Current Psychiatry Reports (2021) 23: 79

https://doi.org/10.1007/s11920-021-01292-2

AUTISM SPECTRUM DISORDERS (ES BRODKIN, SECTION EDITOR)

Recent Updates in Psychopharmacology for the Core and Associated

Symptoms of Autism Spectrum Disorder
Robyn P. Thom1,2,3 · Joseph A. Pereira4 · Danielle Sipsock5,6 · Christopher J. McDougle1,2,3

Accepted: 3 September 2021 / Published online: 13 October 2021

© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021

Abstract
Purpose of Review Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core deficits in social
communication and restricted, repetitive patterns of behavior. This article aims to review the recent literature pertaining
to psychopharmacology for the core and associated symptoms of ASD including social impairment, repetitive behaviors,
irritability, and language impairment.
Recent Findings Recent medication trials targeting social impairment in ASD have focused on neuropeptides (oxytocin and
vasopressin) and memantine. None of these three medications has demonstrated consistent benefit for social impairment in
ASD; however, additional studies are underway. Two double-blind, placebo-controlled studies on selective serotonin reup-
take inhibitors (SSRIs) provide evidence against the use of SSRIs for repetitive behaviors in youth with ASD. Preliminary
studies have investigated cannabidiol (CBD) for irritability in ASD but further studies are needed to demonstrate safety and
efficacy. Finally, three double-blind, placebo-controlled studies provide preliminary evidence for folinic acid for the treat-
ment of verbal language deficits in children with ASD.
Summary The identification of safe and effective pharmacological treatments to ameliorate the core and associated symp-
toms of ASD has proven difficult.

Keywords Autism spectrum disorder · Psychopharmacology · Social impairment · Repetitive behaviors · Irritability ·
Language impairment

Introduction

Autism spectrum disorder (ASD) is a heterogenous neurode-

This article is part of the Topical collection on Autism Spectrum velopmental disorder characterized by core deficits in social
Disorders communication and restricted, repetitive patterns of behavior
[1]. While there are currently no uniformly effective behav-
* Christopher J. McDougle
[email protected] ioral or psychopharmacological therapies for ASD, man-
agement includes early intensive behavioral intervention to
1
Massachusetts General Hospital, 55 Fruit St, Boston, improve social functioning and developmental outcomes [2].
MA 02114, USA Other nonpharmacologic treatments may include interven-
2
Lurie Center for Autism, 1 Maguire Road, Lexington, tion for impaired language and communication, social skills
MA 02421, USA training, occupational therapy, and special education. No
3
Department of Psychiatry, Harvard Medical School, 25 pharmacologic approaches have been clearly demonstrated
Shattuck St, Boston, MA 02115, USA to reverse the core symptoms of ASD; however, risperidone
4
Department of Psychiatry, Columbia University, 630 W and aripiprazole, both second-generation antipsychotic
168th St, New York, NY 10032, USA medications, are approved by the United States Food and
5
Center for Autism and Developmental Disorders, Maine Drug Administration (FDA) for the treatment of irritability
Behavioral Healthcare, 78 Atlantic Place, South Portland, in children and adolescents with ASD. The use of psychop-
ME 04106, USA
harmacology to treat the associated behavioral symptoms
6
Maine Medical Center Research Institute, Scarborough, ME, of ASD and co-occurring psychiatric conditions such as
USA

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 79 Page 2 of 9 Current Psychiatry Reports (2021) 23: 79

attention-deficit/hyperactivity disorder, anxiety disorders, 40 adult males with ASD were randomized to either intra-
and mood disorders is common among individuals with nasal oxytocin 24 IU per day or placebo [6]. The primary
ASD. In fact, a recent large population-based, nationwide, outcome of interest was social impairment, as measured by
managed health plan claims database study of children and self- and informant-rated scores on the Social Responsive-
adults with ASD in the USA demonstrated that 59.6% of ness Scale (SRS) total score. Although improvement on the
study participants received a prescription for a psychotropic SRS occurred in both the oxytocin and placebo groups, there
medication during the 6-year study period [3]. was no significant between-group differences (p = 0.37).
There is an ongoing need for the development of safe and There were significant differences between oxytocin and
effective pharmacologic treatments for ASD. Psychopharma- placebo observed in two of the secondary outcomes meas-
cology research in ASD over the past 3 years has focused ured: reduced feelings of avoidance towards others (p = 0.03)
on re-evaluating the efficacy of selective serotonin reuptake and reduced repetitive behaviors (p = 0.04) which both per-
inhibitors (SSRIs) for the core symptoms of ASD, assessing sisted one year post-treatment. The third and largest study
whether repurposing medications from other fields of medi- was a 6-week double-blind, placebo-controlled trial, which
cine may be an effective approach, and beginning to utilize randomized 106 adult males (18–48 years) with ASD to
biologically defined subtypes of ASD to predict treatment either intranasal oxytocin 48 IU per day or placebo [7•]. The
response. This article aims to review the recent literature primary outcome was the Autism Diagnostic Observation
pertaining to psychopharmacology for the core and associ- Schedule (ADOS) reciprocity subscale. Similar to results
ated symptoms of ASD including social impairment, repeti- from the trial completed by Bernaerts et al., improvement
tive behaviors, irritability, and language impairment. The was observed in both the oxytocin and placebo groups, but
results of recently published randomized, placebo-controlled oxytocin was not found to be superior to placebo (p = 0.69).
trials of psychiatric medications for the core and associated Oxytocin was, however, associated with a statistically sig-
symptoms of ASD are summarized in Table 1. nificant improvement compared to placebo in two of the sec-
ondary outcome measures: the ADOS repetitive behaviors
Social Impairment subscale and duration of gaze fixation on socially relevant
eye regions as measured by eye tracking software. Finally, a
Persistent social impairment occurring across multiple con- large, 6-month multi-site phase two trial investigating flex-
texts is a core symptom of ASD. No pharmacologic treat- ibly dosed intranasal oxytocin (maximum dose 80 IU per
ments have been clearly demonstrated to provide benefit for day) in 290 children and adolescents (3–17 years) with ASD
social impairment in ASD. As such, early intensive behav- [8] has completed enrollment and publication of the results
ioral intervention, which has been found to improve learn- is pending. Preliminary indications are that there was no
ing, communication, and social skills in young children with significant difference between oxytocin and placebo on the
ASD, remains the standard of care. Several medication trials primary outcome measure, the Aberrant Behavior Check-
targeting social impairment in ASD have been published list (ABC) Social Withdrawal subscale. Taken together, the
recently, most of which have focused on neuropeptides (oxy- results from these four trials do not provide convincing evi-
tocin and vasopressin) and memantine. dence to support the use of intranasal oxytocin for the treat-
Oxytocin is a neuropeptide associated with interper- ment of the core social deficits of ASD.
sonal bonding, parenting behaviors, and forming social Vasopressin is a neuropeptide which primarily serves
attachments. Animal models relevant to ASD suggest that to regulate water reabsorption in the kidneys and increase
dysfunction of the oxytocin system may be involved in the peripheral vascular resistance. Recent research suggests that
social deficits of ASD and have demonstrated that exogenous vasopressin may also act centrally to regulate and promote
oxytocin treatment results in increased social behaviors [4]. social behavior. Two trials assessing vasopressin for the
Three randomized controlled trials (RCTs) of intranasal oxy- treatment of social deficits in ASD have been published in
tocin in adults with ASD have been published in the past the past 3 years. Bolognani et al. conducted a randomized
3 years. The first trial was a randomized double-blind, placebo-controlled trial of balovaptan, a selective
placebo-controlled cross-over trial that enrolled 15 males with vasopressin V1a receptor antagonist, in 223 adult males
ASD and 24 healthy controls (18–26 years) [5]. The par- (15–40 years) with ASD. Participants were randomized to
ticipants received either one dose of intranasal oxytocin 20 placebo or one of three balovaptan doses (1.5 mg, 4 mg, or
international units (IU) or placebo spray in a random order 10 mg per day). Balovaptan treatment was not associated
on two consecutive days. Unlike the control group, individu- with changes in the SRS-2 [9]. Parker et al. conducted a
als with ASD demonstrated enhanced social learning when separate pilot 4-week randomized, double-blind, placebo-
given oxytocin compared to placebo. The second study was controlled trial which included 30 children (6–12 years)
a 4-week randomized double-blind, placebo-controlled trial with ASD. The maximum dosage of intranasal arginine
with parallel design conducted by Bernaerts et al. where vasopressin (AVP) was 24 IU per day for children ≤ 9.5 years

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Table 1  Select recent randomized, placebo-controlled trials of psychiatric medications in ASD with minimum sample size of 30 subjects
Target symptom Publication Medication Population Study design Outcomes

Social impairment Bernaerts et al. [6] Oxytocin 40 adult males with 4 weeks No between-group
ASD Parallel groups differences on SRS
Yamasue et al. [7] Oxytocin 106 adult males with 6 weeks No between-group
ASD Parallel groups differences on ADOS
reciprocity subscale
Bolognani et al. [9] Balovaptan 223 adult males with 12 weeks No between-group
ASD Parallel groups differences on SRS-2
Parker et al. [10] Vasopressin 30 children 4 weeks Parallel Vasopressin group had
(6–12 years) with groups greater improvement
ASD in SRS-2 and CGI-I
scores
Hardan et al. [11] Memantine 379 children 12 weeks Withdrawal No between-group
(6–12 years) with trial difference in loss of
ASD who responded therapeutic response
to open-label on SRS
memantine
Karahmadi et al. [12] Memantine as adjunct 60 children 3 months Memantine group had
to ABA therapy (< 14 years) with Parallel groups greater improvement
ASD in GARS total
score and social
interactions subscale,
but no between-
group differences on
the communication
subscale
Repetitive behaviors Reddihough et al. [16] Fluoxetine 146 children 16 weeks No between-group
(7–18 years) with Parallel groups differences on
ASD CY-BOCS-PDD
after controlling for
covariates
Herscu et al. [17] Fluoxetine 158 children 14 weeks No between-group
(5–17 years) with Parallel groups differences on
ASD CY-BOCS-PDD
Politte et al. [22] Extended-release 62 children 8 weeks Extended-release
guanfacine (5–14 years) with Parallel groups; guanfacine group had
ASD analysis of repetitive decreased repetitive
behaviors as behaviors on
secondary outcome CY-BOCS-ASD
measure
Sprengers et al. [23] Bumetanide 92 children 13 weeks No between-group
(7–15 years) with Parallel groups differences on SRS-2
ASD
Irritability Aran et al. [32] CBD and whole-plant 150 individuals 12 weeks CBD was not
cannabis extract (5–21 years) with Crossover design associated with
ASD improvement in
disruptive behaviors
compared to
placebo. Whole-
plant cannabis
extract resulted in
improvement in
disruptive behaviors
compared to placebo

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Table 1  (continued)
Target symptom Publication Medication Population Study design Outcomes

Language impairment Frye et al. [38] Folinic acid 48 children 12 weeks Folinic acid group had
(3–15 years) with Parallel groups greater improvement
ASD in verbal language
as measured by the
CELF
Batebi et al. [40] Folinic acid as 55 children 10 weeks Folinic acid group had
adjuvant to (4–12 years) with Parallel groups greater improvement
risperidone ASD on Inappropriate
Speech subscale of
ABC

ASD, autism spectrum disorder; SRS, Social Responsiveness Scale; ADOS, Autism Diagnostic Observation Schedule; CGI-I, Clinical Global
Impressions-Improvement; ABA, applied behavior analysis; GARS, Gillian Autism Rating Scale; CY-BOCS-PDD, Children’s Yale-Brown Obses-
sive Compulsive Scale, modified for pervasive developmental disorder; CY-BOCS-ASD, Children’s Yale-Brown Obsessive Compulsive Scale,
modified for autism spectrum disorder; CBD, cannabidiol; CELF, Clinical Evaluation of Language Fundamentals; ABC, Aberrant Behavior
Checklist

and 32 IU per day for children 9.6–12.9 years. In this were randomized to memantine 2.5 mg twice daily or
study, AVP was associated with improved caregiver- placebo during a three-month course of ABA therapy.
reported SRS-2 scores and a clinician-rated Clinical Global The participants were blinded to treatment assignment.
Impression-Improvement (CGI-I) score anchored to social- The Gillian Autism Rating Scale (GARS) was completed
communication abilities compared to placebo (p = 0.005) by the participants’ caregiver pre- and post-intervention.
[10]. Arginine vasopressin was well tolerated and there was The memantine group had a statistically significant
no difference in the rate of reported adverse effects between improvement compared to placebo in total GARS scores
AVP and placebo. The findings of this study are tempered and the GARS social interactions subscale, but there
by several important limitations including small sample size was no between-group difference in the communication
and reliance on subjective outcome measures. subscale. The conclusions of this study are significantly
Memantine, a N-methyl-d-aspartate (NMDA) receptor limited by small sample size and the lack of gold standard
antagonist with FDA approval for the treatment of social and communication measures. Finally, a 12-week
Alzheimer disease, has been another medication of RCT of memantine for the treatment of social deficits
interest for the treatment of social impairment in ASD. in youth (8–18 years) with non-verbal learning disorder,
Results from a series of three well-powered, multi-site high-functioning ASD, and related conditions is currently
phase two trials investigating extended-release memantine underway [13]. The results of the double-blind, placebo-
in children (6–12 years) with ASD were reported by controlled withdrawal trial are consistent with the
Hardan et al. [11]. The first was a 50-week open-label negative results from the original 12-week randomized
trial (n = 906), the second was a 12-week randomized double-blind, placebo-controlled study of memantine
double-blind placebo-controlled withdrawal trial which for social impairment in 104 children (6–12 years) with
enrolled responders from the first trial (n = 479), and the ASD which demonstrated no significant between-group
third was a ≤ 48 week open-label safety and tolerability difference on the caregiver-rated SRS [14].
extension trial (n = 747). Sixty percent of participants These recently published studies add to our knowledge
demonstrated improvement in SRS scores after 12 weeks base of psychopharmacology for social impairment, but
of treatment in the open-label phase. In the withdrawal do not significantly change current standards of care. The
trial, participants were randomized to weight-based full- trials assessing oxytocin largely provide evidence against
dose memantine or a dose reduction by ≥ 50%. There was its use in adult males and preliminary indications of the
no difference in loss of therapeutic response on the SRS results of a large phase 2 trial in children and adolescents
however, between memantine (69%) and placebo (66.7%) also do not support its efficacy [8]. While recent studies
in the withdrawal phase. No new safety concerns were of vasopressin were somewhat promising, there is cur-
observed in the open-label extension trial. In a separate rently insufficient evidence to support its use clinically.
study, Karahmadi et al. investigated memantine as an Although the more recent memantine trials demonstrated
adjunct to applied behavior analysis (ABA) therapy mixed results [11, 12], it may be worth investigating fur-
for children in a small randomized single-blind trial in ther and a large RCT of memantine for the treatment of
children (< 14 years) with ASD [12]. Sixty participants social deficits in youth is currently underway [13].

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Repetitive Behaviors adverse events were reported in both groups. Both trials
may have encountered limitations inherent to the use of the
Restricted, repetitive patterns of behavior comprise the sec- CY-BOCS-PDD in individuals with ASD [18]. Individuals
ond core symptom domain of ASD and include repetitive with ASD experience a range of repetitive behaviors,
motor movements, repetitive use of language, circumscribed some of which are pleasurable and others of which
preoccupations, ritualistic behaviors, difficulty coping with are distressing. It is not clear that the CY-BOCS-PDD
change, and unusual sensory interests. Similar to social measures improvement in some of the repetitive behaviors
impairment, there are no medications currently approved of ASD which may be pleasurable or serve an adaptive
by the FDA for repetitive behavior in ASD. Randomized function for the individual, yet cause impairment in daily
controlled trials of second-generation antipsychotics, par- living. Notably, the results from these two trials contrast
ticularly risperidone and aripiprazole, have demonstrated with results from previous trials which included adults
some benefit for repetitive behaviors. A recently published with ASD, suggesting that SSRIs may be more beneficial
systematic review and meta-analysis including 21 RCTs and better tolerated in post-pubertal individuals [19, 20].
(n = 1309) concluded that antisychotics “probably slightly Other pilot studies published within the past 3 years
reduce” repetitive behaviors in children and adolescents with have investigated several other medications including
ASD [15]. In light of this weak evidence and the significant guanfacine, bumetanide, and baclofen for repetitive
side effect burden associated with second-generation antip- behaviors in ASD. An analysis of secondary outcome
sychotics including weight gain, metabolic problems, and measures of a previously reported 8-week randomized
extrapyramidal symptoms, they are not commonly used for double-blind, placebo-controlled trial of extended-
this indication in clinical practice. Alternative safe and effec- release guanfacine, an alpha- 2 agonist, for hyperactivity
tive treatment options remain greatly needed. in 62 youth with ASD (5–14 years) [21], demonstrated
The use of SSRIs for the treatment of repetitive significant between-group differences in repetitive
behavior in ASD has received significant attention over the behaviors as measured by the CY-BOCS-ASD [22].
years with mixed results. Two recent randomized double- Bumetanide, a loop diuretic thought to impact GABA
blind, placebo-controlled trials investigating fluoxetine through regulating chloride homeostasis, was assessed
in children and adolescents with ASD add new evidence in a 91-day randomized double-blind, placebo-controlled
that SSRIs do not provide benefit for repetitive behaviors trial in 92 youth (7–15 years) with ASD. Bumetanide was
compared to placebo as measured by the Children’s not superior to placebo for the primary outcome, the SRS-
Yale-Brown Obsessive Compulsive Scale (CY-BOCS). 2, but was superior to placebo for one of the secondary
Reddihough et al. conducted a 16-week randomized outcomes, the Repetitive Behavior Scale-Revised [23].
double-blind, placebo-controlled, multi-site trial including Baclofen, a selective G ­ ABA B receptor agonist, was
146 children and adolescents (mean age 11.2 years) with investigated as an adjuvant therapy to risperidone in a
ASD [16••]. The primary outcome was the total score on the 10-week randomized double-blind, placebo-controlled
CY-BOCS, modified for pervasive developmental disorder trial including 64 children (3–12 years) with ASD [24].
(CY-BOCS-PDD). Forty-one percent of participants in the Improvements in all the ABC subscales were observed in
fluoxetine group and 36% of participants in the control both treatment groups; the adjuvant baclofen group was
group discontinued participation. The most common superior to placebo plus risperidone only on the ABC
reasons for discontinuation included parent decision hyperactivity subscale, indicating that it did not provide
to discontinue, adverse events, and clinician decision additional benefit beyond risperidone for repetitive
to discontinue. The most common adverse events were behaviors. Finally, as discussed in the previous section,
mood disturbance, particularly irritability; gastrointestinal two recently published double-blind, placebo-controlled
problems; and sleep disorders. Although the between- trials of oxytocin for social deficits in ASD noted
group mean difference in CY-BOCS-PDD score was improvements in repetitive behaviors [6, 7].
statistically significant (p = 0.03) at endpoint, fluoxetine In summary, there is no strong evidence for any medica-
was not found to be superior to placebo after controlling tion or class of medications for the treatment of repetitive
for pre-specified covariates including sex, verbal ability, behaviors in ASD. While antipsychotics may be somewhat
and imbalances in baseline and demographic variables efficacious, clinical use is limited by their side effect pro-
(p = 0.21). Similar results were reported by Herscu et al. file. The two recently published double-blind, placebo-
after completing a 14-week multi-site randomized double- controlled studies on SSRIs provide additional evidence
blind, placebo-controlled trial of fluoxetine in 158 children against the use of SSRIs for repetitive behaviors in chil-
(5–17 years) with ASD [17••]. No significant between- dren and adolescents with ASD. There is, however, some
group differences were observed on the CY-BOCS-PDD new evidence to support the use of extended-release guan-
(p = 0.06) and high rates of behavioral activation and facine for repetitive behaviors.

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Irritability improvement using unblinded parent reports without the use

of a validated scale. The increasingly popular perception that
Irritability is common among individuals with ASD and cannabis-derived products have established efficacy for a
encompasses aggression, self-injurious behavior, prop- wide range of conditions suggests that an underlying placebo
erty destruction, and severe tantrums. A practice pathway effect may be partially influencing the results of these two
published in Pediatrics highlights the need to identify and prospective studies. Finally, the variability in the cannabis
address the medical, psychiatric, communicative, behavio- products, dosage, and route of administration further limits
ral, and social factors that may be contributing to disruptive the conclusions that can be drawn from these two prospec-
behaviors [25]. If such interventions fail, psychopharmaco- tive, open-label studies.
logic treatments may be necessary. As stated earlier, risp- Aran et al. conducted a 12-week randomized double-
eridone and aripiprazole are FDA approved for the treat- blind, placebo-controlled single-site trial studying the effi-
ment of irritability in children and adolescents with ASD. cacy of CBD in 150 individuals (5–21 years) with ASD [32].
Risperidone’s FDA approval was based upon two landmark Participants were randomized to either whole-plant cannabis
8-week randomized double-blind, placebo-controlled trials extract, pure CBD, or placebo followed by a washout and
which each demonstrated significant reductions in irritability single crossover period. All participants received a cannabis
in youth with ASD associated with risperidone compared to product in at least one of the two treatment arms. The co-
placebo [26, 27]. Similarly, aripiprazole received its FDA primary outcomes were change in total scores of the Home
indication for irritability in youth with ASD following the Situation Questionnaire-ASD (HSQ-ASD) and disruptive
publication of two 8-week randomized double-blind, behavior measured using the CGI-I. Forty-nine percent
placebo-controlled trials demonstrating its efficacy [28, 29]. of participants who received whole-plant cannabis extract
The considerable side effect burden of second-generation experienced improvement in disruptive behavior (CGI-I = 1
antipsychotics and lack of response in some patients have “very much improved” or 2 “much improved”), which was
led to an ongoing search for alternative treatments. significantly higher than the placebo response rate of 21%
Recent investigations have focused on the potential role (p = 0.005). However, the improvement in disruptive behav-
of cannabidiol (CBD) in the treatment of irritability in ASD. iors for those treated with pure CBD (38%) was not supe-
Two prospective, open-label trials and one double-blind, rior to placebo (p = 0.08). Both whole-plant cannabis extract
placebo-controlled trial of CBD for irritability in ASD have and CBD were generally well tolerated, with somnolence,
been published within the past 3 years. The first prospective, decreased appetite, tiredness, euphoria, and anxiety being
open-label trial included 53 individuals (4–22 years) with the most commonly reported adverse effects. Since this
ASD who received CBD for a median duration of 2 months trial used a particular standardized formulation of CBD, the
[30]. Each participant received a preparation of 30% CBD in results may not be generalizable to other CBD oils derived
a ratio of 20:1 cannabidiol:Δ9-tetrahydrocannabinol (THC). from alternative strains. Limitations of this study include
Parents reported a change in symptoms of hyperactivity, the heterogenous sample, limiting the ability to determine
sleep problems, self-injury, and anxiety on a three-point whether a particular subgroup may benefit the most from
scale (improvement, no change, or worsening of symptoms). the use of cannabis-derived products. Additionally, while
Sixty-eight percent of participants experienced parent- the crossover design allowed all participants to receive at
reported improvements in self-injury. The most frequently least one type of cannabis formulation, the researchers were
reported adverse effects included somnolence (22.6%) and not able to utilize within-participant analyses as they noted
appetite suppression (11.3%). The second prospective, open- a higher change from baseline in the first treatment period
label study investigated the effectiveness of a medical can- compared to the second, suggesting a placebo effect.
nabis product among 188 participants with ASD (mean age At this time, there is insufficient evidence to suggest that
12.9 years) [31]. Most participants used oil with 30% CBD CBD be used to target irritability in individuals with ASD.
and 1.5% THC sublingually three times daily; however, the Encouragingly, cannabis-derived products were generally
route of administration, preparation, dose, and schedule well tolerated, and in fact may be associated with weight loss
varied among patients. Changes in ASD-associated symp- [32•], a potential advantage over second-generation antip-
toms including restlessness, rage attacks, agitation, sleep sychotics. However, the relatively short durations of these
problems, and anxiety were measured at 6 months using studies limit the ability to detect potential long-term adverse
a seven-point caregiver scale. Rage attacks and agitation effects which may be of particular salience in child and ado-
improved among 89% and 84% of participants, respectively. lescent populations. These may include effects on cognition,
Notably, the dosages of other psychotropic medications were increased risk of cannabis or other substance use disorders,
altered in 43% of patients in this study, possibly confound- and other psychiatric disorders (e.g. psychosis, mood dis-
ing the effect of the cannabis products. The main limita- orders, anxiety). There are several challenges in designing
tion of both these studies was the measurement of symptom high quality clinical trials assessing CBD including the vast

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heterogeneity of compounds available and the observation communication and social interaction subscales. A statisti-
that participants may be able to readily distinguish cannabis cally significant difference in change in global ADOS score
products from placebo due to its potentially psychoactive between groups was not observed; however, statistically sig-
effects. A large, multi-center randomized placebo-controlled nificant greater improvements in the ADOS communication
trial is warranted to help parcel out potential biases, develop (p = 0.02) and social interaction (p = 0.019) subscale scores
an efficacious standardized formulation, and better assess were observed in the folinic acid group compared to placebo.
long-term adverse effects. Until then, the magnitude of The third 10-week randomized double-blind, placebo-
potential risks and benefits remain largely unknown. Cur- controlled trial investigated folinic acid as an adjuvant
rently, there are three double-blind randomized controlled to risperidone for inappropriate speech in 55 children
trials and one open-label trial underway. (4–12 years) with ASD [40]. All participants received ris-
peridone plus either high dose folinic acid (2 mg/kg, up
Language Impairment to 50 mg per day) or placebo. The primary outcome was
change in the Inappropriate Speech subscale of the ABC-
Current estimates suggest that about a quarter to a third of Community (ABC-C). Greater improvements in the ABC-C
children with ASD have verbal language deficits [33, 34]. Inappropriate Speech subscale were observed in the folinic
The inability to fully communicate can lead to distress and acid group compared to the placebo group (p = 0.045).
discomfort that may manifest as agitation and irritability. Unlike the aforementioned studies, Batebi and colleagues
Currently, the most effective treatment for language impair- reported a higher rate of adverse effects, including increased
ment associated with ASD includes early intensive behavio- appetite and diarrhea, although these observations may be
ral, speech, and educational interventions [35]. At this time, confounded by the concurrent use of risperidone.
there are no FDA-approved medications for language deficits Overall, these three studies provide promising prelimi-
in ASD. As such, the search for an effective and tolerable nary evidence for folinic acid for the treatment of verbal
pharmacological intervention remains of critical importance. language deficits in children with ASD. However, larger
Folinic acid has emerged as a potentially promising candi- studies of longer duration are needed to provide conclu-
date [36, 37]. Biochemically, folate metabolism abnormali- sive evidence, optimize dosing, and further characterize
ties have been linked to ASD, including an association with the population (age, type of language deficit) that may be
cerebral folate deficiency [37]. Furthermore, the presence of most responsive to treatment. Finally, since these three tri-
folate receptor-α autoantibodies (FRAAs) may help predict als were all single-site studies, multi-site studies are needed
treatment response [36]. to increase generalizability. Encouragingly, there are three
Three randomized double-blind, placebo-controlled trials ongoing multi-center trials currently registered with clini-
assessing folinic acid for the treatment of language impair- caltrials.gov that have yet to publish results. Nevertheless,
ment in children with ASD have been published. The first the overall positive outcomes presented in these early studies
trial included 48 children (3–15 years) with ASD with a and the safety profile of folinic acid are encouraging.
wide range of language impairment who were randomized
to receive 12 weeks of either high dose folinic acid (two
mg/kg per day, maximum 50 mg per day) or placebo [38•]. Conclusion
Baseline and 12-week verbal language skills were assessed
using the age-appropriate version of the Clinical Evalua- The identification of safe and effective pharmacological
tion of Language Fundamentals (CELF). The results of this treatments to ameliorate the core and associated symptoms
trial demonstrated a statistically significant improvement in of ASD has proven difficult. Psychopharmacology research
verbal communication in the folinic acid group compared to in this area faces several significant challenges including the
placebo (p = 0.02). Folate receptor-α autoantibody status was heterogeneity of ASD without biologically defined endophe-
predictive of response to treatment. Folinic acid was well notypes and the inherent difficulty of using a psychotropic
tolerated and was not associated with any serious adverse medication to reverse neurobiological pathophysiology that
effects. likely occurs either prenatally or very early in development.
The second placebo-controlled trial assessed com- The results from recent clinical trials research over the past
mercially available low dose folinic acid (five mg twice few years also underscore high rates of placebo response in
daily) for 12 weeks [39]. The study included 19 children this population and the need for outcome measures that are
(3–10 years) with ASD and documented language impair- both specific to the target symptoms of interest and capable
ments. Similar to the Frye et al. trial [38•], individuals were not of detecting change as important factors in study design.
excluded based on the severity of their language impairment. Despite these challenges, the field continues to make pro-
The primary outcome measure was the change in ADOS gress. Recent research has provided more conclusive evi-
score and secondary outcome measures included the ADOS dence against the use of some medications such as oxytocin

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 79 Page 8 of 9 Current Psychiatry Reports (2021) 23: 79

for social impairment in children, adolescents, and adults Mol Psychiatry [Internet] Springer Nature. 2020 [cited 2021 Jun
and SSRIs for repetitive behaviors in children, as well as 10];25:1849–58. Available from: https://​pubmed.​ncbi.​nlm.​nih.​
gov/2​ 99551​ 61/. This is the largest study to have examined the
some new promising avenues for further study including effect of oxytocin on social impairment in adults with autism
folinic acid for language impairment. spectrum disorder.
8. Spanos M, Chandrasekhar T, Kim SJ, Hamer RM, King BH,
Acknowledgements DS receives research support from the Thrasher McDougle CJ, et al. Rationale, design, and methods of the
Research Fund. This work was supported, in part, by the Nancy Lurie Autism Centers of Excellence (ACE) network Study of Oxytocin
Marks Family Foundation. in Autism to improve Reciprocal Social Behaviors (SOARS-B).
Contemp Clin Trials [Internet]. Elsevier Inc. 2020 [cited 2021
Jun 10];98. Available from: https://​pubmed.​ncbi.​nlm.​nih.​gov/​
Compliance with Ethical Standards 32777​383/.
9. Bolognani F, Del Valle Rubido M, Squassante L, Wandel C,
Conflict of Interest The authors declare that they have no conflict of Derks M, Murtagh L, et al. A phase 2 clinical trial of a vasopres-
interest. sin V1a receptor antagonist shows improved adaptive behaviors
in men with autism spectrum disorder. Sci Transl Med [Internet]
Human and Animal Rights and Informed Consent This article does not AAAS. 2019 [cited 2021 Jun 10];11. Available from: https://​
contain any studies with human or animal subjects performed by any pubmed.​ncbi.​nlm.​nih.​gov/​31043​521/.
of the authors. 10. Parker KJ, Oztan O, Libove RA, Mohsin N, Karhson DS,
Sumiyoshi RD, et al. A randomized placebo-controlled pilot
trial shows that intranasal vasopressin improves social defi-
cits in children with autism. Sci Transl Med [Internet] AAAS.
2019 [cited 2021 Jun 10];11. Available from: https://​pubmed.​
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