Serotonin Toxicity Associated with Garcinia cambogia Over-the-counter Supplement

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OBSERVATION
Serotonin Toxicity Associated with Garcinia cambogia
Over-the-counter Supplement
Annette M. Lopez &Joshua Kornegay &
Robert G. Hendrickson
#American College of Medical Toxicology 2014
Introduction
Garcinia cambogia, also known as the Malabar tamarind, is a
plant that is commonly used in India and Southeast Asia for its
sour taste and as a food-bulking agent [1]. The plant contains
hydroxycitric acid (HCA) and has recently become a popular
ingredient in over-the-counter supplements designed for
weight loss and weight management [2]. Most of these sup-
plements contain from 20 to 60 % HCA.
There is limited evidence that HCA may increase serotonin
concentrations and thereby increase the risk of serotonin tox-
icity. HCA analogs increase serotonin concentrations within
the brains of rats [1,3], and randomized human studies have
found elevations in free serum serotonin concentrations after
the administration of HCA derivatives [4].
We report a case of suspected serotonin toxicity in the
presence of therapeutic dosing of serotonin reuptake inhibitors
(SSRIs) when combined with a nutritional supplement con-
taining G. cambogia and hydroxycitric acid.
Case Presentation
A 35-year-old woman was in her normal state of health when
she developed stuttering speech and profuse sweating. She
arrived to the emergency department via ambulance, and her
vital signs were notable for hypertension (169/100 mmHg)
and tachycardia (102 beats per min). Initial physical exam
revealed an anxious appearing, diaphoretic female with a
stuttering, but non-aphasic, speech pattern. She was
tachycardiac (120 beats per min), and her neurologic exami-
nation demonstrated spontaneous ankle clonus in the lower
extremities as well as bilateral ocular clonus. She had induc-
ible clonus of her mandible resulting in rhythmic jaw motions
and stuttering. She was hyperreflexic (3+ patellar reflexes)
and tremulous. Pertinent additional findings included
sinus tachycardia on her electrocardiogram, leukocytosis
(22 K/mm
3
), hypokalemia (3.2 mmol/L), and a normal head
CT. The patient’s urine immunoassay (Syva EMIT) was pos-
itive for cannabinoids and oxycodone, both of which were
prescribed to her by her primary provider for a chronic pain
syndrome. The patient provided this information freely on
history and denied any other substance use.
The patient’s medication history was significant for having
consistently taken a G. cambogia supplement daily for the last
2–3 months for weight loss. The product label listed the
following as active ingredients: G. cambogia (fruit rind) extract
(60 % HCA) 1,000 mg, chromium 200 μg, potassium 50 μg,
and calcium 50 μg. The serving size was listed as two capsules,
and the patient confirmed her dose at two capsules three times a
day. She reports that she had been stable on escitalopram
(20 mg) for over 1 year, but 1 month ago and approximately
1–2 months after starting to take G. cambogia, the patient
developed a tremor, flushing, and diaphoresis. She was diag-
nosed with serotonin toxicity, and the escitalopram was
discontinued. At that time, she did not report her G. cambogia
intake to her doctor and had always taken the supplement in the
presence of escitalopram. She was allowed 2 weeks without
escitalopram or any other antidepressant, and then, sertraline
50 mg daily was started approximately 1.5 weeks prior to this
admission. The patient reportedly was compliant in taking
these medications: baclofen, gabapentin, omeprazole, oxyco-
done, silodosin, solifenacin, and diphenhydramine.
A. M. Lopez :J. Kornegay :R. G. Hendrickson (*)
Department of Emergency Medicine, Oregon Health and Sciences
University, SW Sam Jackson Park Road, CSB-550, Portland,
OR 97239, USA
e-mail: hendriro@ohsu.edu
A. M. Lopez :R. G. Hendrickson
Oregon Poison Center, 3181 SW Sam Jackson Park Road, CSB-550,
Portland, OR 97239, USA
J. Med. Toxicol.
DOI 10.1007/s13181-014-0390-7

In the emergency department, she was treated with IV
lorazepam and 8 mg of oral cyproheptadine for presumed
serotonin toxicity. After these interventions, the patient had
significant improvement of her symptoms and was admitted
for further care and monitoring.
The following morning, she was evaluated by the toxicol-
ogy service. She had recurrence of some of her lower extrem-
ity and jaw clonus 8–12 h after her dose of cyproheptadine.
The family at bedside also reported that the patient experi-
enced multiple visual hallucinations overnight. She was again
treated with 8 mg oral cyproheptadine, and her symptoms
improved.
Discussion
G. cambogia has become a popular over-the-counter supple-
ment used for weight loss, reportedly due to the effects of its
active ingredient, HCA. Animal research has suggested that
HCA has appetite-suppressant qualities via the production of
hepatic glycogen and subsequent activation of the
glucoreceptors which generate feelings of satiation. HCA
may also inhibit de novo fat synthesis by competitive inhibi-
tion of adenosine triphosphate citrate (pro-3S) lyase, the re-
quired enzyme needed for fat synthesis, responsible for gen-
erating acetyl coA from citrate [4–6].
Our patient presented with symptoms that are consistent
with serotonin toxicity (hypertension, tachycardia, diaphore-
sis, ataxia, hallucinations, muscle rigidity, tremor, spontane-
ous lower extremity clonus, and ocular clonus) by both the
Hunter Serotonin Toxicity Criteria and the Sternbach Criteria.
The following are the patient’s symptoms that are consis-
tent with serotonin toxicity using the Hunter Serotonin Tox-
icity Criteria [7] in the presence of a serotonergic agent:
1. Spontaneous clonus
2. Inducible clonus and diaphoresis
3. Tremor and hyperreflexia.
The following are the patient’s symptoms that are consis-
tent with serotonin toxicity using the Sternbach criteria [8]:
1. Recent addition/increase in a known serotonergic agent
(G. cambogia and sertraline)
2. Absence of other etiologies
3. No recent addition/increase of a neuroleptic agent
4. At least three of the following symptoms: positive (agita-
tion, myoclonus, hyperreflexia, diaphoresis) and negative
(mental status change, shivering, diarrhea, incoordination,
fever).
There is limited evidence that HCA may increase endoge-
nous serotonin concentrations. Rat studies have suggested that
a novel HCA extract, Super CitriMax (HCA-SX), was capable
of inhibiting the uptake of serotonin in isolated brain cortical
cells in a manner similar to SSRIs [5] and that HCA-SX
increases serotonin concentrations in rat brain tissue [3]. The
mechanism of increased serotonin concentrations is not clear
but has been hypothesized to be from the upregulation of
genes that encode serotonin receptors [1]. A randomized,
placebo-controlled, double-blind pilot study found that in 30
obese human subjects, there was an increase in serum seroto-
nin concentrations of 39.8 % (initial level of 216±23.55 ng/
mL, final level (8 weeks later) 302±26.74 ng/mL), compared
to controls (initial level of 220±17.09 ng/mL, final level
266.3±15.31) [3,4].
Our patient had signs and symptoms consistent with sero-
tonin excess leading to the development of serotonin toxicity
in the presence of an SSRI (escitalopram) and G. cambogia,
followed by a resolution of symptoms once the SSRI was
removed. Upon rechallenge with another SSRI (sertraline) at
therapeutic doses in the continued presence of G. cambogia,
the patient again developed symptoms consistent with seroto-
nin toxicity. Further supporting evidence for the presence of
serotonin toxicity in this case includes the improvement of
symptoms upon addition of cyproheptadine at 8 mg dosing,
with return of symptoms once the medication was cleared.
Upon readministration of the cyproheptadine, her symptoms
resolved. The delay of 1–2 months from the start of the HCA-
containing product may be explained by the noted elevation
over time in serum serotonin levels by participants in the pilot
study conducted by Preuss et al. [4]. In this study, statistically
significant differences in serotonin levels were noted between
4 and 8 weeks in the groups receiving HCA. Thus, there
appears to be a delay in the buildup of intrinsic serotonin.
This patient received a psychiatric consultation as part of her
hospital course to help with medication recommendations.
Given the severity of her symptoms, her SSRIs and
G. cambogia supplementation were discontinued. On
follow-up, the patient had not been rechallenged with SSRIs
and was started on an antipsychotic (quetiapine) for adjunctive
depression disorder management.
We do not have definitive proof of a cause and effect
relationship between G. cambogia and serotonin toxicity.
We were unable to obtain blood testing to exclude all other
pharmaceutical causes of serotonin toxicity, and it is possible
that our patient took another xenobiotic, though she denied
this on direct questioning. It is possible that our patient devel-
oped serotonin toxicity from the single-agent SSRI and that
G. cambogia is unrelated. However, she had been on a stable
dose of escitalopram without symptoms for over 1 year and
had only developed serotonin toxicity after the addition of
G. cambogia. Given the unregulated nature of the nutritional
supplement industry, another potential explanation for the
noted effects could be adulteration or contamination of the
products being used by the patient. Finally, there is a
J. Med. Toxicol.

physiological basis for her development of serotonin toxicity
since G. cambogia increases serotonin concentrations and acts
as a reuptake inhibitor.
We are not aware of previous cases of serotonin toxicity
associated with G. cambogia use. In the largest prospective
trial on G. cambogia that included 100 subjects, there was no
difference in the rate of side effects in the study or placebo
groups, and no clinical signs of serotonin excess were report-
ed. However, this study specifically excluded subjects who
were taking any prescription medications.
Conclusion
G. cambogia extracts and its hydroxycitric acid (HCA) deriv-
atives are being used by individuals in attempts to lose weight
and/or to maintain weight loss. These agents have experimen-
tal animal and human data supporting increases in the con-
centrations of endogenous serotonin. This case illustrates how
the addition of G. cambogia to an SSRI regimen was associ-
ated with the development of symptoms consistent with sero-
tonin toxicity. We postulate that serotonin toxicity in our
patient was due to elevated serotonin concentrations due to
the combination of G. cambogia and two different SSRIs.
Funding None.
Conflict of Interest No conflicts to declare.
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