip smacking, forehead wiping, and vocalizations”. Other
tics and dyskinesias found in the study included mouth movements; eye blinking, rolling, or devia-
tion; throat clearing or vocalizations; eye “bugging”; neck turning; and face rubbing. Five of the chil-
dren had more than one type of dyskinesia. There were no differences in rates on MPH and AMPH.
Children developed the tics or dyskinesias with drug exposures varying from less than 1 week to 23
months.
Schmidt, Kruesi, Elia, Borcherding, Elin et al. (1994) recorded changes in calcium and magnesium
concentrations in the blood during treatment with MPHand AMPHthat they believe may contribute to
theabnormalmovements.
Ticscanbestigmatizing, embarrassing, andevendisfiguring.Manychildrenwouldprobablypreferto
sufferfrom“ADHD-like”symptomsratherthanenduretics.
3.5. Summaryoffindings inclinical trials
Eventhoughmostoftheseclinicaltrialswereshort-term andlowdose(Table2),manyseriousADRs
werereported.2ThetotalestimatednumberofsevereADRsis30outof359children(8%).Usingbroader
criteria, theraterisestoprobably between10–20%.
If clinically observable, potentially significant ADRs are included, the rate is much higher, in the
20–50% (or more) range. For example, in the three studies that examined obsessive/compulsive ADRs
(includingoverfocusingorperseveration), theseADRswereextraordinarily common–25,42,and51%,
respectively, forCastellanos etal.(1997), Borcherding etal.(1990)andSolantoandWender(1989).
Despite such high rates for serious, severe ADRs,the rates and severity ofADRsshould be expected
tobemuchhigherunder routineclinical conditions. Theseconditions include muchlongerexposures to
stimulants (months orevenyears instead ofthe1–3 weeksinmostofthecontrolled trials), often higher
doses (morethanthe0.3–0.6 mg/kgMPHinmostofthecontrolled trials), polypharmacy, lessadequate
medical evaluations and supervision, and parents and teachers who are not educated to identify ADRs
andtoterminatetreatment beforetheyworsen.
2SolantoandWender(1989)arenotincludedsincethechildrenreceivedonlyonedoseperdayforthreedaysandoverall
ADRswerenotlisted.
P.R.Breggin/PsychostimulantsinthetreatmentofADHD 11
3.6. Lessonsfromstimulant-induced psychosis
Many studies have compared stimulant-induced psychoses to the symptoms of schizophrenia
(Ellinwood and Tong, 1996; Murray, 1998; Rebec and Bashore, 1984; Segal, Weinberger, Cahill, and
McCunney, 1980). MPH is used experimentally to produce or worsen psychotic symptoms in adults
diagnosed schizophrenic (Koreen, Lieberman, Alvir, and Chakos, 1997; Lieberman, Kane, and Alvir,
1987). Stimulant abuse isalso knowntocause adisorder that mayremain chronic andbecome indistin-
guishable fromschizophrenia (FlaumandSchultz,1996).
3.7. Effectsofselectiveserotonin reuptakeinhibitors (SSRI’s)inchildren
Psychoactive drugs will probably tend to produce mental disorders, including psychosis, at a higher
rateinchildrenthanadults.Forexample,therateformania/hypomaniainducedbytheSSRI-typeantide-
pressant fluoxetine (Prozac) inall USclinical trials with adults was0.7% (Physicians’ DeskReference,
1998,p.860).Inmanyoftheshortplacebo-controlled clinicaltrials,itwasevenless(rangeof0–0.8%).
However, in a recent placebo-controlled clinical trial of fluoxetine in children and adolescents (Emslie,
Rush, Weinberg, Kowatch, Hughes et al., 1997), three out of 48 children dropped out due to “manic
symptoms”(6.2%).
King, Riddle, Chappell, Hardin, Anderson etal. (1991) described the “Emergence of self-destructive
phenomena in children and adolescents, ages 10 to 17, during fluoxetine treatment”. They found “self-
injurious ideationorbehavior appeareddenovoorintensified”in6of47patientsbeingtreatedwithflu-
oxetine for obsessive-compulsive disorder. Fourofthe cases required hospitalization and three required
“restraints, seclusion, or one-to-one nursing care”. Riddle, King, Hardin, Scahill, Ortet al., 1990/1991)
foundthat12of24childrenandadolescents,ages8to16,developedtwoormorebehavioralsideeffects
inreactiontofluoxetine.Mostoftheyoungsterswerebeingtreatedforobsessivecompulsivesymptoms.
The drug-induced effects included motor restlessness sufficient to cause concern to parents or teach-
ers, insomnia, social disinhibition manifested by garrulousness or subtle impulsivity, and a subjective
sense of discomfort due to restlessness, agitation, or excessive energy. The group included three chil-
dren with attention deficit-hyperactivity disorder (ADHD), all of whom became worse. The behavioral
abnormalities remained stable for weeks until the fluoxetine was reduced or stopped, and were easily
confused with the children’s original emotional problems. The seven children on placebo developed no
sucheffects.
4. ADRReportsfromtheFDASpontaneousReportingSystem3
A review of the 2,821 reports of adverse drug events to the Spontaneous Reporting System for MPH
(1985–March 3, 1997) revealed some potential often ignored ADRs (Food and Drug Administration,
1997). Here are some highlights (analyzed by Breggin, 1998b; methodology of analysis discussed in
Breggin,1998c;Kessler,1993;Leber,1992):
3TheFDAlistscriteriathatcanbeusedfor“assessing”the“causalrelationship”betweenadrugandadversedrugeventsthat
arereportedtooccurinassociationwithit(FoodandDrugAdministration,1996, p.6;Breggin,1997, 1998c). Spontaneous
reports sent to the agency play a major role in driving FDAdecisions concerning medications, including removal from the
marketplace(GeneralAccountingOffice,1990).Clinicaltrialsaretypicallytoosmall,toobrief,toonarrowinpopulation,and
often too biased toward positive medication effects to demonstrate relatively common but serious adverse effects (Breggin,
1997,1998c;Leber,1992).
12 P.R.Breggin/PsychostimulantsinthetreatmentofADHD
(1) More than 150 reports of liver abnormalities, mostly abnormal liver function tests. This signal
becomes especially important in the light of recent disclosures of liver tumors in mice (Dunnick
andHailey,1995;NationalToxicology Program,1995).
(2) Sixty-nine reports of convulsions, including 18specified asgrand mal. Theconvulsive properties
ofstimulantsareimportantbutseldom mentionedinreviews.
(3) Eighty-seven reportsofdrugdependency andaddiction, and30reportsofdrugwithdrawal.
(4) Twohundredfiftyreportsofhairloss.
(5) Morethan50reportsofleukopenia (abnormally lowwhitebloodcellcount).
(6) Hundreds of psychiatric ADRs, including agitation (55), hostility (50), depression (48) and psy-
choticdepression(11),abnormalthinking(44),hallucinations (43),psychosis(38),andemotional
lability (33). There were more than 50 reports in the combined categories of overdose, overdose
intentional, andsuicideattempt.
5. Cardiovascularproblemsassociated withMPH
Ellinwood and Tong (1996) summarized case reports of arrhythmias, shock, and cardiac muscle
pathology (p. 20). The FDA’s (1997) Spontaneous Reporting System collected 121 reports of cardio-
vascular problems (excluding hypertension). Most were arrhythmias and conduction problems, as well
as9cardiacarrestsand4heartfailures.
AMPH, M-AMPH, and MPH are known to overstimulate the sympathetic nervous system. Several
studieshavenowconfirmedthattheyhaveadirectcardiotoxic effect(Karch,1996,pp.213–215).
Inan electronmicroscopy study of mice and rats, Henderson and Fischer (1994) found that MPHhas
cardiotoxic effects in “minimum dosages (7.5 mg/kg/week in mice, 6.0 mg/kg/week in rats)” that “fell
within the range of therapeutic dosage prescribed for patients with attention deficit disorder” (p. 77).
Changes first appeared as early as 3 weeks and worsened over 14 weeks. Pathology (including various
membraneabnormalities)wasstillapparentinthemyocardium12weeksafterterminatingtheinjections.
The injections produced similar results to those found by the authors in unpublished data of oral doses
in animals. Henderson and Fisher believe that humans treated with routine clinical doses are at-risk for
thedevelopmentofcardiacpathology.
Ishiguro and Morgan (1997) in a study of ferret papillary (ventricular) muscles found that MPH at
concentrations consistent withclinical usageproduces anegativeeffectonmusclecontractibility (direct
negativeinotropic effectorNIEs).
Psychostimulants also raisetheblood pressure ofchildren, adding further stress tothecardiovascular
system.Inadults, elevatedbloodpressure isconsidered amajorhealthriskforstrokeandheartattack.
African American youngsters are at higher risk for adult hypertensive disorders, including life-
threatening kidney failure. Brown and Sexson (1988) conducted a placebo-controlled study of 11 black
maleadolescent boystaking 6weeksofMPH(0.15,0.30, and0.5mg/kg). Theyfound asignificant rise
in blood pressure (placebo mean, 69 diastolic; drug mean, 83 at the higher doses). They recommended
closermonitoring ofthebloodpressureofadolescent boys.
6. Stimulant-inducedrebound,withdrawal,anddependence
According toFeussner(1998) oftheU.S.DrugEnforcementAdministration, “Anextensive scientific
literature spanning more than 30 years of research unequivocally indicates that MPH has a high abuse