Appetite 137 (2019) 62–72

Contents lists available at ScienceDirect

Appetite
journal homepage: www.elsevier.com/locate/appet

Use of cyproheptadine to stimulate appetite and body weight gain: A T

systematic review
Megan E. Harrisona,b,∗, Mark L. Norrisa,b, Amy Robinsona,b, Wendy Spettigueb,c,
Morgan Morrisseyd, Leanna Isserlinb,c
a
Department of Paediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada
b
Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
c
Department of Psychiatry, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada
d
Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada

A R T I C LE I N FO A B S T R A C T

Keywords: Objective: A systematic review identifying the use of cyproheptadine (CY) as an appetite stimulant was com-
Appetite stimulation pleted.
Avoidant restrictive food intake disorder Method: Studies of any design exploring the efficacy of CY as an appetite stimulant in all age groups and po-
Cyproheptadine pulations were included. Primary outcomes of studies included were weight gain, appetite stimulation, and/or
Eating disorder
caloric/nutritional intake increase. The review was completed in accordance with PRISMA standards.
Results: A total of 46 articles across 21 different treatment populations met criteria for the review, including 32
randomized controlled trials, 4 prospective cohort studies, 4 retrospective cohort studies, 4 case reports and 2
case series. Of these, 39 demonstrated that CY resulted in significant weight gain in the sample under study.
Studies exploring the use of CY in those with malignant/progressive disease states, such as HIV and cancer,
showed minimal to no benefit of the medication. Transient mild to moderate sedation was the most commonly
reported side effect. Studies included were heterogeneous in terms of methods as well as study patient demo-
graphics, characteristics and concurrent medical conditions. Few studies provided objective measures of appetite
change.
Discussion: CY appears to be a safe, generally well-tolerated medication that has utility in helping facilitate
weight gain in patients drawn from a variety of underweight populations. Future prospective randomized
controlled studies in low weight patients that include objective measures of appetite and intake are needed to
better understand the mechanism by which CY augments weight gain.

1. Introduction
Cyproheptadine (CY) is a serotonin 5-HT2 and histamine H1 an-
tagonist that was introduced for the treatment of allergic states. The
medication was studied in 1959 in children with hay fever, with the
authors noting a significant increase in appetite, body weight (BW) and
linear growth as side effects (Lavenstein, Dacaney, & Metre, 1962). In
the years that followed, these side effects were confirmed in those with
and without allergies (Bergen, 1964; Drash, Elliott, Langs, Lavenstein, &
Cooke, 1966; Francini, Santana, & Kitrosen, 1967). Over the last 50
years, numerous investigators have studied the medication's utility as
an appetite stimulant in malnourished and/or underweight patients
with a variety of health conditions, such as cancer, metabolic disease,
failure to thrive, malnutrition, HIV, anorexia nervosa (AN) and cystic
fibrosis (CF) Although considered an ‘older’ drug, and one not typically
used now in the treatment of eating disorders (EDs), it is worth re-
considering CY's potential role in the treatment of under-nourished
adults and children, including those with avoidant restrictive food in-
take disorder (ARFID).
The primary objective of this study was to conduct a systematic
review of CY's use and ability to act as a stimulant of appetite and
weight gain, using internationally accepted search criteria such as that
outlined by PRISMA guidelines (Moher, Liberati, Tetzlaff, & Altman,
2009). Our secondary objectives were to: review the safety of CY and
identify commonly noted side effects attributed to CY; and describe
whether CY appears to be more effective in particular age groups or for

∗
Corresponding author. Division of Adolescent Medicine, Department of Pediatrics, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, Ontario, K1H
8L1, Canada.
E-mail address: mharrison@cheo.on.ca (M.E. Harrison).

https://doi.org/10.1016/j.appet.2019.02.012
Received 19 October 2018; Received in revised form 11 February 2019; Accepted 18 February 2019
Available online 27 February 2019
0195-6663/ © 2019 Published by Elsevier Ltd.
M.E. Harrison, et al.
particular diagnoses.
In accordance with PRISMA guidelines, our systematic review pro-
tocol was registered with the International Prospective Register of
Systematic Reviews (PROSPERO) on 19 September 2016 (registration
number CRD42016047875).
2. Method
2.1. Search strategy
The following databases were searched focusing on CY use as an
appetite stimulant: MEDLINE including Epub Ahead of Print, In-Process
& Other Non-Indexed Citations (1946–June 22, 2018) and Embase
(1980–June 22, 2018) and the CENTRAL Trials Registry of the
Cochrane Collaboration (May 2018 Issue) using the Ovid interface.
Searches were designed and conducted by a librarian experienced in
systematic reviews, using a method designed to optimize term selection
(Bramer, Giustini, & Kramer, 2016). Search strategies are presented in
Appendix 1. Non-English articles were included assuming they could be
translated sufficiently, using Google Translate, for evaluation. Biblio-
graphies of manuscripts were also searched to ensure any relevant ar-
ticles were included in the initial screen.
2.2. Eligibility criteria
Studies of any design, including published case reports, that in-
volved pediatric and adult patients with any medical or psychiatric
condition and in any setting were included. Studies were included
where CY was the exposure and where the primary outcomes for the
studies were: 1) weight gain, and/or 2) appetite stimulation, and/or 3)
caloric/nutritional intake increase. Studies that were reviews, com-
mentaries or conference abstracts, or could not be translated during the
review timeframe were excluded.
2.3. Abstract and article selection
After initial online duplicate removal, records retrieved by the
electronic search were downloaded and imported into a Reference
Manager database, where any remaining duplicate references were re-
moved. Throughout the review, newly identified records were in-
tegrated into the set for screening. Records were uploaded to
CrowdScreen (Nama et al., 2017) and appraised against the inclusion
criteria. First, two reviewers independently reviewed the titles and
abstracts of the papers identified from the search, using the inclusion
criteria. In cases where reviewers did not agree on the study's eligibility,
a third reviewer helped determine suitability. The full text of eligible
studies was assessed for suitability by two review team members, with
input from a third provider when necessary. Results were uploaded into
a secure RedCap electronic database (Harris et al., 2010). Reviewers
were not blinded to study authors or institutions during the review.
3. Results
In total, 591 records were identified through the initial database
search, resulting in 530 records for screening after duplicates were re-
moved. Reference lists identified 8 additional reports that were assessed
for eligibility. A total of 46 articles met criteria for the review (Fig. 1);
32 randomized controlled trials (RCTs), 4 prospective cohort studies, 4
retrospective cohort studies, 4 case reports and 2 case series.
3.1. Cyproheptadine use in healthy adults
A total of 5 studies were identified that examined CY's as a stimulant
of appetite and weight gain in healthy, “normal weight” adults
(Table 1). In each of these studies, investigators sought to better un-
derstand CY's mechanism of action and effect on the biochemical and
63
Appetite 137 (2019) 62–72
metabolic profile of patients. Small sample sizes and varying durations
of treatment precluded formal comparisons of studies. Only one study
(Comer, Haney, Fischman, & Foltin, 1997) included an objective mea-
sure for appetite. In this 18 day residential trial of 7 normal weight
volunteers, the authors demonstrated that CY increased caloric intake
as measured by the number of eating occasions but not as a result of
increased meal size.
3.2. Cyproheptadine use in underweight adults
Seven studies, including 6 RCTs were identified that explored the
use of CY in underweight but otherwise healthy adults (Table 2).
The RCTs showed mainly positive results regarding CY's efficacy in
promoting weight gain (Noble, 1969; Pawlowski, 1975; Sardesai et al.,
1970; Silbert, 1971; Silverstone & Schuyler, 1975) with only one RCT
showing no significant weight gain in elderly patients treated with CY
(Andronic & Di Mascio, 1971). Silbert examined the use of CY in chil-
dren and adults with multifactorial loss of appetite over 4 weeks, using
CY doses that ranged from 2 to 8 mg/day (Silbert, 1971). A statistically
greater increase in weight in the CY group was reported at weeks 8 and
12 regardless of dose. Pawlowski et al. demonstrated a greater increase
in weight for patients chronically underweight at each 2 week interval
for their CY group (12 mg/day), with the CY group gaining 3 kg as
compared to 1.3 kg for the placebo group at the conclusion of the 12
week trial.
3.3. Cyproheptadine use in anorexia nervosa
Five RCTs examined the use of CY in adults with AN, four of which
were conducted on hospital inpatient units and one of which took place
in a hospital outpatient setting (Table 3). Additionally, Benady pub-
lished a case report that described favourable weight gain effects of CY
in a 12 year old female with AN (Benady, 1970). In the RCTs, patients
received doses of CY ranging from 2 mg/day to 32 mg/day in divided
doses (e.g. three or four times daily). The primary outcome in the RCTs
was weight gain (Halmi, Eckert, & Falk, 1983, 1982; Goldberg, Halmi,
Eckert, Casper, & Davis, 1979; Halmi, Eckert, LaDu, & Cohen, 1986;
Vigersky & Loriaux, 1977, pp. 349–356). Secondary outcomes were
included in 3 studies and consisted of appetite, and mood symptoms as
rated by the Hamilton Rating Scale and Beck Depression Inventory
(Halmi, Eckert, & Falk, 1982, 1983, 1986). Four of the five RCTs
(Goldberg et al., 1979; Halmi et al., 1982, 1983, 1986) demonstrated a
statistically significant increase in weight in CY-treated patients. Two of
the five RCTs (Halmi et al., 1983, 1986) appeared to be a continuation
of an earlier reported RCT (Halmi et al., 1982). In the largest of these
studies, Halmi et al. (1986) reported a differential drug effect attributed
to CY in patients with and without symptoms of bulimia. The drug
significantly increased the efficacy of treatment for those whose en-
dorsed primary restrictive symptoms, whereas the CY impaired treat-
ment efficacy in patients who endorsed symptoms of bulimia. In the
single study that failed to demonstrate a difference in weight gain be-
tween CY and placebo (Vigersky & Loriaux, 1977, pp. 349–356), the
maximum dose used was far lower than in the other studies (12 mg/day
vs 32 mg/day); the study was small (n = 13 for the CY group); and the
study took place in an outpatient setting as compared to an inpatient
setting. Table 3 further describes these studies.
3.4. Cyproheptadine use in adults with mixed disease states
A total of 5 RCTs and one parallel, non-blinded, non-randomized
trial was included (Table 4). Four of these studies reported significant
increases in weight. All of these studies had significant limitations, in-
cluding using heterogeneous sample populations in terms of medical
diagnosis (ie. “psychiatric leanness,” dystonia, neurasthenia, duodenal
ulcers, gastritis, hepatitis, chronic urticaria, etc) (Irsy & Szatloczky,
1977; Tiszai & Szasz, 1972), as well as failing to account for
M.E. Harrison, et al.
Fig. 1. PRISMA 2009 Flow Diagram. Study: The use of cyproheptadine as an appetite stimulant: a systematic review.
confounding factors (i.e. socioeconomic status) (Rahman, 1975), short
study periods (Irsy & Szatloczky, 1977; Tiszai & Szasz, 1972), and lack
of objective measures of appetite stimulation. In disease states invol-
ving anorexia and cachexia as symptoms of disease progression, no
observable effect of CY on weight gain was noted. Irsy et al. reported
stimulation of appetite and increased weight gain in healthy volunteers
as well as the majority of individuals studied with varying chronic ill-
nesses, although no appreciable effects on appetite or weight were
demonstrated in a group of patients suffering from malignant diseases.
It must be noted however that authors failed to include the mechanism
by which appetite change was measured. In a larger, multicenter trial
involving patients with advanced malignant cancer, Kardinal et al.
found mildly enhanced appetites reported by patients on CY, but no halt
in progressive weight loss (average weight loss of 2 kg/month in the
treatment group versus 2.2 kg/month in the placebo group, p = 0.72),
even when adjusted for potential prognostic factors (Kardinal et al.,
1990).
In a study comparing CY versus megestrol acetate in HIV out-
patients, Summerbell et al. showed an increase in mean daily energy
intake in both treatment groups compared to pretreatment assessment;
energy intake increased by 500 kcal/day in both groups (p < 0.05),
however decreased after treatment (Summerbell, Youle, McDonald,
Catalan, & Gazzard, 1992). Despite this, variable weight gain was seen
with CY-treated patients (weight gain in 3/7 patients, weight loss in 2/
7, stable weight in 1/7, one patient death). In another double blind
placebo controlled study of CY's effect on patients with irritable colon
64
Appetite 137 (2019) 62–72
syndrome, Mainguet, (1972) reported greater weight gain and appetite
stimulation in those treated with CY. In this study, appetite stimulation
was measured by appetite level in combination with caloric intake,
although the specific details by which this data was collected were not
specified.
3.5. Cyproheptadine use in malnourished and underweight children
Ten articles investigating the utility of CY for appetite stimulation in
pediatric malnourished and underweight patients were included in this
review (Table 5). Randomized controlled trials were most common
study design identified (n = 8). None of the studies included objective
measures of appetite. Although a total of 509 patients were included
across all of the RCTs, variation in study sample age (1.3–16 years),
study design, drug dosing and active comparator descriptions, as well as
length of trials, prevented the completion of a meta-analysis. All studies
that investigated the effect of CY on weight in underweight children
showed some degree of improvement on medication. Further, studies
that sought to also investigate CY's effect on growth also showed a
positive effect when study designs were 3 months in length or more
(Mahachoklertwattana, Wanasuwankul, Poomthavorn, Choubtum, &
Sriphrapradang, 2009; Penfold, 1971). Only one study examined
growth effects with outcomes at less than 3 months, with no effect
demonstrated (Najib et al., 2014). CY was typically well tolerated in all
studies in this category, with no significant adverse effects reported.
The most common side effect noted was sedation, which was noted to
 Table 1
Cyproheptadine use in Healthy “Normal Weight” Adults.
Author(s) Study design Age (mean Sex Sample size Setting+ Medication dose Study Outcomes
yrs,range) duration
M.E. Harrison, et al.

Najjar and Khachadurian, (1969) Prospective cohort 23.7 (13–39) 17 M 4 F 20 healthy adults, one ND CY 4 mg tid 1–4 wks Appetite stimulation in 17/20*; mean weight gain
adolescent 1.2 kg in 1 wk (n = 20), 2.4 kg in 4 wks (n = 9)
Stiel et al., (1970) RCT in study A; single blind in 30.6 (22–48) 7F 5M 12 healthy adults O CY 4 mg tid 6 wks Higher mean weight gain on CY (mean 2.2 kg in
study B; case studies in study C 2 wks) (P < 0.001)and increased reported
appetite*
Saleh, Yang, Van Itallie and Prospective case series 28 (25–31) 2M 2 healthy adults, one HO CY 4 mg tid 33 & 35 days Increased weight gain with CY versus placebo
Hashim (1979) underweight (p < 0.01), more apparent in underweight subject
Fantino et al., (1990) RCT 30.1 (19–48) 8M 14 healthy adults (mean HL CY 4 × 4 mg doses in prior 24 h No effect on hunger/appetite sensation*
-cross-over study 6F BMI 22.26) 21 h
-placebo vs CY
-patients were own controls
Comer et al., (1997) RCT 26.3 (21–33) 4M 7 healthy adults (mean BMI CL CY 4 mg tid daily; 18 days Total caloric intake increased by 500 kcal/d when
-cross-over study 3F 24.4 ± 2.7 kg/m2) Regular, low- or high- taking CYP as compared to placebo (p < 0.007)
-placebo vs CY carbohydrate diets
-patients were own controls

+ND = not documented; O = outpatient; HO = hospital outpatient; HL = hospital laboratory; CL = community laboratory.
*appetite measured via self-report.

65
Table 2
Cyproheptadine use in underweight adults.
Author(s) Study design Age (Mean, Range in Sex Sample size Settingˆ Medication dose Study duration Outcomes
yrs)

Noble (1969) RCT 28; 18 - 48 F& M+ 20 O CY 4 mg tid 56 d Greater mean percentage weight-gain (CY 3.8 vs Control 1.3 kg) (p < 0.05) and mean
appetite increase* (p < 0.01)
Sardesai et al., (1970) RCT 16–23 27 M 40 O CY 4 mg tid 12 wks Increased weight gain with CY (2.1 kg) versus placebo (0.4 kg) (p < 0.05)
13 F
Silbert (1971) RCT 16, 3-43 F& M+ 65 HO CY 2–8 mg/d 3 mos Significantly greater appetite* and weight gain in CY groups, mean range 1.5 kg (CY 2 mg)
to 4.3 kg (CY 8 mg) vs placebo (0.2 kg)
+
Andronic and Di Mascio, RCT 63–86 F&M 30 HI CY 4 mg tid 56 d No statistically significant increase in body weight or appetite ratings**
(1971)
+
Pawlowski (1975) RCT 32, 15-58 F&M 26 HO CY 12 mg/d 3 mos Weight increase higher in CY group (3 kg) vs placebo (1.3 kg)
Increase in appetite higher in CYP group*
Silverstone and Schuyler, RCT cross- 21.6, 19-24 13 M 16 O CY 4 mg tid 8 wks Weight increase higher in CY group (2 kg) vs placebo (0.2 kg) (p < 0.001)
(1975) over 3F Increase in appetite higher in CYP group*
Higher daily caloric increase in CY group (2905 kcal) vs placebo (2633 kcal)
Genazzani et al., (2001) Case Series Not documented F 8 CO CY 4 mg/d 120 d None of the patients resumed menstruation
Non-significant increase in BMI was observed
No significant changes in the quality of quantity of the food consumed

*Appetite measured via self-report.

**nurses' ratings of appetite
+details not provided.
ˆ
O = outpatient; HO = hospital outpatient; HI = hospital inpatient; CO = community outpatient.
Appetite 137 (2019) 62–72
M.E. Harrison, et al. Appetite 137 (2019) 62–72

typically improve a few days after starting medication. In addition to

Weight gain of 0.68 kg/wk for 6 mos after starting treatment with CY. Patient achieved menarche.

Significant CY effect on HAM-Dˆ and on weight gain (increase from 75% of “normal” weight to

CY significantly increased treatment efficiency for restricting subtype patients and significantly
Significant CY effect on weight gain (increase from 76.8% of “normal” weight to 98.8% in CY

amitriptyline- and placebo-treated groups. CY group experienced a significant decrease in the

Non-significant weight gain in CY group (5.1 kg) va placebo (4.3 kg). Greatest benefit seen in
the factors listed above, other important limitations exist within these

impaired treatment efficiency for the binge-purge subtype patients when compared with the
studies, including possible effects of concurrent medical issues amongst
sample size (ie. high rate of parasitic infections noted in one study)
(Sanzgiri, Mohamad, & Raja, 1969) and high sample attrition
(Mahachoklertwattana et al., 2009; Najib et al., 2014; Penfold, 1971).

3.6. Cyproheptadine use in malnourished and/or underweight children with

concurrent chronic medical conditions
No difference in weight gain between CY and control groups.

patients with largest % weight loss at initiation of the study.

Twelve studies, that examined the effects of CY on weight gain and/

or appetite in various childhood conditions were included in the review
(Table 6). As noted in other sections, these studies also varied sig-
group) and HAM-D scores, no effect on BDI# scores.

nificantly in design, size (n ranging from 1 to 70), patient population

characteristics (ie. disease conditions) and length of study treatment
(ranging from 7 weeks to 12 months).
CY's effectiveness has been studied in underweight children with CF
by 2 research groups (Epifanio et al., 2012; Homnick et al., 2004;
Homnick, Marks, Hare, & Bonnema, 2005). Homnick et al. (2004) in-
itially performed a well-designed 12 week randomized blinded placebo
controlled study of 18 patients with CF and ideal body weight for
height < 100%. Weight increased significantly more in the treatment
98% in CY group).

group as compared to the placebo group (3.45 kg vs 1.1 kg,

HAM-D ratings.

P < 0.0001), as did percent ideal body weight, skin fold measure-
Outcomes

ments, and BMI (all P < 0.0001). Following the RCT, an open-label
design continued for an additional 9 months and all placebo patients
were prescribed CY (total n = 12; 7 from the original treatment group
in the 2004 study and 5 from the placebo group from the original study)
(Homnick et al., 2005). Patients who changed from placebo to CY
6 months

3 months
duration

8 weeks

3 weeks

3 weeks
Unclear

gained weight over 3–6 months, with less weight gain near the end of
Study

the study. Authors cited variable adherence to medication dosing as a

possible explanation for less weight gain in the second portion of the
study, as well as possible decreased effect of the medication over time.
In another well-designed 12 week double blind placebo controlled
CY 12 mg/day to
Medication dose

study, Epifanio found significant increases in weight and BMI in pe-

CY 12 mg/day

CY 32 mg/day

CY 32 mg/day

CY 32 mg/day

diatric patients with CF (n = 25) who were treated with CY as com-

CY 4 mg tid

32 mg/day

pared to those on placebo (Epifanio et al., 2012).

There are 2 reports of CY's use in pediatric patients with cancer
(Couluris et al., 2008; Erdem, Emir, Demir, & Tunç, 2014). In an open
Setting

label prospective cohort study, Couluris found that CY was effective in

HO*
HI&

HO

promoting weight gain in children with cancer and treatment related

HI

HI

HI

HI

cachexia (Couluris et al., 2008). Fifty of the 66 patients in the study

Sample size

responded to CY treatment with significant weight gain (mean weight

gain 2.6 kg CI 1.93–3.27); interestingly, those with hematologic cancers
responded more than those with non-hematologic cancers (p = 0.04).
13

41

13

19

23
1

In a retrospective patient chart review of children with cachexia related

F& M

to cancer treatment (n = 14), Erdem reported an increase in weight in

Sex

11/14 patients and self-reported increase in appetite in 10 patients

Age in Years (Mean,

(71%) in those who were treated with CY (Erdem et al., 2014).

CY has also been effective in increasing weight in those with an-
Cyproheptadine use in Adults with Anorexia Nervosa.

*HI = hospital inpatient; HO = hospital outpatient.

Not reported

orexia and low weight due to other conditions, including asthma

20.5, 13-36
21, 13-36

21, 13-36

(Bergen, 1964; Lavenstein et al., 1962), metabolic disease (Lerman-

Range)

Sagie & Mimouni, 1995), tuberculous meningitis (Muranjan et al.,

28.9
12

1994), GH deficiency (Kaplowitz & Jennings, 1987), ADHD treatment-

related weight loss (Daviss & Scott, 2004), and Silver-Russell syndrome
Case report

(Lemoine et al., 2018) (Table 6). Although several studies noted im-
design
Study

provements in appetite based upon self report or parental observation,

RCT

RCT

RCT

RCT

RCT

objective measures of appetite were not included.

= Beck Depression Index.
ˆ = Hamilton Rating Scale.
Goldberg et al., (1979)

3.7. Tolerability of cyproheptadine

Vigersky and Loriaux,

Halmi et al., (1982)

Halmi et al., (1983)

Halmi et al., (1986)

Benady (1970)

In general, CY was well tolerated in all studies with no serious ad-

verse effects reported. As noted throughout the tables, mild to moderate
(1977)
Author(s)

drowsiness was commonly reported across many studies but was rarely
Table 3

severe enough to lead to medication discontinuation. In one study,

authors noted that sedation appeared to be dose dependent (Silbert,
#

66
 M.E. Harrison, et al.

Table 4
Cyproheptadine use in Adults with mixed disease states.
Author(s) Study design Age (mean Sex Sample size Setting Targeted disease Medication dose Study duration Outcomes
yrs,range)

Mainguet (1972) RCT 43, 15-79 48 F 97 O* Irritable colon syndrome CY 12 mg/day 12 wks Weight gain significantly higher in CY group at each 4
49 M week interval (p < 0.001); at 12 weeks, CY group gained
5.5 kg vs 1.1 kg in placebo. Only patients consuming
< 1800 cal/d experienced a significant improvement in
appetite throughout study.∼
Tiszai and Szasz Prospective 55.2 (16–78) 26 F 36 O Group A (n = 16): mixed CY 5 × 4 mg daily 14 days Increased average weight gain (2.5 kg) in patient group
(1972) Cohort study 10 M diseases++ with mixed diseases+++ (p < 0.01); no effect on average
Group B (n = 13): mixed body weight of DM or T2DM patients
diseases+++ & DM
Group C (n = 7): mixed
diseases+++ and T2DM
Rahman (1975) RCT 30.5 (16–50) 15 M 23 I* Chronic pulmonary CY 4 mg TID 12–16 wks Increase in mean weight gain versus placebo (4.8 kg vs
8F tuberculosis 1.9 kg)
Irsy and Szatloczky, RCT 43.3 Group I: 25 I&O Group I: mixed chronic CY 4 mg TID - QID 3–10 wks Significant weight gain in CY weeks in placebo-controlled
(1977) -cross-over study 16 F 10 diseases**; Group II: patients (0.7 kg vs 0.2 kg; p values < 0.05 to < 0.001)+
9M 5 neoplastic diseases*** ˆ;
Group II: Group III: controls CY more effective than placebo in 70% of cases.
3F No effect on weight of patients suffering from malignant

67
7M disease. ˆ
Group III:
1F
4M
Kardinal et al., (1990) RCT 65 (19–86) 164 M 293 O Advanced malignant CY 8 mg TID Variable, median Mildly enhanced appetites (p = 0.01)$, but no halt in
129 F cancer++ 36 daysdays progressive weight loss (p = 0.78)
Summerbell et al., RCT Not specified Not specified 14 O HIV CY 12 mg daily (vs up to 2 mos Increase in mean daily energy intake in both groups
(1992) 160 mg daily megestrol compared to pretreatment assessment (increase of
acetate) 500 kcal/day; p < 0.05); variable effect on weight gain,
no difference between CY or megestrol acetate

#
dropped to 55 patients by week 16 of the trial.
∼appetite increase measured via increase in caloric intake.
DM = subclinical diabetes mellitus; T2DM = type2 diabetes mellitus.
∗
O = outpatients; I = inpatients.
∗∗
examples include psychiatric leanness, dystonia, neurasthenia, duodenal ulcers, gastritis, hepatitis.
∗∗∗
examples include Hodgkin Lymphoma, breast cancer, multiple myeloma, colon cancer.
+
stats analyzed per week of treatment for 21 (13 in treatment group, 8 in control group) patients of total sample of 40.
++
primary tumor sites included were lung, GI, other.
+++
examples include chronic uticaria, neurasthenia, gastritis, bronchial asthma, depressive neurosis, angina pectoris, chronic enteritis, bronchopneumonia, cardiac insufficiency.
ˆ
no data provided on how increase in appetite was measured.
$
appetite increase measured via self-report.
Appetite 137 (2019) 62–72
 M.E. Harrison, et al.

Table 5
Cyproheptadine use in underweight and/or malnourished children.
Author(s) Study design Age (mean, Sex Sample size Setting+ Medication dose Study Outcomes
range) duration

Sanzgiri et al., (1969) RCT 4–8 yrs 26 F 40 CO CY 2 mg tid 3 mos Superior weight gain in CY group vs placebo (2.3 kg vs 0.3 kg)
14 M
Kibel (1969) RCT 1–13 yrs 49 F 96 HO CY 4 mg bid 12 wks Superior weight gain and appetite improvement* in CY treated sample vs
49 M placebo group
Juillard et al. (1985) RCT 3–16 yrs 62 F 129 HO CY 8 mg daily 6 wks Greater weight gain in CY group vs placebo (5.9% increase vs 3.4% increase,
67 M p < 0.01); increase in appetite in CY group at week 2 and 4*
Penfold (1971) RCT 8 yrs Not provided 36 HO CY 2 mg tid titrated to 4 mg 3 mos Greater weight gain in CY group vs vit B treated group (2.1 kg vs 1 kg)
tid
Burrows and Muzzo, (1981) RCT 1–4 yrs Not provided 70 HO > 2years: CY 10 mL bid; 8 wks Greater weight gain in CY group (293% increase in weight vs 155% increase

68
< 2 years: CY 5 mL bid in weight, p < 0.0025)
Berni Canini and Berni Canini RCT 2–11 yrs 20 F 40 HO CY 0.4 mg/kg/day divided 4 wks Improvement in weight in both groups (absolute change higher in the
(1988) 20 M tid before meals supplement + CY group); growth higher in the supplement + CY group
Mahachokler-twattana et al., RCT 2–10 yrs 11 F 21 HO CY 0.1 mg/kg/day hs 4 mos Greater weight gain (0.7 kg/2mos vs 0.1 kg/2mos), growth (1.7 cm/2 mos vs
(2009) 10 M 0.8 cm/2 mos), appetite* and IGF-1 scores in CY group vs placebo
Benjasuwantep (2009) Case Report 3 yrs 1M 1 HO CY 0.25 mg/kg/day divided 8 wks Weight gain (1 kg) noted by 4 weeks
tid
Najib et al., (2014) RCT 2–5 yrs 25 F 77 HO CY 0.25 mg/kg/day divided 1 mos Higher weight in CY group vs placebo at 1 month (0.6 kg vs 0.1 kg); no
52 M bid difference in weight or height at 2 months
Sant'Anna et al. (2014) Retrospective Cohort 34 ± 4.8 70 M 127 HO 0.25 mg/kg/day divided 6 mos Improvement in weight**, mealtime and feeding behaviors; CY well
months 57 F BID tolerated overall

+
CO = community outpatients; HO = hospital outpatients.
*appetite increase/improvement measured via self-report.
**measured by weight for age Z-scores.
Appetite 137 (2019) 62–72
 M.E. Harrison, et al.

Table 6
Cyproheptadine use in underweight children with mixed disease states.
Author(s) Study design Age(mean Sex Sample size Diagnoses Setting+ CYP dose Study duration Outcomes (mean weight gain, appetite)
yr,range)

Lavenstein et al., RCT 1–11 23 M 28 Asthma HO CY 4 mg qid 20–28 wks Weight gain: 254% of normal/expected weight gain in CY
(1962) 5F group vs 120% in chlorpheniramine grp(4 mg qid)
Appetite increase in CY group*
Bergen (1964) RCT 6–13 9M 16 Asthma HI CY 4 mg qid 15 wks Weight gain: CY group had a 16.4% increase in weight as
7F Vs placebo compared to 4.6% in the placebo control group
Appetite* and food intake increase: Moderate to marked
increase in CY gr.
Kaplowitz and RCT cross over study 2–11 6 GH deficiency Unclear CY 0.25–0.4 mg/kg/d 16 wks Weight gain: weight velocity increased from 1.3 ± 1.3 to 7.8
Jennings, (1986) ± 3.6 kg/y
Appetite increase noted in 5/6 patients*
Muranjan et al., (1994) Case report 4 F 1 TB meningitis Anorexia HI&HO CY starting at 0.5 mg/kg/day unclear Weight gain: 4.4 kg over 12 weeks; 6 kg over 6 months
Undernutrition Appetite increase noted*
Lerman-Sagie and Case report 11 F 1 Partial OTC deficiency HI CY 0.2 mg/kg/day 7 wks Weight gain: 3.5 kg in 7 weeks
Mimouni, (1995) Appetite increase noted*
Daviss and Scott, Retrospective cohort 8 18 M 21 ADHD and PO 4–8 mg CY nightly (mean dose 104.7 days Weight gain: 2.2 kg; mean weight velocity 32.3 g/day
(2004) 3F comorbiditiesˆ 4.9) ∗∗
Homnick et al., (2004) RCT 17 6M 16 CF HO CY 4 mg qid 12 wks Weight gain: 3.45 kg CY vs 1.1 kg
10 F

69
Homnick et al., (2005) Open label, 15 8 Fe 12 CF HO As above 9 mos Weight gain: Placebo patients gained weight (3.8 kg) in 3–6
prospective cohort 4M months when switched to CY
Couluris et al., (2008) Prospective cohort 12 40 M 70 Various forms of Cancer HI CY 0.25 mg/kg/day div bid 8 wks Weight gain: 50 patients (76%) responded to CY, weight gain
study 30 F If no response by 4 weeks, 2.6 kg (95% CI: 64–85%)
changed to megestrol acetate Hematologic CA had higher response (21/23 patients) vs
for remaining 4 wks nonhematologic CA (29/43) (p = 0.04)
Epifanio et al., (2012) RCT 5–18 25 CF HI CY 4 mg tid 12 wks Weight gain: 0.7 kg vs 1.6 kg
BMI: Increased 0.02 kg/m2 vs 0.5
Erdem et al., (2014) Retrospective cohort 4.5 (2–16) 9M 14 Various forms of Cancer unclear 8 wks Weight gain: 11 patients (78.5%) had increased weights
5F (1.4 kg)
Appetite increase noted in 71% (10 patients)*
Lemoine et al., (2018) Retrospective cohort 2 23 Silver- Russell CY 0.25 mg/kg/day div bid 12 mos 91% of patients responded to treatment with a gain of at least
syndrome (max dose 0.4 mg/kg/day) 0.5 SDS of weight during 1 year. Weight gain þ 0.1 SDS/mos of
treatment and length/height gain þ 0.05 SDS/mos of treatment

Leukemia (19); Sarcoma (15); Brain tumour (13); Lymphoma (6); Other (16).
All patients also taking GH 0.08 U/kg 3 times/wk.
Neuroblastoma (4); Lymphoma (2); Germinoma (3); Other (5).
+
HO = hospital outpatient; HI = hospital inpatient; PO = psychiatry outpatient.
ˆ
ADHD = attention deficit hyperactivity disorder (n = 21); ODD = oppositional defiant disorder (n = 14); CD = conduct disorder (n = 2); GAD = generalized anxiety disorder (n = 1); PDD = pervasive developmental
disorder (n = 2); SU = substance use (n = 1).
*appetite increase measured via self-report or parent report.
**All patients also on stimulant medication −11 on Adderall, 5 on Concerta, 2 on Adderall XR, 2 on dextroamphetamine tablets, 1 on methylphenidate.
Appetite 137 (2019) 62–72
M.E. Harrison, et al.
1971). Irritability was also reported as a side effect in one study
(Lemoine et al., 2018) and nausea and dizziness in another (Irsy &
Szatloczky, 1977).
Studies that explored possible biochemical and laboratory changes
in those taking CY showed no significant alterations to results either
pre-versus post-trial or in treatment versus placebo groups, including
fasting glucose (Najjar & Khachadurian, 1969; Stiel, Liddle, & Lacy,
1970), plasma insulin (Najjar & Khachadurian, 1969; Stiel et al., 1970),
plasma growth hormone (Stiel et al., 1970), plasma free fatty acids
(Stiel et al., 1970), plasma free amino acids (Najjar & Khachadurian,
1969), glucose tolerance (Najjar & Khachadurian, 1969), or urea
(Noble, 1969). One study found greater levels of IGF-1 in research
participants taking CY (Mahachoklertwattana et al., 2009). A sig-
nificant increase in urinary sodium and creatinine excretion was ex-
plained by an increase in overall food intake with cyproheptadine use
by Stiel et al.(Stiel et al., 1970).
4. Discussion
A total of 46 studies across 21 different treatment populations were
identified in this systematic review. Of these, 39 demonstrated that CY
prescription resulted in significant weight gain in the sample under
study, of which 27 were RCTS, and 12 case studies. Only a few studies
included appetite as an outcome, and of these, only 6 included mea-
sures of appetite and/or caloric intake (Bergen, 1964; Comer et al.,
1997; Genazzani et al., 2001; Mainguet, 1972; Silverstone & Schuyler,
1975; Summerbell et al., 1992). Comer et al.‘s study (1997) findings
were interesting as their results indicated that CY affected postprandial
satiety or hunger mechanisms, as opposed to food reward or meal-de-
rived satiation. The small study sample and short administration cycle
(2 days) limits any conclusions or observations regarding sustained
changes in appetite and weight. Due to the heterogeneity of study
methods as well as study patient demographics, characteristics and
medical conditions included, we are unable to provide a specific level
or grade of evidence for the use of CY as an appetite stimulant.
While overall CY appears to improve weight gain in many diverse
patient populations, it is important to note that studies that explored
the use of CY in those with malignant or progressive disease states, such
as HIV and certain types of cancer, showed minimal to no benefit of the
medication (Erdem et al., 2014; Irsy & Szatloczky, 1977; Kardinal et al.,
1990; Summerbell et al., 1992). It is also interesting to note that the
studies with the eldest patient groups, Andronic (n = 30; mean age 73
years) (Andronic & Di Mascio, 1971) and Kardinal (n = 295; mean age
65 years) (Kardinal et al., 1990), found no significant changes in weight
in those taking CY as compared to placebo. The latter two studies,
however, have significant differences that make them difficult to
compare and draw conclusions, including the variability in patient di-
agnoses (advanced malignant diseases vs unspecified psychiatric con-
ditions), definitions of “underweight”/history of weight loss, CY dose
(8 mg tid in Kardinal study vs 4 mg tid in Andronic study), concurrent
medications being used by study participants as well as length of
treatment (34 days Kardinal vs 56 days Andronic). Of interest, in Halmi
et al.‘s study (1986), CY negatively influenced the treatment efficacy of
those with bulimia subset. Although the authors could not definitively
account for the reasons that contribute to this occurrence, they specu-
lated that differences in appetite regulation between those with and
without concomitant bulimia may have accounted for the differences.
Given the propensity for CY to increase treatment efficacy and decrease
days required to reach treatment goal weight in patients with AN,
further study is required to better understand the mechanisms that
might account for differences between subgroups. Each of the re-
maining studies that failed to show any benefit of CY as an appetite
stimulant had many limitations as discussed in sections above (Fantino,
Brondel, Swiergiel, & Lebec, 1990; Genazzani et al., 2001; Tiszai &
Szasz, 1972; Vigersky & Loriaux, 1977, pp. 349–356).
Despite the high number of studies with positive outcomes, many
70
Appetite 137 (2019) 62–72
designs were limited, with small sample sizes, various dosing, short-
term follow up, and other confounding factors that had the potential to
affect findings. As an example, studies that involved subjects with
mixed chronic diseases were typically fraught with a number of un-
controlled confounders (i.e. disease activity) with the potential to in-
fluence results, and thus limit their generalizability. Of further concern,
not all studies controlled for, or referenced measures taken to limit, the
extent to which factors such as poverty or admission to hospital might
affect access to nutrition and thus also affect outcome. The issue of
socioeconomic status has specific relevance given that results from one
study that did control for access to nutrition/availability of nutrition
suggested a faster but less robust treatment response in subjects treated
with medication with uncompensated malnutrition (Burrows & Muzzo,
1981). As a result, weight gain was not greater compared to the placebo
group at the 4-week mark (although weight gain was greater in those
with compensated malnutrition at week 4). Outcomes between those
with uncompensated and compensated nutrition at the 2 month mark
were both significantly greater for those children taking CY than for
those not treated with medication. Although not mentioned in other
studies, Burrows & Muzzo speculate that the underlying reasons for the
malnutrition also have the potential to affect outcome (Burrows &
Muzzo, 1981). Similarly, there is little information available regarding
activity levels, and whether some patients who did not respond may
have been more active than others, or not had adequate nutrition to
compensate for activity levels. In addition, more dated studies did not
consistently report on whether there were randomization processes,
blinding procedures (or in cases where blinding was reported, the
method was not specified), research ethics board approval, details of
how medications compliance was monitored, or how data regarding
appetite increases were measured. Also, although most studies provided
cursory descriptions as to how patients were investigated medically, it
is possible that undiagnosed underlying medical issues may have im-
pacted treatment responses. As an example, in Sanzgiri et al.‘s study,
most of the included children had co-occurring parasitic infections,
which were considered endemic to that population in India (Sanzgiri
et al., 1969). Many studies had only short-term follow up, despite the
possibility that appetite stimulation and weight gain may only be short-
lived, and few of the studies commented on whether the weight gain
was considered clinically significant.
In addition to the limitations outlined above, calculation of mal-
nourishment and determinations of underweight status varied de-
pending on the study. Many studies did not describe how they de-
termined patients to be “low weight” or “lower than ideal” (Homnick
et al., 2004; Irsy & Szatloczky, 1977; Mainguet, 1972; Penfold, 1971;
Sanzgiri et al., 1969; Sardesai et al., 1970; Silbert, 1971). Burrows &
Muzzo defined first degree malnutrition as weight between the 10th
and 25th percentiles, second degree between 10th and 5th percentiles,
and third degree malnutrition if under the 5th percentile (Burrows &
Muzzo, 1981). Malnutrition was considered compensated if the weight
for height was above the 25th percentile and decompensated if the ratio
was below the 25th percentile. Other examples that illustrate the di-
versity of malnourishment or “low weight” determination include the
arbitrary use of Metropolitan Life Insurance Tables to define “under-
weight” (Andronic & Di Mascio, 1971; Noble, 1969; Pawlowski, 1975;
Silverstone & Schuyler, 1975), the use of the Gomez calculation to
determine severity of malnutrition (Najib et al., 2014), defining low
weight as more than 2 standard deviations below the mean
(Mahachoklertwattana et al., 2009), or as < 50th% on Stuart anthro-
pometric charts (Kibel, 1969; Lavenstein et al., 1962). The variation in
definition of underweight or malnourishment affects how results can be
compared and generalized.
Unfortunately, despite the number of studies identified through this
review, very few included objective measures of appetite. As such, our
analysis does not provide much insight into the manner by which CY
acts as a stimulant of appetite. Comer et al.‘s (1997) study provided
interesting results that suggested that CY contributed to increased
M.E. Harrison, et al.
number of eating occasions, suggesting that the mechanism of action
may be linked more to satiety/hunger signaling as compared to food
reward pathways. This has relevance given the medications effect at 5-
HT2 and H1 receptors.
Despite the observed limitations in published studies, there is cer-
tainly enough data to suggest that further controlled studies that in-
volve patients with conditions where appetite is poor are warranted.
Although there were no serious side effects noted in the studies
reviewed in this paper, it is important to note that there are cases re-
ported in the literature of anticholinergic toxicity in pediatric patients
in the context of CY overdose (ie. Accidental over-ingestion) (Blaustein,
Gaeta, Balentine, & Gindi, 1995; McGovern, McNamee, Marcus, &
Kashani, 2017; Richmond & Seger, 1985).
5. Conclusion
Based on this literature review and studies completed to date, CY
appears to be a safe, generally well-tolerated medication that has utility
in helping facilitate weight gain in patients drawn from a variety of
underweight populations. Moving forward, further studies that examine
CY should incorporate specific measures of appetite stimulation in
order to better decipher how appetite signaling, satiety, and food re-
ward pathways influence the medications effect on nutritional intake.
These studies should also serve to increase knowledge relating to
medication indication and tolerance, optimal dosing, and side effect
potential, in varying populations. Future randomized controlled studies
with more homogeneous populations would also allow for meta-ana-
lyses that can better inform evidence-based guidelines.
Declarations of interest
None.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Acknowledgements
We thank Jenna Pepper, MA and Katie O'Hearn, Msc, (Children's
Hospital of Eastern Ontario Research Institute) for methodological as-
sistance and Margaret Sampson, MLIS, PhD, AHIP (Children's Hospital
of Eastern Ontario) for developing the electronic search strategies. We
would also like to acknowledge the assistance of Mrs. Patricia Graziano
for her help in article retrieval and table editing.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.appet.2019.02.012.
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