JOURNAL OF FOOD NUTRITION AND METABOLISM | ISSN 2674-2411

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Research Article
Effects of Cannabis Oil on Cannabinoid-Induced Tetrad, Blood Pressure, and
Metabolic Parameters in an Experimental Model of Metabolic Syndrome
Valentina Degrave1, Michelle Berenice Vega Joubert1, Cristian Vaccarini2, Daniela Sedan2, Darío Andrinolo2, María
Eugenia D’Alessandro1* and María Eugenia Oliva1*
1
Laboratorio de Estudio de Enfermedades Metabólicas relacionadas con la Nutrición. Facultad de Bioquímica y Ciencias Biológicas. Universidad
Nacional del Litoral. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Santa Fe, Argentina
2
Centro de Investigaciones del Medio Ambiente (CIM) / Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) -Universidad Nacional
de La Plata, La Plata, Argentina

ARTICLE INF O ABSTRACT

Article history: Objective: The aim of the present study was to analyse the effects of cannabis oil on cannabinoid-induced
Received: 9 March, 2023 tetrad, blood pressure, and metabolic parameters in rats normal fed a sucrose-rich diet (SRD).
Accepted: 4 April, 2023 Methods: Male Wistar rats were fed the following diets for 21 days: Reference Diet (RD): standard
Published: 17 April, 2023 commercial laboratory diet, SRD and SRD+Cannabis oil (SRD+Ca): the oral administration of 1 mg/kg of
Keywords: body weight of cannabis oil daily. Cannabis oil present a total cannabinoids CBD:THC 2:1 ratio. During
Cannabis oil the experimental period, body weight, food intake, blood pressure, body temperature, locomotion, catalepsy
cannabinoid-induced tetrad and analgesia were evaluated. At the end of the experimental period, levels of glucose, triglycerides,
blood pressure cholesterol, uric acid, AST, ALT and AP in serum were evaluated. In liver were determined AST, ALT and
metabolic parameters AP enzymes and triglycerides and cholesterol content.
sucrose-rich diet Results: A cannabis oil administration significantly increased (P<0.05) analgesia, and locomotion was also
significantly decreased, which was found to be increased in the SRD group. Systolic and diastolic blood
pressure decreased during the experiment. In the SRD+Ca group, serum triglycerides and cholesterol levels
significantly decreased, reaching values similar to RD group, without changes in glucose levels. In addition,
serum uric acid and AP levels significantly decreased, although did not obtain reference values. AST and
ALT levels in serum and liver significantly decreased, reaching reference values. At the liver, the
triglycerides and cholesterol content significantly decreased with the administration of cannabis oil,
although not reaching to reference values.
Conclusions: Our results suggest that cannabis oil could be useful as a therapeutic strategy to prevent some
of the alterations present in Metabolic Syndrome, including hypertension, dyslipidemia and liver damage.
In addition, the analgesic effect of cannabis oil could be observed in SRD-fed rats.

© 2023 M.E. Oliva & M.E. D’Alessandro. Hosting by Science Repository.

*Correspondence to: M.E. Oliva, Ph.D., Laboratorio de Estudio de Enfermedades Metabólicas relacionadas con la Nutrición. Facultad de Bioquímica y Ciencias
Biológicas. Universidad Nacional del Litoral. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), cc242 (3000) Santa Fe, Argentina; E-mail:
meoliva@fbcb.unl.edu
M.E. D’Alessandro, Ph.D., Laboratorio de Estudio de Enfermedades Metabólicas relacionadas con la Nutrición. Facultad de Bioqu ímica y Ciencias Biológicas.
Universidad Nacional del Litoral. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), cc242 (3000) Santa Fe, Argentina; Tel:
+543424575211; Fax: +543424575221; E-mail: medaless@fbcb.unl.edu.ar
© 2023 M.E. Oliva & M.E. D’Alessandro. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Hosting by Science Repository.
http://dx.doi.org/10.31487/j.JFNM.2023.01.01
Effects of Cannabis Oil on Cannabinoid-Induced Tetrad, Blood Pressure, and Metabolic Parameters in an Experimental Model of Metabolic Syndrome 2

Graphical Abstract

Introduction
In total, more than a thousand compounds have been identified in the
Metabolic Syndrome (MS) increases the risk of Type 2 diabetes and plant, including cannabinoids, terpenes, terpenoids, flavonoids,
cardiovascular disease. Its main components are dyslipidemia, elevation flavonoid glycosides, polyphenols, steroids, among others.
of arterial blood pressure, dysregulated glucose homeostasis, abdominal Cannabinoids are classified as phytocannabinoids (of plant origin) to
obesity and insulin resistance. Recently, other abnormalities such as distinguish them from endocannabinoids (non-plant). The main
chronic proinflammatory and prothrombotic states and non-alcoholic cannabinoids in cannabis include tetrahydrocannabinol (THC),
fatty liver disease (NASH) have been added to the entity of this cannabidiol (CBD) and cannabichromene (CBC), their precursor
Syndrome. MS is a combination of metabolic disorders influenced by cannabigerol (CBG) and cannabinol (CBN) [10, 11]. Recent studies
genetic and environmental factors, now reaches epidemic proportions in show that the endocannabinoid system can have a significant influence
the world [1, 2]. Several studies have experimentally demonstrated that by decreasing the production of reactive oxygen species, inflammation
rats fed sucrose-fructose rich diets display many of the metabolic and subsequent tissue damage, in addition to having some effects on lipid
changes observed in the human MS phenotype [3-5]. We previously and glucose metabolism. Some recent studies have focused on two
showed that rats fed a SRD during 3 weeks have dyslipidemia, with a cannabinoids, such as CBD and THC, which have great therapeutic
combination of increased VLDL-Tg secretion and a defective removal potential in inflammatory diseases, diabetes and diabetic complications
mechanism of Tg from the circulation. This was accompanied by a [12-14].
significant increase in liver triglyceride storage [6, 7].
In this study, we investigate the effects of cannabis oil on cannabinoid-
Currently, there are only a few specific pharmaceutical strategies induced tetrad, blood pressure, and metabolic parameters present in
available to treat MS. In recent years, the therapeutic properties of the experimental Metabolic Syndrome induced by SRD-fed rats. To our
chemical compounds present in Cannabis (cannabinoids) have generated knowledge, this is the first study to examine the metabolic effects of oral
great expectations in society. Although the Cannabis plant has been used administration of cannabis oil (CBD:THC 2:1 ratio) in SRD-fed rats.
in medicine for thousands of years, its therapeutic use currently raises a
debate rarely seen in the study of other natural products. Cannabis sativa Materials and Methods
is native to Asia, it is an annual plant that belongs to the Cannabaceae
family. It has been used as a herbal medicine for tens of centuries to treat I Cannabis oil Preparation and Characterization
various diseases and symptoms. Therefore, it is believed that its
consumption has positive effects against diseases such as depression, Cannabis oil was obtained from dried inflorescences of the Cannabis
diabetes, multiple sclerosis, glaucoma, asthma, autoimmune diseases sativa CAT1 variety grown at Environmental Research Center (CIM-
and cancer; in pain management, insomnia, lack of appetite, nausea, CONICET-UNLP) (RESOL-2021-3236-APN-MS). Briefly, in order to
vomiting, epilepsy and cerebral ischaemia, among others. The most obtain neutral cannabinoides the inflorescences were first decarboxilated
common form of consumption is inhaled or in the form of oil. Adverse in oven (145 ºC) during 7 min. After that, an alcoholic extraction (10 ml
reactions are minimal, transitory and of low toxicity, and its use as a ethanol 96º per gram of inflorescence) was carried out and subsequently
complementary and/or alternative treatment to traditional medicine for the ethanol was evaporated at low temperature with rotavapor (Buchi R
the aforementioned diseases has been proven [8, 9]. 3000). The resulting resin was diluted in corn oil and the cannabinoids
in the oil were quantified by HPLC/UV-DAD techniques and analytical

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Effects of Cannabis Oil on Cannabinoid-Induced Tetrad, Blood Pressure, and Metabolic Parameters in an Experimental Model of Metabolic Syndrome 3

standards (Cerilliant Co.) as described in Sedan et al. [15]. Cannabis oil The animals were initially fed a standard powdered rodent commercial
contains 0.60 mg/ml CBD and 0.43 mg/ml THC, with a CBD:THC ratio diet (GEPSA FEED, Buenos Aires, Argentina). When the rat’s weight
of 2:1. Finally, the adequate dilution was carried out to obtain the was 180-190 g, they were randomly divided into three experimental
working oil with a concentration of 1 mg/ml. groups during 21 days: 1) Rats fed a standard powdered rodent
commercial diet (Reference diet, RD, n = 6). 2) Rats fed a semisynthetic
II Animals and Diets sucrose rich diet (SRD, n = 6). 3) Rats fed a SRD plus oral administered
cannabis oil (SRD+Ca, n = 6). The cannabis oil was administered orally,
Male Wistar rats (n=18) purchased from the Veterinary Sciences using a dose of 1 mg/kg body weight daily during the experimental
Institute of Litoral (Instituto de Ciencias Veterinarias del Litoral, protocol (21 days). The diet compositions are given in (Table 1). The
ICIVET-Litoral) -Facultad de Veterinaria, Universidad Nacional del individual body weight and food intake of animals in each group were
Litoral (Esperanza, Santa Fe, Argentina) were maintained with assessed twice a week throughout the experimental period (21 days). At
unrestricted access to water and food under controlled temperature (22 ± the end, the food was removed at 07.00 h and experiments were
1 °C), humidity (50-60%) and air flow conditions, with a fixed 12-h performed between 07.00 and 09.00 h. The animals were anaesthetized
light/dark cycle (light on 07.00 AM to 7.00 PM). Adequate measures with intraperitoneal sodium pentobarbital (60 mg/kg body weight).
were taken to minimize the pain or discomfort of the rats and we used Blood samples were collected from the inferior vena cava, rapidly
the smallest number of animals possible. This study was performed in centrifuged and serum was either immediately assayed or stored at -20
strict accordance with the NIH guidelines for the care and use of °C until used. The liver of each rat was totally removed, weighed, and
laboratory animals and was approved by the Institutional Ethics stored at the temperature of liquid N2. The animals were euthanized by
Committee of the Faculty of Biochemistry and Biological Sciences. removal of vital organ (heart).

Table 1: Composition of experimental diets.

SRDa
Diet ingredients (g/kg diet)
Sucrose 580
Casein (vitamin free)b 165
Corn oil 105
Salt mix 35
Vitamin mix 10
Choline Chloride 2
Methionine 3
Fiber (cellulose) 100
Energy (kJ/g) 16.3
a
The home-made SRD experimental diet is based on the modified AIN-93M diet. b Casein was provided by Saputo Molfino Hermanos S.A., Buenos Aires,
Argentine.
Reference diet (RD): Rodent commercial diet (GEPSA FEED, Buenos Aires, Argentina) containing (g/kg diet): carbohydrate (corn, sorghum, wheat, oats,
barley) 427; protein 180; fat 39; fiber 55; minerals and vitamins 169; moisture 130; digestible energy 12.5 kJ/g.

III Determination of Blood Pressure horizontal bar and the hind legs on the floor of the cage. The timer is
started, stopped when the rat descends from the bar. Analgesia was
Blood pressure was measured in the three dietary groups in conscious assessed 85 min after cannabis oil administration in the tail immersion
animals during the experimental period using a CODA™ Monitor of tail- assay, where each rat was hand-held and 1 cm of the tail was submerged
cuff non-invasive blood pressure system (Kent Scientific Corporation, into a 52-53°C water bath. The latency for the rat to withdrawal its tail
Torrington, CT, USA) as previously described [16]. was scored.

IV Cannabinoid-Induced Tetrad Test V Analytical Methods

Rats were evaluated for hypolocomotion (open feld test), hypothermia Serum triglyceride, cholesterol, uric acid and glucose levels were
(body temperature), cataleptic (bar test) and analgesic (hot plate test) measured by spectrophotometric methods using commercial enzymatic
efects, using the procedures of the tetrad tests as reported by Metna- kits according to the manufacturer’s protocols (Wiener Lab., Argentina;
Laurent et al., with some modifications [17]. Briefly, locomotor activity Randox Laboratories Limited, United Kingdom). The activities of serum
was assessed 30 min after treatment, for a 5 min period in a and hepatic aspartate aminotransferase (AST), alanine aminotransferase
polycarbonate box (60 × 60 × 25 cm), and Anymaze software (Stoelting, (ALT) and alkaline phosphatase (AP) enzymes were measured by
Wood Dale, Illinois) was used to determine distance traveled. Rectal spectrophotometric methods using commercial enzymatic kits according
temperature was assessed 50 min after cannabis oil administration, using to the manufacturer’s protocols (Wiener Lab., Argentina). For preparing
an infrared thermometer. Catalepsy was assessed 55 min after cannabis the liver homogenate, the frozen tissue was homogenized in 10-volumes
oil administration in a box with a 0.7 cm in diameter placed 4.5 cm off of ice-cold 0.1 M potassium phosphate buffer (pH 7.4). The homogenate
of the ground. The front paws of the rat are placed gently on the was centrifuged at 10,000 rpm for 15 min, and the supernatant used by

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Effects of Cannabis Oil on Cannabinoid-Induced Tetrad, Blood Pressure, and Metabolic Parameters in an Experimental Model of Metabolic Syndrome 4

measure the hepatic damage enzyme activity. Triglycerides and total test. P values lower than 0.05 were considered to be statistically
cholesterol content in liver were extracted with chloroform-methanol significant (SPSS 17.0 for Windows, SPSS INC. Chicago, Illinois).
(2:1) mixture. Aliquots were evaporated and total cholesterol and
triglycerides were analysed using enzymatic methods mentioned before. Results

VI Statistical Analysis I Body Weight, Food Intake and Liver Weight

Results were expressed as mean ± SEM. Statistical comparisons were Figure 1A shows that throughout the experimental protocol (21 days)
made transversely between different dietary groups. Data were tested for there was no significant difference in body weight in the experimental
variance using Levene’s test and normality by Shapiro-Wilk’s test. The groups. Final food intake and liver weight did not differ between the
statistical difference between groups (RD, SRD and SRD+Ca) was groups (Figure 1B and 1C).
determined by one-way ANOVA followed by post-hoc Newman-Keuls'

Figure 1: Body weight, food intake and liver weight of rats fed a control diet, sucrose-rich diet (SRD) or SRD with cannabis oil (SRD+Ca).
A) Body weight during the experimental period. Cannabis oil was administrated from the beginning of the experiment and during 3 weeks. Values are means
for six animals per group, with standard errors represented by vertical bars. B) Food final intake and C) liver weight. Values are mean ± SEM (n= 6). Bars
that do not share the same letter are significantly different, (P<0.05).

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Effects of Cannabis Oil on Cannabinoid-Induced Tetrad, Blood Pressure, and Metabolic Parameters in an Experimental Model of Metabolic Syndrome 5

II Time Course of Systolic and Diastolic Blood Pressure week 2 until the end, the animals SRD-fed showed a significant increase
(P<0.05) in systolic and diastolic blood pressure compared with the RD-
Table 2 shows the time course of systolic and diastolic blood pressure fed group. The administration of Cannabis oil (SRD+Ca) resulted in a
throughout the experimental period in the three dietary groups. In the significant reduction (P<0.05) in both parameters from the second week
first week of diet administration there were no significant differences in of administration, compared to the SRD group, reaching reference
diastolic and systolic pressure between the experimental groups. From values.

Table 2: Time course of systolic and diastolic blood pressure throughout the experimental period in rats fed a reference diet (RD), sucrose-rich diet (SRD)
or SRD with cannabis oil (SRD+Ca).
RD SRD SRD+Ca
Diastolic Blood Pressure (mmHg)
Week 1 (day 0 to 7) 75.14 ± 1.51a 76.572 ± 1,491 a 74.30 ± 1.07 a
b a
Week 2 (day 8 to 15) 74.27 ± 1.10 80.540 ± 1.550 76.05 ± 1.06 b
b a
Week 3 (day 16 to 21) 78.20 ± 1.34 87.909 ± 1.382 79.53 ± 1.05 b
Systolic Blood Pressure (mmHg)
Week 1 (day 0 to 7) 111.17 ± 0.63 a 109.78 ± 1.36 a 108.52 ± 1.03 a
Week 2 (day 8 to 15) 109.00 ± 0.75 b 120.28 ± 1.04 a 110.80 ± 1.72 b
Week 3 (day 16 to 21) 119.58 ± 0.98 b 132.96 ± 0.19 a 117.67 ± 0.25 b
Values are expressed as mean ± SEM, n=6. Values in a line that do not share the same superscript letter are significantly different (P < 0.05) when one
variable at a time was compared by one-way ANOVA followed by Newman-Keuls´ test.

III Cannabis Effects in the Tetrad Assay incorporation of cannabis oil (SRD+Ca) significantly increased (P<0.05)
analgesia. The locomotion, which was found to be increased in the SRD
The cannabinoid activity of cannabis oil was evaluated by the tetrad of group, was significantly decreased (P<0.05) in the SRD+Ca group,
behavioural tests on rats. The tetrad includes the assessment of reaching reference values. There were no significant differences in body
spontaneous activity (locomotion), immobility index (catalepsy), temperature and catalepsy between the experimental groups.
analgesia and changes in rectal temperature. Figure 2 shows that the

Figure 2: Cannabinoid-Induced Tetrad test in rats fed a reference diet (RD), sucrose-rich diet (SRD) or SRD with cannabis oil (SRD+Ca).
A) locomotion, B) temperature, C) catalepsy and D) analgesia.. Values are mean ± SEM (n= 6). Bars that do not share the same letter are significantly
different, (P<0.05).

IV Serum Metabolites and Liver Damage Enzyme Activity SRD-fed rats compared with RD-fed rats. The administration of
Cannabis oil (SRD+Ca) significantly decreased (P<0.05) serum Tg and
Table 3 shows that at the end of experimental protocol, both serum cholesterol levels reaching reference values and uric acid levels was
triglyceride, cholesterol and uric acid levels were significantly higher in significantly reduced (P<0.05), although the values was still higher than

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Effects of Cannabis Oil on Cannabinoid-Induced Tetrad, Blood Pressure, and Metabolic Parameters in an Experimental Model of Metabolic Syndrome 6

RD group. No changes in serum glucose were recorded in the three (P<0.05) reached values similar to those observed in the RD group. AP
dietary groups. Serum AST, ALT and AP levels were significantly enzyme was significantly reduced (P<0.05), although the values was still
increased (P<0.05) in SRD-fed rats compared to RD-fed rats. In the higher than RD group.
SRD+Ca group, AST and ALT enzymes significantly decreased

Table 3: Serum metabolites and liver damage enzyme activity in rats fed a reference diet (RD), sucrose-rich diet (SRD) or SRD with cannabis oil (SRD+Ca).
RD SRD SRD+Ca
Glucose (mM) 7.71 ± 0.11a 7.84 ± 0.07a 7.62 ± 0.22a
Triglyceride (mM) 1.32 ± 0.09b 3.08 ± 0.16a 1.46 ± 0.11b
b a
Cholesterol (mM) 2.07 ± 0.07 2.63 ± 0.06 2.20 ± 0.11b
c a
Uric acid (mM) 49.20 ± 5.77 122.22 ± 8.83 72.49 ± 4.19b
b a
AST (U/L) 19.56 ± 0.75 27.31 ± 0.82 21.54 ± 1.35b
b a
ALT (U/L) 20.93 ± 1.39 29.92 ± 0.73 21.57 ± 1.97b
c a
AP (U/L) 672.42 ± 54.61 1183.01 ± 25.07 1032.03 ± 11.95 b
Values are expressed as mean ± SEM, n=6. Values in a line that do not share the same superscript letter are significantly different (P < 0.05) when one
variable at a time was compared by one-way ANOVA followed by Newman-Keuls´ test.

V Metabolites and Damage Enzyme Activity in Liver while the cholesterol content returned to RD-group values. Furthermore,
the SRD-fed rats had significantly higher (P<0.05) AST, ALT and AP
In (Figure 3) shows that in the liver, triglyceride and cholesterol content hepatic levels, compared to RD-fed rats. In the SRD+Ca group, the
were significantly increased (P<0.05) in the SRD group compared to the values of AST and ALT hepatic enzymes returned to the values found in
RD group. In the SRD+Ca group, triglyceride content significantly the RD-fed rats. AP hepatic enzyme was significantly reduced (P<0.05),
decreased (P<0.05), although the values were still higher than RD group, although the values was still higher than RD group.

Figure 3: Metabolites hepatic and biomarkers of liver injure.

A) Triglyceride, B) cholesterol hepatic content, C) AST, D) ALT and E) AP liver enzymes. Values are mean ± SEM (n = 6). Bars that do not share the same
letter are significantly different, (P<0.05).

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Effects of Cannabis Oil on Cannabinoid-Induced Tetrad, Blood Pressure, and Metabolic Parameters in an Experimental Model of Metabolic Syndrome 7

Discussion Cannabis sativa has been used for more than four centuries to treat a
variety of medical conditions including pain. Cannabis plant as a whole
Cannabis preparations have been used for recreational and therapeutic has analgesic properties. In our study, we demonstrated that the
purposes for thousands of years. These or some of their components administration of cannabis oil (CDC:THC 2:1) significantly increased
activate an endogenous system of the body, the so-called analgesia in rats. In this line, Harris et al. demonstrated that THC
endocannabinoid system, which is a complex physiological system that administration produced robust analgesia equivalent to the full cannabis
acts on metabolic pathways, which have not yet been explored. In this extract in male Sprague-Dawley rats [30]. Moore & Weerts showed a
study, we present data showing that administration of a cannabis oil rich greater potency of oral THC to produce thermal antinociceptive effects
in CBD-THC (2:1) resulted of significant improvement in the several in male rats, but oral CBD no antinociceptive effects were detected in
parameters present of MS. We observed that cannabis oil did not affect the tail flick test, and in fact, increased pain sensitivity was observed
the body weight, food intake and liver weight. In this line, Assa-Glazer after the highest dose of CBD (30 mg/kg) [31].
et al. observed that none of the plant extracts administrated in the study
affected food consumption in mice a high-fat/cholesterol diet for 6 weeks Cannabinoids have demonstrated beneficial effects on diabetes and lipid
[18]. During this period, cannabis extracts (CN1: rich in CBD, CN2: rich metabolism. In our study, we observed that cannabis oil administration
in THC, and CN6: similar concentrations of both phytocannabinoids) to SRD-fed rats, significantly improved serum triglyceride, cholesterol
were administrated orally at a concentration of 5 mg/kg every 3 days. and uric acid levels with no change in glucose levels. Enzymes AST and
Wierucka-Rybak et al. revealed that CBD injections (3 mg/kg for 3 days) ALT are used as markers of liver injury. The cannabis oil administration
in rats fed high sucrose diet did not cause significant change in food presented reduction in these enzymes in serum and liver, together with
intake and body weight [19]. an improvement in the hepatic content of triglyceride and cholesterol,
suggesting a significant decrease in steatosis and liver damage, showing
However, other studies that investigated the impact of CBD or THC on the hepatoprotective effect of cannabis oil used in present study. In this
food intake showed contradictory results. It has been reported that THC line, some studies suggest that the cannabinoids Δ9-THC and/or CBD
increases appetite and subsequent food intake [20]. Studies show that the increase HDL-C concentration, reduce total cholesterol and triglyceride
hyperphagic effects of THC are mostly acute and are absent after a few in serum and decreases hepatic triglyceride accumulation and liver
days of administration. THC administered orally at a dose of 2 mg/kg, damage in other animal models [32-35]. Although none of them were
increased appetite 1 h after administration although the animals performed in male Wistar rats fed with a SRD. In clinical studies, have
subsequently compensated for their hyperphagia, so that 24-h intakes shown that several cannabinoids (CBD, THC or THCV) has beneficial
were similar to controls [21]. On the other hand, Ignatowska-Jankowska effects on biochemical parameters, such as blood glucose, total
et al. demonstrated that CBD (2.5 and 5 mg/kg) induced a decrease in cholesterol, high density lipoprotein (HDL) cholesterol, and
body weight gain in rats, while other studies have shown no significant triglycerides, and liver damage which are altered in diabetic patients [36,
impact on food intake and body weight in mice and rats, respectively 37].
[22-24]. This contradiction may be explained by the concentrations of
cannabinoids (i.e., THC and/or CBD) administered, time and route of Cannabinoid-based therapies may also protect against diabetic
administration used in the experiments. complications. The results of this study provide new information on the
beneficial effects of the administration of cannabis oil, with CBD and
Endocannabinoids are implicated in the pathogenesis of hypertension THC ratios of 2 to 1, useful in the treatment of several parameters
[25]. In our study, we show that the cannabis oil administration included in the MS, among as hypertension, dyslipidemia and liver
decreased systolic and diastolic blood pressure in dyslipidemic and damage. However, to discover the complete mechanism behind these
hypertensive rats fed with a SRD. There are very few studies on the phenomena, further research is needed.
effects of cannabis or cannabinoids on hypertension. In this line, the
majority of clinical evidence suggests that CBD dose not impact blood Conclusions
pressure in the populations assessed. In addition, there are very few
clinical studies carried out in populations with high blood pressure, since The present study demonstrates the beneficial effect of cannabis oil upon
CBD intervention studies have generally been carried out in healthy hypertension, dyslipidemia, mitigating steatosis and liver damage
individuals or with non-cardiovascular conditions exposed to stress induced by a SRD. In addition, the analgesic effect of cannabis oil could
(cold, physical activity, public speaking), and more studies are required be observed in SRD-fed rats. Furthermore, our results suggested that
to determine if CBD supplementation can reduce blood pressure in cannabis oil could serve as a new therapeutic agent to prevent or
patients with hypertension [26, 27]. On the other hand, in a study ameliorate metabolic disorders related included in MS.
conducted with THC, they showed that inhalation of cannabis smoke
from cigarettes (2.8% Δ9-THC) lowered blood pressure more durably in Finally, although care must be taken when extrapolating these results
hypertensive subjects compared to normotensive subjects [28]. In animal from rats to humans, this animal model proves to be useful to study the
studies, the effects of CBD on blood pressure were inconsistent and mechanisms that determine the influence of nutrients/nutraceuticals in
varied depending on the model of hypertension [29]. This is the first the development and management of metabolic diseases.
study evaluating the effect of cannabis oil (CBD-THC, 2:1)
administration on systolic and diastolic blood pressure in SRD-fed
hypertensive rats.

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Effects of Cannabis Oil on Cannabinoid-Induced Tetrad, Blood Pressure, and Metabolic Parameters in an Experimental Model of Metabolic Syndrome 8

Acknowledgments Tg: Triglyceride

CBDVA: Cannabidivaric acid
The authors would like to thank Silvia Rodríguez for their skillful CBDV: Cannabidivarin
technical assistance. CBDA: Cannabidiolic acid
CBGA: Cannabigerolic acid
Author Agreement CBG: Cannabigerol
CBD: Cannabidiol
We the undersigned declare that this manuscript is original, has not been THCV: Tetrahidrocannabivarin
published before and is not currently being considered for publication THCVA: Tetrahidrocannabivarinic acid
elsewhere. We confirm that the manuscript has been read and approved CBN: Cannabinol
by all named authors and that there are no other persons who satisfied ∆-9-THC: ∆-9-Tetrahidrocannabinol
the criteria for authorship but are not listed. We further confirm that the ∆-8-THC: ∆-8-Tetrahidrocannabinol
order of authors listed in the manuscript has been approved by all of us. CBC: Cannabichromene
We understand that the Corresponding Author is the sole contact for the THCA: Tetrahydrocannabinolic acid
Editorial process. She is responsible for communicating with the other
authors about progress, submissions of revisions and final approval of REFERENCES
proofs.

1. Lemieux I, Després JP (2020) Metabolic Syndrome: Past, Present and

Author Contributions
Future. Nutrients 12: 3501. [Crossref]
2. Sherling DH, Perumareddi P, Hennekens CH (2017) Metabolic
MEO: Funding acquisition, Conceptualization, Investigation,
Syndrome. J Cardiovasc. Pharmacol Ther 22: 365-367. [Crossref]
Methodology, Data curation, Formal analysis, Supervision, Writing the
3. Lombardo YB, Drago S, Chicco A, Fainstein Day P, Gutman R et al.
manuscript. MVJ: Investigation, Methodology, Data curation, Formal
(1996) Long-term administration of a sucrose-rich diet to normal rats:
analysis, Writing the manuscript. VD: Investigation, Data curation,
relationship between metabolic and hormonal profiles and
Formal analysis, Writing the manuscript. CV: Investigation, Data
morphological changes in the endocrine pancreas. Metabolism 45:
curation, Formal analysis. DS: Investigation, Data curation, Formal
1527-1532. [Crossref]
analysis, Writing the manuscript. DA: Investigation, Data curation,
4. Toop CR, Gentili S (2016) Fructose Beverage Consumption Induces a
Formal analysis, Writing the manuscript. MED: Conceptualization,
Metabolic Syndrome Phenotype in the Rat: A Systematic Review and
Methodology, Data curation, Formal analysis, Writing the manuscript.
Meta-Analysis. Nutrients. 8: 577. [Crossref]
5. Wei Y, Wang D, Topczewski F, Pagliassotti MJ (2007) Fructose-
Conflicts of Interest
mediated stress signaling in the liver: implications for hepatic insulin
resistance. J Nutr Biochem 18: 1-9. [Crossref]
None.
6. Chicco AG, D’Alessandro ME, Hein GJ, Oliva ME, Lombardo YB
(2009) Dietary chia seed (Salvia hispanica L.) rich in a-linolenic acid
Ethical Statement
improves adiposity and normalises hypertriacylglycerolaemia and
insulin resistance in dyslipaemic rats. Br J Nutr 101: 41-50. [Crossref]
This study protocol was reviewed and approved by the Institutional
7. Rossi AS, Oliva ME, Ferreira MR, Chicco A, Lombardo YB (2013)
Ethics Committee of the Faculty of Biochemistry and Biological
Dietary chia seed induced changes in hepatic transcription factors and
Sciences (Universidad Nacional del Litoral, Santa Fe, Argentina),
their target lipogenic and oxidative enzyme activities in dyslipidaemic
approval number Acta 03/21.
insulin-resistant rats. Br J Nutr 109: 1617-1627. [Crossref]
8. Bonini SA, Premoli M, Tambaro S, Kumar A, Maccarinelli G et al.
Funding
(2018) Cannabis sativa: A comprehensive ethnopharmacological
review of a medicinal plant with a long history. J Ethnopharmacol 227:
This work was supported by Agencia Santafesina de Ciencia, Tecnología
300-315. [Crossref]
e Innovación from Argentina (PEICID-2021-003).
9. Bridgeman MB, Abazia DT (2017) Medicinal Cannabis: History,
Pharmacology, and Implications for the Acute Care Setting. P T 42:
Abbreviations
181-188. [Crossref]
10. Hussain T, Jeena G, Pitakbut T, Vasilev N, Kayser O (2021) Cannabis
ALT: Alanine Aminotransferase
sativa research trends, challenges, and new-age perspectives. iScience
AP: Alkaline Phosphatase
24: 103391. [Crossref]
AST: Aspartate Aminotransferase
11. Radwan MM, Chandra S, Gul S, ElSohly MA (2021) Cannabinoids,
CBD: Cannabidiol
Phenolics, Terpenes and Alkaloids of Cannabis. Molecules 26: 2774
MS: Metabolic Syndrome
[Crossref]
SRD: Sucrose-rich Diet
12. Bielawiec P, Harasim Symbor E, Chabowski A (2020)
RD: Reference Diet
Phytocannabinoids: Useful Drugs for the Treatment of Obesity?
SRD+Ca: SRD+Cannabis Oil
THC: Tetrahydrocannabinol

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Effects of Cannabis Oil on Cannabinoid-Induced Tetrad, Blood Pressure, and Metabolic Parameters in an Experimental Model of Metabolic Syndrome 9

Special Focus on Cannabidiol. Front Endocrinol (Lausanne) 11: 114- 26. Azari EK, Kerrigan A, O’Connor A (2020) Naturally Occurring
125. [Crossref] Cannabinoids and their Role in Modulation of Cardiovascular Health.
13. [13] Gruden G, Barutta F, Kunos G, Pacher P (2016) Role of the J Diet Suppl 17: 625-650. [Crossref]
endocannabinoid system in diabetes and diabetic complications. Br. J. 27. Jadoon KA, Tan GD, O’Sullivan SE (2017) A single dose of
Pharmacol. 173: 1116-1127. [Crossref] cannabidiol reduces blood pressure in healthy volunteers in a
14. Horváth B, Mukhopadhyay P, Haskó G, Pacher P (2012) The randomized crossover study. JCI Insight 2: e93760. [Crossref]
Endocannabinoid System and Plant-Derived Cannabinoids in Diabetes 28. Baranowska Kuczko M, Kozłowska H, Kloza M, Sadowska O,
and Diabetic Complications. Am. J. Pathol 180: 432-442. [Crossref] Kozłowski M et al. (2020) Vasodilatory effects of cannabidiol in
15. Sedan D, Vaccarini C, Demetrio P, Morante M, Montiel R et al. (2023) human pulmonary and rat small mesenteric arteries: modification by
Cannabinoid Content in Cannabis Flowers and Homemade Cannabis- hypertension and the potential pharmacological opportunities. J
Based Products Used for Therapeutic Purposes in Argentina. Cannabis Hypertens 38: 896-911. [Crossref]
Cannabinoid Res 8: 197-206. [Crossref] 29. Remiszewski P, Jarocka Karpowicz I, Biernacki M, Jastrząb A,
16. Creus A, Benmelej A, Villafañe N, Lombardo YB (2017) Dietary Salba Schlicker E et al. (2020) Chronic Cannabidiol Administration Fails to
(Salvia hispanica L) improves the altered metabolic fate of glucose and Diminish Blood Pressure in Rats with Primary and Secondary
reduces increased collagen deposition in the heart of insulin-resistant Hypertension Despite Its Effects on Cardiac and Plasma
rats. Prostaglandins Leukot Essent Fatty Acids 121: 30-39. [Crossref] Endocannabinoid System, Oxidative Stress and Lipid Metabolism. Int
17. Metna Laurent M, Mondesir M, Grel A, Vallee M, Piazza PV (2017) J Mol Sci 21: 1295. [Crossref]
Cannabinoid-Induced Tetrad in Mice. Curr. Protoc Neurosci. 80: 30. Harris HM, Rousseau MA, Wanas AS, Radwan MM, Caldwell S et al.
9.59.1-9.59.10. [Crossref] (2019) Role of Cannabinoids and Terpenes in Cannabis-Mediated
18. Assa Glazer T, Gorelick J, Sela N, Nyska A, Bernstein N et al. (2020) Analgesia in Rats. Cannabis Cannabinoid Res 4: 177-182. [Crossref]
Cannabis Extracts Affected Metabolic Syndrome Parameters in Mice 31. Moore CF, Weerts EM (2022) Cannabinoid tetrad effects of oral Δ9-
Fed High-Fat/Cholesterol Diet. Cannabis Cannabinoid Res. 5: 202- tetrahydrocannabinol (THC) and cannabidiol (CBD) in male and
214. [Crossref] female rats: sex, dose-effects and time course evaluations.
19. Wierucka Rybak M, Wolak M, Bojanowska E (2014) The effects of Psychopharmacology (Berl) 239: 1397-1408. [Crossref]
letin in combination with a cannabinoid receptor 1 antagonist, AM 251, 32. Comelli F, Bettoni I, Colleoni M, Giagnoni G, Costa B (2009)
or cannabidiol on food intake and body weight in rats fed a high-fat or Beneficial effects of a Cannabis sativa extract treatment on diabetes-
free-choice high sugar diet. J Physiol Pharmacol 65: 487-496. induced neuropathy and oxidative stress. Phytother Res 23: 1678-1684.
[Crossref] [Crossref]
20. Fearby N, Penman S, Thanos P (2022) Effects of ∆9- 33. Silvestri C, Di Marzo V (2013) The Endocannabinoid System in
Tetrahydrocannibinol (THC) on Obesity at Different Stages of Life: A Energy Homeostasis and the Etiopathology of Metabolic Disorders.
Literature Review. Int J Environ Res Public Health 19: 3174-3202. Cell Metab 17: 475-490. [Crossref]
[Crossref] 34. Wang Y, Mukhopadhyay P, Cao Z, Wang H, Feng D et al. (2017)
21. Williams CM, Rogers PJ, Kirkham TC (1998) Hyperphagia in Pre-Fed Cannabidiol attenuates alcohol-induced liver steatosis, metabolic
Rats Following Oral Δ9 -THC. Physiol Behav 65: 343-346. [Crossref] dysregulation, infammation and neutrophil-mediated injury. Sci. Rep
22. Ignatowska Jankowska B, Jankowski MM, Swiergiel AH (2011) 21: 12064. [Crossref]
Cannabidiol decreases body weight gain in rats: Involvement of CB2 35. Wargent ET, Zaibi MS, Silvestri C, Hislop DC, Stocker CJ et al. (2013)
receptors. Neurosci Lett 490: 82-84 [Crossref] The cannabinoid D9 -tetrahydrocannabivarin (THCV) ameliorates
23. Riedel G, Fadda P, McKillop Smith S, Pertwee RG, Platt B et al. (2009) insulin sensitivity in two mouse models of obesity. Nutr Diabetes 3:
Synthetic and plant-derived cannabinoid receptor antagonists show e68. [Crossref]
hypophagic properties in fasted and non-fasted mice. Br J Pharmacol 36. Adejumo AC, Alliu S, Ajayi TO, Adejumo KL, Adegbala OM et al.
156: 1154-1166. [Crossref] (2017) Cannabis use is associated with reduced prevalence of non-
24. Wiley JL, Burston JJ, Leggett DC, Alekseeva OO, Razdan RK et al. alcoholic fatty liver disease: A cross-sectional study. PLoS One 12:
(2005) CB1 cannabinoid receptor-mediated modulation of food intake e0176416. [Crossref]
in mice. Br J Pharmacol 145: 293-300. [Crossref] 37. Jadoon KA, Ratcliffe SH, Barrett DA, Thomas EL, Stott C et al. (2016)
25. Malinowska B, Baranowska Kuczko M, Schlicker E (2012) Triphasic Efficacy and Safety of Cannabidiol and Tetrahydrocannabivarin on
blood pressure responses to cannabinoids: do we understand the Glycemic and Lipid Parameters in Patients With Type 2 Diabetes: A
mechanism? Br J Pharmacol 165: 2073-2088. [Crossref] Randomized, Double-Blind, Placebo-Controlled, Parallel Group Pilot
Study. Diabetes Care 39: 1777-1786. [Crossref]

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