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

Authors:
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 patients 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 patients medication history was significant for having
consistently taken a G. cambogia supplement daily for the last
23 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
12 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 812 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 [46].
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 patients 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 patients 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 12 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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... The HCA (30) present in G. cambogia is a potent and competent inhibitor of adenosinetriphosphate (ATP) citrate lyase, which is a key enzyme in the synthesis of fatty acids, cholesterol, and triglycerides [85,108]. It also regulates the level of serotonin, which has been associated with satiety, increased oxidation of fat, and decreased gluconeogenesis [85,109]. This explains how the compound exerts weight-loss activity, with reduced food ingestion and reduction of accumulated gain of body fat [85,[108][109][110]. ...
... It also regulates the level of serotonin, which has been associated with satiety, increased oxidation of fat, and decreased gluconeogenesis [85,109]. This explains how the compound exerts weight-loss activity, with reduced food ingestion and reduction of accumulated gain of body fat [85,[108][109][110]. HCA (30) presents a chemical structure similar to citric acid and, therefore, inhibits the action of adenosine triphosphate (ATP) citrate lyase in the citric acid cycle. ...
... HCA (30), the main active ingredient of G. cambogia extracts, presents effects of inhibiting the recapture of serotonin, inhibiting acetylcholinesterase, increasing the oxidation of fatty acids, and reducing lipogenesis [85]. The serotoninergic effects of HCA (30) are worrisome and can contribute to serotonin syndrome when combined with serotonin recapture inhibitors [109]. ...
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Obesity is a global public health problem, with about 315 million people worldwide estimated to fall into the WHO-defined obesity categories. Traditional herbal medicines may have some potential in managing obesity. Botanical dietary supplements often contain complex mixtures of phytochemicals that have additive or synergistic interactions. The dried fruit rind of Garcinia cambogia, also known as Malabar tamarind, is a unique source of (-)-hydroxycitric acid (HCA), which exhibits a distinct sour taste and has been safely used for centuries in Southeastern Asia to make meals more filling. Recently it has been demonstrated that HCA-SX or Super Citrimax, a novel derivative of HCA, is safe when taken orally and that HCA-SX is bioavailable in the human plasma as studied by GC-MS. Although HCA-SX has been observed to be conditionally effective in weight management in experimental animals as well as in humans, its mechanism of action remains to be understood. We sought to determine the effects of low-dose oral HCA-SX on the body weight and abdominal fat gene expression profile of Sprague-Dawley rats. We observed that at doses relevant for human consumption dietary HCA-SX significantly contained body weight growth. This response was associated with lowered abdominal fat leptin expression while plasma leptin levels remained unaffected. Repeated high-density microarray analysis of 9960 genes and ESTs present in the fat tissue identified a small set (approximately 1% of all genes screened) of specific genes sensitive to dietary HCA-SX. Other genes, including vital genes transcribing for mitochondrial/nuclear proteins and which are necessary for fundamental support of the tissue, were not affected by HCA-SX. Under the current experimental conditions, HCA-SX proved to be effective in restricting body weight gain in adult rats. Functional characterization of HCA-SX-sensitive genes revealed that upregulation of genes encoding serotonin receptors represent a distinct effect of dietary HCA-SX supplementation.
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A review of the literature on the serotonin syndrome in animals and human beings was conducted, and 12 reports of 38 cases in human patients were then analyzed to determine the most frequently reported clinical features and drug interactions, as well as the incidence, treatment, and outcome of this syndrome. The serotonin syndrome is most commonly the result of the interaction between serotonergic agents and monoamine oxidase inhibitors. The most frequent clinical features are changes in mental status, restlessness, myoclonus, hyperreflexia, diaphoresis, shivering, and tremor. The presumed pathophysiological mechanism involves brainstem and spinal cord activation of the 1A form of serotonin (5-hydroxytryptamine, or 5-HT) receptor. The incidence of the syndrome is not known. Both sexes have been affected, and patients' ages have ranged from 20 to 68 years. Discontinuation of the suspected serotonergic agent and institution of supportive measures are the primary treatment, although 5-HT receptor antagonists may also play a role. Once treatment is instituted, the syndrome typically resolves within 24 hours, but confusion can last for days, and death has been reported. The serotonin syndrome is a toxic condition requiring heightened clinical awareness for prevention, recognition, and prompt treatment. Further work is needed to establish the diagnostic criteria, incidence, and predisposing factors, to identify the role of 5-HT antagonists in treatment, and to differentiate the syndrome from neuroleptic malignant syndrome.
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Hydroxycitric acid, the active ingredient in the herbal compound Garcinia cambogia, competitively inhibits the extramitochondrial enzyme adenosine triphosphate-citrate (pro-3S)-lyase. As a citrate cleavage enzyme that may play an essential role in de novo lipogenesis inhibition, G cambogia is claimed to lower body weight and reduce fat mass in humans. To evaluate the efficacy of G cambogia for body weight and fat mass loss in overweight human subjects. Twelve-week randomized, double-blind, placebo-controlled trial. Outpatient weight control research unit. Overweight men and women subjects (mean body mass index [weight in kilograms divided by the square of height in meters], approximately 32 kg/m2). Subjects were randomized to receive either active herbal compound (1500 mg of hydroxycitric acid per day) or placebo, and both groups were prescribed a high-fiber, low-energy diet. The treatment period was 12 weeks. Body weight was evaluated every other week and fat mass was measured at weeks 0 and 12. Body weight change and fat mass change. A total of 135 subjects were randomized to either active hydroxycitric acid (n = 66) or placebo (n = 69); 42 (64%) in the active hydroxycitric acid group and 42 (61%) in the placebo group completed 12 weeks of treatment (P = .74). Patients in both groups lost a significant amount of weight during the 12-week treatment period (P<.001); however, between-group weight loss differences were not statistically significant (mean [SD], 3.2 [3.3] kg vs 4.1 [3.9] kg; P = .14). There were no significant differences in estimated percentage of body fat mass loss between treatment groups, and the fraction of subject weight loss as fat was not influenced by treatment group. Garcinia cambogia failed to produce significant weight loss and fat mass loss beyond that observed with placebo.
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The efficacy of optimal doses of highly bioavailable (-)-hydroxycitric acid (HCA-SX) alone and in combination with niacin-bound chromium (NBC) and a standardized Gymnema sylvestre extract (GSE) on weight loss in moderately obese subjects was evaluated by monitoring changes in body weight, body mass index (BMI), appetite, lipid profiles, serum leptin and excretion of urinary fat metabolites. HCA-SX has been shown to reduce appetite, inhibit fat synthesis and decrease body weight without stimulating the central nervous system. NBC has demonstrated its ability to maintain healthy insulin levels, while GSE has been shown to regulate weight loss and blood sugar levels. A randomized, double-blind, placebo-controlled human study was conducted in Elluru, India for 8 weeks in 60 moderately obese subjects (ages 21-50, BMI >26 kg/m(2)). Subjects were randomly divided into three groups. Group A was administered HCA-SX 4667 mg, group B was administered a combination of HCA-SX 4667 mg, NBC 4 mg and GSE 400 mg, while group C was given placebo daily in three equally divided doses 30-60 min before meals. All subjects received a 2000 kcal diet/day and participated in supervised walking. At the end of 8 weeks, body weight and BMI decreased by 5-6% in both groups A and B. Food intake, total cholesterol, low-density lipoproteins, triglycerides and serum leptin levels were significantly reduced in both groups, while high-density lipoprotein levels and excretion of urinary fat metabolites increased in both groups. A marginal or non-significant effect was observed in all parameters in group C. The present study shows that optimal doses of HCA-SX and, to a greater degree, the combination of HCA-SX, NBC and GSE can serve as an effective and safe weight-loss formula that can facilitate a reduction in excess body weight and BMI, while promoting healthy blood lipid levels.
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Obesity is associated with cardiovascular disease, diabetes and certain forms of cancer. Popular strategies on weight loss often fail to address many key factors such as fat mass, muscle density, bone density, water mass, their inter-relationships and impact on energy production, body composition, and overall health and well-being. (-)-Hydroxycitric acid (HCA), a natural plant extract from the dried fruit rind of Garcinia cambogia, has been reported to promote body fat loss in humans without stimulating the central nervous system. The level of effectiveness of G. cambogia extract is typically attributed solely to HCA. However, other components by their presence or absence may significantly contribute to its therapeutic effectiveness. Typically, HCA used in dietary weight loss supplement is bound to calcium, which results in a poorly soluble (<50%) and less bioavailable form. Conversely, the structural characteristics of a novel Ca2+/K+ bound (-)-HCA salt (HCA-SX or Super CitriMax) make it completely water soluble as well as bioavailable. An efficacious dosage of HCA-SX (4500 mg/day t.i.d.) provides a good source of Ca2+ (495 mg, 49.5% of RDI) and K+ (720 mg, 15% of RDI). Ca2+ ions are involved in weight management by increasing lipid metabolism, enhancing thermogenesis, and increasing bone density. K+, on the other hand, increases energy, reduces hypertension, increases muscle strength and regulates arrhythmias. Both Ca and K act as buffers in pH homeostasis. HCA-SX has been shown to increase serotonin availability, reduce appetite, increase fat oxidation, improve blood lipid levels, reduce body weight, and modulate a number of obesity regulatory genes without affecting the mitochondrial and nuclear proteins required for normal biochemical and physiological functions.
The use of Garcinia extract (hydroxycitric acid) as a weight loss supplement: a systematic review and meta-analysis of randomized clinical trials
  • I Onakpoya
  • S K Hung
  • R Perry
  • B Wider
  • E Ernst
Onakpoya I, Hung SK, Perry R, Wider B, Ernst E (2011) The use of Garcinia extract (hydroxycitric acid) as a weight loss supplement: a systematic review and meta-analysis of randomized clinical trials. J Obes, Article ID 509038, 9 pages. doi:10.1155/2011/509038