ORIGINAL CONTRIBUTION

The Safety and Effectiveness of High-Dose Propranolol as a

Treatment for Challenging Behaviors in Individuals With
Autism Spectrum Disorders
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Eric B. London, MD,* J. Helen Yoo, PhD,* Eric D. Fethke, MD,† and Barbie Zimmerman-Bier, MD‡

and mode of communication, and social interest and awareness,

Abstract: with particular consideration for the behaviors that may impede
Purpose/Background: Individuals with autism spectrum disorders pres- daily life.
ent with social communication deficits and a rigid adherence to sameness. The core symptoms of ASD comprise social communication
Along with these symptoms, many individuals also present with severe chal- deficits and rigid adherence to routines and repetitive behaviors.
lenging behaviors that place themselves as well as their families and Despite advances in early diagnosis and behavior intervention,
communities at risk for injury. For these individuals, new and effective there is no Food and Drug Administration (FDA)-approved med-
treatments are acutely needed. Propranolol has been used worldwide for ication specifically targeting these symptoms to date. Several
over 50 years. Its primary indication is for hypertension, but there is evi- pharmacological studies targeting the core symptoms of ASD
dence that, at higher doses, propranolol inhibits rage and anger through have been conducted using oxytocin, with no significant change,4
its effects on the central nervous system. This effect has been demonstrated whereas repeated transcranial magnetic stimulation (rTMS) had a
in a variety of neuropsychiatric disorders. moderate effect on social behavior, repetitive behaviors, and accu-
Methods/Procedures: Here, we present 46 retrospective analyses of racy in executive function tasks.5
clinical cases that were followed by a psychiatrist. Propranolol was pre- In addition to social deficits and stereotyped behaviors, many
scribed as an add-on to the patients' existing medications. The doses ranged individuals with ASD also present with comorbid behavioral symp-
from 120 to 960 mg per day (mean = 462 mg). toms, including tantrums, aggression, self-injury, hyperactivity, anxi-
Findings/Results: Thirty-nine (85%) of 46 patients were found to be ety, and rapid changes in mood, among others.6 These symptoms,
much improved or very much improved on the physician-rated Clinical especially the most severe among them—aggression and self-
Global Impression Improvement scale. There were few side effects noted, injurious behaviors (SIB)—are often the chief complaint of par-
with only 2 subjects unable to tolerate the propranolol. ents and educators and at times far outweigh the core symptoms
Implications/Conclusions: It appears that high-dose propranolol can as problems.7–9 The prevalence of these symptoms in ASD cases
be given safely with minimal adverse cardiovascular problems, provided varies according to the patient samples studied, however, with re-
that close clinical monitoring is maintained. A more rigorous clinical trial ports as high as 68%.7,10 Presently, the treatments for these symp-
is needed to elucidate and verify its clinical utility, clinical practice param- toms continue to yield only partial benefits for many.
eters, and the effects of propranolol as a monotherapy versus as an add-on Two antipsychotic medications, risperidone and aripiprazole,
to the patient's existing medication regimen. are the only FDA-approved (in the United States) medications for
Key Words: propranolol, autism, challenging behaviors the treatment of ASD, and more specifically, for the “irritability
associated with ASD” (tantrums, aggression, and self-injury). Al-
(J Clin Psychopharmacol 2020;40: 122–129)
though they are very successful for some, their efficacy is far from
optimal, with 1 study showing that 40% of the sampled individ-
T he autism spectrum disorders (ASDs) are a heterogeneous
group of neurodevelopmental disorders with multiple etiolo-
gies, pathophysiologies, and behavioral presentations.1,2 This sug-
uals were resistant to all pharmacotherapy.11 Furthermore, these
medications are associated with many adverse side effects, mak-
ing their long-term use problematic.12 The need for improved
gests that any unitary treatment for the disorder is unlikely. Rather,
treatments for these symptoms is acute.
optimal management of the symptoms, especially the severe
Behavior-analytic interventions for challenging behaviors have
symptoms, would require combining components of effective be-
been successfully used for many years. Behavior-analytic methods
havioral and pharmacologic interventions into a multimodal pack-
are based on cause–effect relationships, and the treatment is accom-
age.3 Moreover, such a multimodal treatment package requires
plished by altering the environmental component of the relation-
individualization based on the patient's clinical symptoms and charac-
ship.13 The success of applied behavior analysis has been well
teristics, such as age (due to increased body size and strength, some
documented in the literature.14,15 In fact, failure to use individual-
behavioral treatments become difficult or impossible), level
ized behavior intervention may lead to needless delays in imple-
menting effective treatment procedures,15 countertherapeutic
From the *Department of Psychology, New York State Institute for Basic Re-
search, Staten Island; †Pediatric Cardiology, Boston Children's Health Physi-
outcomes from arbitrarily selected interventions, or unnecessary,
cians, Middletown, NY; and ‡Department of Pediatrics, Rutgers University, sometimes aversive, procedures,16 including the use of physical
New Brunswick, NJ. force, takedowns, and 4-point restraint.17
Received April 23, 2019; accepted after revision October 18, 2019. Perhaps, the main barrier to using behavioral methods is the
Reprints: Eric B. London, MD, Department of Psychology, New York State
Institute for Basic Research, 1050 Forest Hill Road, Staten Island, NY
limitation caused by the inadequate number of behavior analysts
10314 (e‐mail: [email protected]). with the knowledge and ability to implement function-based strat-
Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. This egies, as well as the cost associated with intensive intervention.
is an open access article distributed under the Creative Commons Attribution Even if the service delivery systems are optimal, there are limita-
License 4.0 (CCBY), which permits unrestricted use, distribution, and repro-
duction in any medium, provided the original work is properly cited.
tions to using behavioral methods alone. In individuals who en-
ISSN: 0271-0749 gage in SIB, 25% of the behaviors were found to be maintained
DOI: 10.1097/JCP.0000000000001175 by “automatic reinforcement.” In other words, the behavior was

122 www.psychopharmacology.com Journal of Clinical Psychopharmacology • Volume 40, Number 2, March/April 2020
 Journal of Clinical Psychopharmacology • Volume 40, Number 2, March/April 2020 Safety and Effectiveness of High-Dose Propranolol

not in response to any demonstrable environmental variable.18 In- METHODS

stead, automatically reinforced, sensory-maintained behaviors are
thought to be self-reinforcing, and therefore internal biologic mech- Participants
anisms are likely to be driving the behavior.19 Because a challeng-
We report on a retrospective chart review of 46 cases, which
ing behavior may also serve multiple functions, the behavior may
were treated by 1 physician (first author) over approximately
be facilitated, at least in part, by the biologic underpinnings of that
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10 years. The inclusion criteria for being reported in this series

individual,20 implying that combination of treatments would be
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are: (1) a clinically based DSM-IV diagnosis of ASD; (2) a chief

synergistic (ie, potentiation) and, therefore, superior.21
complaint to the psychiatrist of either aggression, SIB, or severely
Broader public health issues also need to be considered.
disruptive behaviors; (3) based on these challenging behaviors, the
There are frequent emergency psychiatric hospitalizations in this
patient had a Clinical Global Impression Severity scale (CGI-S)
population, with 10.8% of children with ASD having had a hospi-
score of 6 or 7; 4) a previous trial and failure with at least 1 anti-
talization, most commonly for SIB or aggression.22 Medicaid ex-
psychotic medication (although the vast majority of cases had
penditures are 10 times higher for those diagnosed with ASD than
been tried on many psychotropic medications); and (5) clinical
for other children, and the difference is largely attributable to inpa-
follow-up, which allowed for dose titration to optimize the dose
tient psychiatric care.23 As the children age, the expenditure for
(up to 960 mg per day) based on response to medication. Patients
these behavioral challenges increases, and there is a concomitant
whose medication was terminated at the discretion of the treating
decrease in the expenditure for other services which are more con-
physician or the consenting guardian due to adverse effects or lack
sistent with medical home aspirations and life skills.23,24 There-
of efficacy were included in the study.
fore, a relatively substantial portion of the resources devoted to
Exclusion criteria included cases (1) which were lost to
ASD goes to the management of those with severe symptoms at
follow-up and (2) in which the medication was terminated due
the expense of other less emergent but necessary goals.
to withdrawal of parent or guardian's consent before achieving a
In the literature, large, well-designed studies for the chronic
therapeutic dose. Follow-up of at least 6 months was required un-
and serious challenging behaviors associated with ASD are scarce
less terminated earlier by the physician. It is not known whether
(excluding the 2 abovementioned FDA-approved medications).
these patients were different in any way from those who remained
However, there have been many anecdotal or small case series re-
in treatment.
ports that show some promise. One of these strategies involves the
beta-adrenergic blocking agent propranolol. Ratey et al25 reported
a case series of 8 adults with violent or SIB. They described a “re- Medication Dosage
markable” effect on previously intractable aggressive behavior, Given that all patients included in the data analysis presented
which was consistent with similar findings for individuals with with serious challenging behaviors and each patient had been on
schizophrenia, brain damage, and severe intellectual disabilities, medications previously with variable efficacy, propranolol was
among others.26–29 In a recent review of the effect of beta- added while the patients remained on their existing medications.
adrenergic blockers on the challenging behaviors of individuals During the time on propranolol, if any benefit was noted, attempts
with developmental disability, it was reported that many had pos- were made to lower or discontinue other mediations, although
itive outcomes, supporting the efficacy of this indication. How- there was often a lack of incentive clinically to adjust a newly suc-
ever, it was noted that the overall quality of the research was cessful regimen. The propranolol was generally started at low
poor, with no randomized controlled studies.30 In a review of stud- doses (eg, 10 mg, three times per day) and titrated up. High doses
ies on individuals with brain injury presenting with aggression, it were prescribed based on the literature indicating effectiveness at
was concluded that beta blockers have the best evidence for effi- a dosage of 640 mg in alleviating challenging behaviors.28 As
cacy, but the lack of high-quality studies was also highlighted.31 this was a clinical retrospective review, the titration was done
It is notable that propranolol has shown other benefits in ASD, in- variably based on the circumstances of the case. Propranolol
cluding verbal problem solving,32 word fluency,33 facial scanning,34 was given in both immediate-release and extended-release forms
and conversation reciprocity.35 depending on the clinical needs of the patient.
Despite the urgent need for effective treatment for these de-
bilitating symptoms and the anecdotal evidence of success pro-
pranolol has had for challenging behaviors across a range of Dependent Measure and Safety Precautions
diagnoses, it appears that it is not commonly used for individuals The cases were retrospectively reviewed. The treating psy-
with ASD. In the United Kingdom, adrenergic blocking agents are chiatrist met with the patient and his/her caregiver and obtained
rarely prescribed, with only 2% of patients with ASD receiving relevant clinical information regarding the frequency and intensity
any type of beta blockers.36 In a study of pharmacologic treat- of the challenging behavior. The severity of the symptoms and the
ments in Germany, no beta blockers were listed among the 25 efficacy of the medication were quantitated using the Clinical
most commonly prescribed medications for ASD.37 In systematic Global Impression (CGI) scales. The CGI Severity (CGI-S) score
reviews of treatments for ASD, propranolol is either not men- was ascertained immediately before the first dose of propranolol
tioned or only briefly mentioned in the context of the paucity of and again at the time of the retrospective review (some continued
high-quality studies to demonstrate its efficacy.38,39 in treatment up to the time of the review, while others were no lon-
In light of the above, we report a retrospective case series ger in treatment), and it was based on the treating psychiatrist's re-
of 46 individuals who had been diagnosed with ASD with high sponse to the question, Considering your total clinical experience
levels of aggression, SIB, and disruptive behaviors and were with this particular population, how mentally ill is the patient at
treated with high-dose propranolol. In each case, the patient had this time? by using the following 7-point scale: 0, not assessed;
received prior treatment with at least 1 antipsychotic medication. 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4,
In most cases, many medications had been tried, with either a lack moderately ill; 5, markedly ill; 6, severely ill; 7, among the most
of efficacy or only partial efficacy, calling for further treatment at- extremely ill patients.
tempts. The majority of the patients (although not all) had received Then, the CGI Improvement (CGI-I) scale was used to obtain
reasonably high-quality behavioral intervention before the introduc- the patient's global functioning based on observed and reported
tion of propranolol. symptoms before and after medication administration on a similar

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124
TABLE 1. Summary of the Trial on Propranolol
London et al

CGI-I Time on
Case Age/Sex Dx DSM-5 Concurrent Medications Dose (mg) Score Prop Challenging Behaviors Comments
1 11/M F84.0 R, A, O, V, S, P 300 4 1y Agg, SIB, Incontinence No improvement on any meds,
severe family issues
2 18/M F84.0 A, F, Li 320 1 5y SIB, picking, Agg quick temper Rare to 0 behaviors on Prop for 5 years
3 10/M F84.0 R, C 300 2 2y SIB – bangs, hits, and bites On Prop +R much lower frequency
6 mo self; tantrums, Agg and severity
4 13/M F84.0 R, Oxa, Lam, Lev, Foc, Dex, Gu 120 1 3y Agg Blood pressure lowered, stopped
Prop and relapsed, resumed Prop
5 34/M F84.0 A, Z, Lor, Car 640 2 1y Compulsions—aggressions Side effects on antipsychotics

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6 mo
6 15/M F84.0 A, Cpz, O, C, Alp, V 480 1 2y Aggression (injuries) O worked but broke thru, Prop +Alp now
6 mo
7 14/M F84.0 R, Q, Mol, H, Oxa, Gu, F, S, Lor, Car 480 2 3y Agg, (injuries) Well on Prop, Lor, H, Car
8 12/M Tri 15 F84.0 V, Add, C, Mir, tra 600 2 1y Agg, screaming, hyper, off task, On Prop+ Mirt behaviors are at a low level
SIB, sleep problems
9 12/F F84.0 R, A, Gab, Top, Add, SSRIs 480 4 2y Anx skin pinch, hyper, moody Prop worked but broke thru similar
6 mo to other medicines
10 15/F F84.0 A, O, R, Oxa, Lam, Ver, Alp.Mir, C, Gu 300 1 <6 mo Agg, anxiety perseverations Best ever on Prop, bronchospasm d/c'd
11 15/F F84.0 A, R, Z, F, Chl, Top, V, Oxa, Lor, Clo 360 1 3y Agg, disrobing, sleep problems Doing well on Prop, Oxa, V and R.
6 mo Needs all
12 16/M F84.0 O, Gu, Li, 400 2 2y Agg, SIB, repetitive Agg and SIB markedly reduced;
repetitive behavior unchanged
13 18/M F84.0 Q, V, Lev 320 3 3y Agg, SIB, crying, hyper, Status varies with seizures
sensory sensitivities
14 12/M F84.0 R, O, 240 1 2y Agg, SIB, rituals Agg, SIB eliminated, rituals = or worse
15 13/M F84.0 R, Q, Top, Oxa, Bac, Nal, 960 2 3y Agg, SIB, tantrums. Mood Doing well on Pro, Oxa, and Top.
V, S, P, Clo, Bus lability, hyper
16 17/M F84.0 R, P, Li 240 2 1y Agg, headbutts, SIB hits head, hyper Occasional Agg, parent refused
6 mo further dose increase
17 12/M F84.0 R, Q, A, Met, Oxa, V 480 1 3y Agg, bites, kicks, hyper, drops, Agg and SIB close to 0; still very hyperactive
6 mo whistles, attention seeking
18 19/M F84.0 O 120 1 6 mo Agg, public masturbation. Z effective for years, broke thru,
on Prop 0 Agg
19 16/F F84.0 R, V, C 300 2 6 mo Agg, hitting, slap, kick bite, Agg responded, mood and rigidity
repetitive, mood lability remain, recent seizures
20 20/M F84.0 R, Z, A, Lev, V, Tra, Hyd, Gu, Zol 640 1 2y Agg, pinch, hit, headbutt, Agg = 0 on Prop gained 100 lbs on R
sleep problems
21 11/M F84.0 A, C, Gu, S 480 2 6 mo Agg, pinch kick hairpull, SIB, Agg and SIB better, rituals ongoing
bites, hits head, severe rituals
22 15/M F84.0 FAS R, V, Lev, F, C, Bac 360 2 6 mo SIB, hits head (hours) Better, but parent refused increased dose
Q86.0

© 2020 The Author(s). Published by Wolters Kluwer Health, Inc.

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23 13/M F84.0 A, Z, V, Met, Tra, Zol, Tem 600 2 4y Agg, digs nails, SIB, hits head and On Pro, Z, Tem, Tra some cycling
induced hemiparesis hyper, rep, sleep
24 16/M F84.0 H, Z, V, Gu, Met 600 2 3y Agg hits, suddenly spits hyper Agg much better, laughs when he hits,
6 mo indicating secondary reinforcement
25 18/M F84.0 R, Gu 480 1 3y Agg, bites SIB, sleep Agg 900 episodes per month on R,
problems, screams down to 0 on Prop
26 13/M F84.0 R, O, H, A, V, Top, Li, Clo 600 3 3 y on and off Agg, headbutt, SIB throws self Agg, SIB down on Prop, seems to
on floor (IC bleed) impulsive enjoy behaviors, very unfocused
27 32/M F84.0 R, O, Gu, Car, Hyd 720 4 6 mo Agg, pulls hair, grabs and throws Nothing successful Parents refuse
polypharmacy so only used each med alone
28 14/M F84.0 A, Esc, F, Bup, Mir 600 2 6 mo Agg attacks when redirected, SIB, Prop eliminated Agg—mood declined
hits self, tantrums
29 13/M F84.0 R, S, Oxa, Gu 600 2 4y Agg, fights, bites, kick tantrums On R and Oxa with Prop
30 11/M F84.0 A, S, Cit, Gu, C 480 2 1y Agg, hits, kicks, headbutts, SIB Doing well on Pro, A and Gu
head bang, hyper, tantrums
31 19/M F84.0 R, Z, Q, F, S, P, Gu, C, Bus, 480 1 1y Agg, scratch, headbutt, kick, rituals Agg 36/month—0 Agg on pro
Ari, Add, Top, Lam, Lev, 6 mo
Oxa, Sab, Vim
32 17/M F84.0 R, V 240 1 6 mo Agg, SIB headbanging On R, V and Prop, SIB ~0. prior

© 2020 The Author(s). Published by Wolters Kluwer Health, Inc.

30 episodes per month
33 15/M F84.0 R, O, Tra, Lor, Hyd 720 2 2y Agg, hit teachers, strangers, + mom Previously hospitalized twice, CGI 1 for 2 for
6 mo years until recent slip, parents divorcing
34 8/M F84.0 A, Z, O, Gu 180 1 6 mo Agg, attacked young sibs Did well but discontinued due to wheezing,
also side effects on antipsychotics
35 21/M F84.0 A, R, O 640 2 6 mo Agg, lashes out unpredictable, Prop with O, Agg minimal, occasional SIB
SIB, hits head, picks at self
36 22/M F84.0 Frag R, Nef, Alp 640 2 2y Agg, punches, pulls strangers hair, On Prop, Alp R, rare aggression,
X Q99.2 SIB hits head but breaks thru with stress
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37 10/M F84.0 Z, A, R, O, Q, F, Oxa, Lam, Lev, Bac 640 2 9y Agg. hitting, hyper, perseveration, fears On Prop, O, Lam, F, Bac, rare Agg and SIB
38 16/M F84.0 Z, R, Clp, Thi, F, V, C, Gu, Lor Tra 480 4 6 mo Agg, rages, SIB, crying insomnia No benefit on Prop
39 14/F F84.0 O, R Lur, A, Q, S, Esc, Gu, Stim 640 2 6 mo Agg, scratches, hits, SIB, screams Agg and SIB much better, still screams
40 18/M F84.0 R, O 360 1 10 y SIB, hits head and deformed skull On Prop + O doing very well
41 21/F F84.0 A, Q, R, Oxa, Gab, Gu, Bus, Esc, C, 480 2 6y Agg, pinches, SIB, hits, bites self, On Prop, A, Lac, S, Agg, and SIB
Dia, Li, Lam tantrums, screams much lower rates
42 12/F F84.0 R, A, Li, C, S, Tra, Mir, D, Esc, Oxa 360 2 1y Agg, harness in car, SIB, repetitive SIB and Agg minor, still tantrums
6 mo behavior, disrobing and repetitive
43 13/M F84.0 R, A, H, O, Z, Q, Oxa, Top, V, Flu, 600 2 4y Agg, loses interest, sleep problems Improves on antipsychotics, but
Mir, Tra, Lor, Zol, Tem side effects are problematic
44 21/M F84.0 R, A, P 600 2 10 y Agg, SIB, sleep problems, crying, Still cries and repetitive, Agg SIB rare
repetitive behaviors
45 32/F F84.0 R, Z, Q, H, Tra, Clo, V, Lor 240 2 6y Agg, severe leads to Experienced bleeding and low
frequent hospitalizations blood pressure, so Prop D/C'd
46 12/M F84.0 R, O, Z, A, V, Oxa, Li, Nal, C, F, 360 6 1 mo Agg, SIB, hits self, screams Worsened dramatically but d/c A

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Mir, Ato, Alp, Zol, Dia at same time
Agg, aggression; hyper, hyperactivity; prop, propranolol; FAS, fetal alcohol syndrome; Frag X, fragile X; M, male; F, female.
Safety and Effectiveness of High-Dose Propranolol

125
 London et al Journal of Clinical Psychopharmacology • Volume 40, Number 2, March/April 2020

7-point scale: 0, not assessed; 1, very much improved since the frequent vital sign evaluation while receiving propranolol. The major-
initiation of treatment; 2, much improved; 3, minimally improved; ity of these patients were also taking other psychotropic medica-
4, no change from baseline (the initiation of treatment); 5, mini- tions, as described above. A chart review and discussion with
mally worse; 6, much worse; 7, very much worse since the initia- caretakers did not reveal evidence of any adverse cardiorespira-
tion of treatment. tory symptoms or events except for 1 case in which lethargy and
Adverse effects were also noted. Despite being a generally peripheral cyanosis occurred, though it is unclear if this was re-
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safe medication, the effects of high doses on children and those lated to beta blocker therapy. There were no incidents of delete-
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with developmental disabilities have not been sufficiently docu- rious arrhythmias, adverse bradycardia, or hypotension, or any
mented. We, therefore, conducted (in addition to standard medical evidence of decreased cardiac output or cardiomyopathy based
care) an in-depth cardiology evaluation on 45 patients. This eval- on clinical evaluation or diagnostic studies.
uation was done in the later part of the period under review. There-
fore, although some of the cases overlap (ie, some patients had
both behavioral and cardiologic reviews), others with the cardiol- DISCUSSION
ogy workup were not part of the retrospective chart review. Thus, Challenging behaviors such as aggression, SIB, and severely
we have data on the cardiologic effects of high-dose propranolol disruptive behaviors demand attention from the clinical and re-
on subjects with ASD, but we are not able to correlate the cardio- search community serving those with ASD.9,23,40 Despite the ex-
logic effects with behavioral effects, as they were at least partially istence of promising reports using propranolol for challenging
from distinct populations. behaviors for over 30 years, methodologically rigorous research
has been scarce. This has resulted in propranolol and other beta
blocking agents being marginal in the armamentarium of medica-
RESULTS
tions which could provide reduction in these symptoms. This ret-
The behavioral results of this retrospective review are pre- rospective chart review, although anecdotal, contributes to the
sented in Table 1. Thirty-nine (85%) of 46 patients were much im- literature by supporting the potential of propranolol for this indica-
proved or very much improved (CGI-I 1 or 2) in their challenging tion. We make a new contribution by offering the largest body of
behaviors. Two (4%) of 46 were slightly improved (CGI-I 3), case series evidence for the use of propranolol in conjunction with
whereas 5 (11%) of 46 of the cases were not improved or wors- antipsychotics for individuals with ASD presenting with challeng-
ened (CGI-I 4 or greater). Although not quantitated, there was lit- ing behaviors. In addition, we provide long-term follow-ups of the
tle to no benefit in commonly reoccurring symptoms such as patients (mean, 2.5 years) and document the extent of the cardiovas-
hyperactivity, repetitive behaviors, and mood. cular effects of using high doses of propranolol in this high-need
The 46 patients included 8 females and 38 males. Ages population. Therefore, it appears that moderate and high-dose beta
ranged from 8 to 32 years (mean, 16 years). The propranolol dose blocker therapy can be given safely without adverse cardiovascular
ranged from 120 to 960 mg per day (mean, 462 mg). The duration problems provided that close clinical monitoring is maintained.
on propranolol ranged from 1 month (1 patient who deteriorated on Thirty-nine (85%) of 46 patients were rated as much improved
propranolol, although he discontinued an antipsychotic at the same or very much improved on the CGI-I. This improvement and effi-
time) to 10 years (mean = 2.6 years). The mean number of medica- cacy is outstanding and would be superior to any medication cur-
tions previously and/or currently being tried was 6.2 (the abbrevia- rently used if this finding is confirmed with more rigorous clinical
tions for the medications in Table 1 can be found in Table 2). research methodologies. To validate and optimize its clinical use,
many other questions need to be answered. The literature on the
Cardiology Results use of propranolol for challenging behaviors suffers from various
As part of the clinical care, 45 patients were evaluated for any limitations. Most previous studies were also case studies, although
cardiac abnormalities under the supervision of a pediatric cardiol- there have been 6 small double-blind and/or placebo-controlled
ogist (E.F.) due to their taking moderate to high doses of beta studies.41 These studies, which targeted aggression, self-injury, and
blocker therapy for severe challenging behaviors. Forty (88%) of destructive behaviors, were done on many different psychiatric diag-
the 45 patients received a 24-hour Holter monitor (the other 5 noses, including intermittent explosive disorder (with and without
were repeatedly uncooperative with the Holter monitor). All of known brain damage), conduct disorders, attention deficit disorder,
them underwent a baseline and follow-up EKG, and 20 of them schizophrenia, atypical psychosis, schizoaffective disorder, drug
underwent echocardiographic assessment. All the patients had abuse, seizure disorder, borderline personality disorder, various

TABLE 2. Medication Abbreviations

A—Aripiprazole Clp—Chlorpromazine Lev—Levetiracetam R—Risperidone

Add—Adderall Dex—Dexedrine Lor—Lorazepam S—Sertraline
Alp—Alprazolam Dia—Diazepam Lur—Lurasidone Tem—Temazepam
Ato—Atomoxetine Dul—Duloxetine MetvMethylphenidate Thi—Thioridazine
Bac—Baclofen Esc—Escitalopram Mir—Mirtazapine Top—Topiramate
Bup—Bupropion F—Fluoxetine Mol—Molindone Tra—Trazodone
Bus—Buspirone Flu—Fluvoxamine Nal—Naltrexone V—Valproate
C—Clonidine Gab—Gabapentin Nef—Nefazodone Ver—Verapamil
Car—Carbamazepine Gu—Guanfacine O—Olanzapine Vim—Vimpat
Cit—Citalopram H—Haloperidol Oxa—Oxcarbazepine Z—Ziprasidone
Clo—Clonazepam Hyd—Hydroxyzine P—Paroxetine Zol—Zolpidem
Clom—Clomipramine Lam—Lamotrigine Q—Quetiapine

126 www.psychopharmacology.com © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.
 Journal of Clinical Psychopharmacology • Volume 40, Number 2, March/April 2020 Safety and Effectiveness of High-Dose Propranolol

types of intellectual disabilities with various etiologic origins, and effects became apparent. In fact, side effects were rarely a problem
dementia.28,30,42 Some studies used mixed diagnostic populations. at very high doses, raising the possibility that the cardiovascular
The studies were done on a wide range of ages, from children to ge- effects might have hit a ceiling effect after the saturation of periph-
riatric populations, and over a wide range of intellectual abilities. eral receptors. In this sample, we saw a few cases which responded
The symptoms being targeted—aggression, self-injury, and to doses as low as 120 mg per day; however, the average final dose
disruptive behaviors—may constitute a very heterogeneous group was 462 mg, with only a few cases responding well to doses lower
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of problems. Carroll et al7 subdivided aggression and found that in than 300 mg per day. In our experience, there was often a clinical
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ASD, there were 5 different subtypes. They used the concept of urgency to treat the symptoms, as the challenging behaviors often
“hot” and “cold” aggression. In “cold” aggression, the aggressive created danger to the patients themselves, their peers, and their
behavior is intended to achieve a desired outcome, and it occurs caregivers. This led to an urgency to identify the therapeutic dose
without anger or prior provocation. On the other hand, “hot” ag- quickly. It is possible that with a slower titration and more time at each
gression occurs in response to a provocation and is often impulsive. lower dose, we might have seen benefit at lower doses. In this report,
It is possible that “cold” aggression types were underrepresented in the end-point dose was a clinical decision. We ended the titration
our sample, as those cases were more successfully treated with when parents and staff were pleased enough with the behavioral im-
function-based behavioral interventions and may not have received provement that they wanted to stop the titration. It is also possible
referrals for medication treatment. Therefore, it is likely that pro- that some patients might have further improved on higher doses.
pranolol is more effective in treating “hot” aggression associated In this case series, the propranolol was added to the patients'
with autonomic and emotional dysregulation. Some of our few existing medications, so we are unable to observe how propranolol
treatment failures had clear antecedents (precipitants) to their ag- might influence these symptoms if it were to be used as the only
gressive episodes and were likely aimed at a desired outcome and pharmaceutical agent. Ethical considerations of doing research
thus of the “cold” aggression variety. on violent and danger-inducing behaviors make taking the patient
off of partially effective medications difficult, if not impossible.
Limitations Attempts to lower or discontinue the antipsychotic medications af-
ter deriving the benefits of propranolol generally resulted in dete-
In the context of evidence-based medicine, randomized
rioration (although we did not document this systematically),
control-group trials are considered the gold standard. Given the
which lends some support to the idea that propranolol by itself
economical and practical challenges of conducting a rigorous clin-
would not be as successful. Some previous studies did note the
ical trial with a vulnerable population such as those with ASD, ob-
ability to reduce or stop other medications when on propranolol
servations made from a clinical series can also contribute to our
in some cases,42–44 while other studies found, as we did, that stop-
current knowledge about treating refractory patients who do not
ping or reducing the other medications resulted in a reemergence
fit into predetermined research selection criteria.
of symptoms.45
Here, the inclusion of only chronically refractory patients
provides us with a relatively skewed but homogeneous group of
patients with similar behavioral topography independent of their Mechanism of Action
comorbid intellectual impairment or psychiatric diagnoses. This
Several possible mechanisms of action have been discussed
group remains understudied at least partially due to the difficulties
in the literature; however, direct support for any of them is lack-
in studying this population. In the current series, patients were all
ing.41 One proposed mechanism is the blockade of peripheral
given the same intervention and standard of care, such as ongoing
sympathetic activity, and this is supported by those studies which
behavior interventions, frequency of follow-up appointments, and
used nadolol and other less lipophilic agents, which are less likely
management of complications. Therefore, although case series are
to have central effects.46,47 In our sample, the clinical improve-
highly susceptible to extraneous variables, the findings from this case
ment seemed to come at high doses, which might suggest that pe-
series provide another set of anecdotal evidence for the use of pro-
ripheral mechanisms alone cannot explain the benefits noted, as
pranolol in patients with ASD presenting with challenging behaviors.
central effects have been reported to increase with higher doses.48
There are several inherent methodological limitations of a
Another hypothesis is that the benefits may be due to central
case series report such as this. First, the treating psychiatrist was
effects. Beta adrenergic stimulation of the amygdala has been
not blinded, which may have influenced the retrospective scoring
shown to enhance the fear mechanisms and may contribute to
of the CGI, possibly contributing to the robustness of the findings
the persistence and severity of traumatic memories.49 There is pre-
and therefore the validity of the results. Second, apart from the
liminary evidence that the blockade of this adrenergic tone with a
treating psychiatrist's CGI scores, no other data were systemati-
beta blocker can attenuate the symptoms of posttraumatic stress
cally collected. Therefore, no absolute risk or relative effect can
disorder (PTSD). Noradrenergic signaling is critical for memory
be calculated from this case series. In addition, propranolol was
consolidation and reconsolidation.50 Inhibition of beta adrenergic
prescribed as an add-on to the existing treatment regimen, without
receptor activity during reconsolidation leads to memory disrup-
any control for psychotropic medications, making it difficult to at-
tion within both appetitive and aversive memory paradigms.51
tribute any behavioral changes solely to propranolol.
This suggests that beta blockers can block the reconsolidation of
emotionally charged memories (both positive and negative). In
Practice Parameters non-verbal or minimally verbal people, the association between
Based on the extant literature, it is challenging to derive prac- memories and behavior is difficult to observe because challenging
tice parameters for the clinician. One very important parameter is behaviors are often triggered by what appear to be relatively be-
dosing. The studies in the literature used various dosing strategies, nign stimuli. Given that individuals with ASD are often in a
and with the above described heterogeneity, it is not surprising that hypersympathetic state and/or a central hyperadrenergic state,52–57
the effective doses reported were wide-ranging, from 60 mg per it is plausible that a PTSD-type reaction might be triggered by
day to 1760 mg per day. Based on these reports which obtained stimuli which are difficult for others to readily identify. Likewise,
benefit at very high doses, we elected to continue titrating the dose individuals with PTSD may be triggered by idiosyncratic stimuli,
up until we obtained acceptable benefit (as determined by the although in that case, the origin of these triggers can be self-
treating physician and the consenting family or guardian) or side reported. Functional connectivity scanning research58,59 suggests

© 2020 The Author(s). Published by Wolters Kluwer Health, Inc. www.psychopharmacology.com 127
 London et al Journal of Clinical Psychopharmacology • Volume 40, Number 2, March/April 2020

another central effect which may lead to a decrease in aggression 3. McDougle CJ, Stigler KA, Posey DJ. Treatment of aggression in children
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