ArticlePDF Available

Morinda citrifolia (Noni) Fruit Juice Inhibits Endocannabinoid Degradation Enzymes

Journal of Biosciences and Medicines, 2019, 7, 22-34
ISSN Online: 2327-509X
ISSN Print: 2327-5081
10.4236/jbm.2019.77003 Jul. 11, 2019 22
Journal of Biosciences and Medicines
Morinda citrifolia (Noni) Fruit Juice Inhibits
Endocannabinoid Degradation Enzymes
Brett J. West, Shixin Deng, C. Jarakae Jensen
Research and Development, Morinda, Inc., American Fork, Utah, USA
Morinda citrifolia
(noni) fruit juice has been shown to have a
wide variety of
potential health benefits in human clinical trials. It may also influence the
endocannabinoid system of the body. Since the main ingredient of the prod-
uct studied in these clinical trials was juice made from noni fruit puree from
French Polynesia, it was evaluated for its ability to inhibit the two major en-
docannabinoid degradation enzymes
in vitro
. Noni fruit juice inhibited both
fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) in a
concentration-dependent manner, sugges
ting that it may help maintain
anandamide and 2-arachidonoylglycerol levels. Samples of the puree were al-
so analyzed for the presence of characteristic phytochemical markers of au-
thentic noni fruit such as scopoletin, rutin, quercetin, deacetylasperulosidic
acid and asperulosidic acid,
all of which were present. Also present was
which is reported for the first time as being identified in noni
fruit or its juice. Some of these compounds may contribute to the FAAH and
MAGL inhibiting activity of
noni juice. These results reveal another set of
mechanisms by which noni juice possibly supports mental health,
joint health, relieves discomfort and modulates the immune system.
Morinda citrifolia
, Endocannabinoid System, Fatty Acid Amide Hydrolase,
Monoacylglycerol Lipase
1. Introduction
The endocannabinoid system (ECS) serves an important regulatory function
within the human body. It influences the nervous and immune systems exten-
sively and has an impact on digestion, reproduction and bone mass [1] [2]. The
ECS also has interrelations with the respiratory, renal, endocrine and cardiovas-
How to cite this paper:
West, B.J.,
S.X. and
Jensen, C.J. (2019)
Morinda citr
(Noni) Fruit Juice Inhibits Endocan-
nabinoid Degradation Enzymes
Journal of
Biosciences and Medicines
, 22-34.
May 22, 2019
July 8, 2019
July 11, 2019
Copyright © 201
9 by author(s) and
Research Publishing Inc.
This work is licensed
under the Creative
Commons Attribution International
License (CC BY
Open Access
B. J. West et al.
10.4236/jbm.2019.77003 23
Journal of Biosciences and Medicines
cular systems [3] [4]. Indeed, the ECS has a wide effect on the body and helps
maintain overall health. The ECS is composed of G protein-coupled receptors
(GPCRs) within cell membranes, lipid signaling molecules (endocannabinoids)
and the enzymes responsible for endocannabinoid synthesis and catabolism. The
two most prominent ECS receptors are cannabinoid receptor type 1 (CB1) and
cannabinoid receptor type 2 (CB2). Other GPCRs, currently designated as or-
phan receptors, have been more recently discovered. There are two main endo-
cannabinoids produced by the body, N-arachidonoylethanolamine (anandamide
or AEA) and 2-arachidonoylglycerol (2-AG). AEA and 2-AG are synthesized
from arachidonic acid derivatives, N-arachidonoyl phosphatidylethanolamine
(NAPE) and diacylglycerol, by phospholipases and diacylglycerol lipases. AEA is
eventually degraded by fatty acid amide hydrolase (FAAH) to arachidonic acid
and ethanolamine. 2-AG is hydrolyzed by monoacylglycerol lipase (MAGL) and
FAAH [5]. AEA and 2-AG are CB1 and CB2 ligands, and it is through their in-
teractions with these receptors that many of their physiological effects are me-
diated [6].
Morinda citrifolia
is a small to medium sized tree that grows in tropical re-
gions. It is commonly known as noni or Indian mulberry. The tree produces
fruit year-round, which has been used as both food and medicine [7]. The leaves
and other plant parts also had significant roles in the Pacific, South Asian,
Southeast Asian, and the Caribbean traditional medicine [8]. The noni tree was
reportedly the most important and widely used Polynesian medicinal plant prior
to the European era [9]. Various parts of the plant were used by local healers for
a broad range of health conditions [10] [11] [12]. Traditional perceptions of the
health benefits of noni appear to be validated by the results of human clinicals
trials, especially those involving noni fruit juice. Among the recorded effects of
noni juice ingestion are control of inflammation, improved joint mobility, relief
of discomfort, immune system modulation, protection against oxidative damage,
maintenance of bone health, and improved mental health outcomes [13].
The array of noni juice benefits observed in human studies suggests that it in-
teracts with multiple bodily systems, among which the ECS may have a signifi-
cant role. In fact, we have previously reported that noni juice exhibits CB2 re-
ceptor agonist activity [14]. But as the major endocannabinoids produce effects
within the body that are similar to those reported for noni juice, we further in-
vestigated noni juice’s interaction with the ECS by assessing its potential to
maintain AEA and 2-AG levels through FAAH and MAGL inhibition.
2. Materials and Methods
Noni fruit was harvested in French Polynesia and allowed to fully ripen. The
fruit was then processed into a puree by mechanical removal of the seeds and
skin, followed by pasteurization at a good manufacturing certified fruit
processing facility in Mataiea, Tahiti. This source of noni fruit puree was ap-
proved by the European Commission in 2003 as a safe novel food for use in pas-
B. J. West et al.
10.4236/jbm.2019.77003 24
Journal of Biosciences and Medicines
teurized beverages [15]. It was also later approved as a safe novel food ingredient
for use in a wide variety of food categories within the European Union [16]. For
our study, the noni fruit puree was centrifuged to remove insoluble fiber. The
resultant clarified juice was then filtered through a 0.45 μm PTFE filter.
Samples of this filtered noni juice were analyzed by high performance liquid
chromatography (HPLC), according to a previously validated method, for irido-
id markers of authentic noni fruit, including deacetylasperulosidic acid (DAA)
and asperulosidic acid (AA) [17]. As we have since discovered the presence of
scandoside in noni fruit by LC-MS analysis, we included this in our HPLC ana-
lyses. Samples were diluted with methanol-H2O (1:1) and filtered through a 0.45
µm nylon membrane filter. Chromatographic separation was performed with a
C-18 column (4.6 mm × 250 mm; 5 μm, Waters Corporation, Milford, MA,
USA). Two mobile phases were used: A; acetonitrile (MeCN), and B; 0.1% for-
mic acid in H2O (v/v). The elution rate was 0.8 mL/min. with consecutive linear
gradients of 100% B for 0 - 5 min. followed by 70% B and 30% A for 40 min. A
photodiode array (PDA) detector was used to monitor the eluted compounds
within 210 - 400 nm. Sample injection volume was 10 µL, and column tempera-
ture was 25˚C.
Analyses of scopoletin, rutin, and quercetinadditional phytochemical
markers of authentic noni fruitwere also performed by HPLC according to a
previously validated method [18]. Chromatographic separation was performed
on a Waters 2690 separations module, coupled with a Waters 996 photodiode
array (PDA) detector, and a C-18 column. Three solvents were used to compose
the mobile phase. These were MeCN (solvent A), MeOH (solvent B), and 0.1%
formic acid in H2O (solvent C). The following linear gradient was used for the
separation: 0 min. of 10% A, 10% B, and 80% C; 15 min. of 20% A, 20% B, and
60% C; 26 min. of 40% A, 40% B, and 20% C; 28 - 39 min. of 50% A, 50% B, and
0% C; and 40 - 45 min. of 10% A, 10% B, and 80% C. The flow rate was 1.0
mL/min. Chromatograms were integrated at 365 nm. In both HPLC methods,
retention times and peak areas were compared against standards to determine
analyte concentrations in the samples.
The total polyphenol content of each sample was determined by the Fo-
lin-Ciocalteu method [19]. Samples were centrifuged and diluted 1:10 with deio-
nized water. Next, 10 µL of each sample was mixed with 50 µL Folin-Ciocalteu
(2N) and an additional 800 µL deionized water. The mixture was incubated at
room temperature for a few minutes, followed by addition of 150 µL Na2CO3
(saturated) and incubation at room temperature for 2 hours. Gallic acid stan-
dards were prepared with the same procedure. Afterwards, the absorbance of
each sample and standard was measured at 765 nm with a microplate reader.
Sample absorbance vs. gallic acid concentration was used to determine the total
phenol content of the samples, expressed as gallic acid equivalents (GAE).
FAAH and MAGL inhibition assays were carried out as previously described,
but with some modifications [20]. Human recombinant FAAH, human recom-
B. J. West et al.
10.4236/jbm.2019.77003 25
Journal of Biosciences and Medicines
binant MAGL, 7-amino-4-methyl coumarin-arachidonamide (AMC-AA), and
4-nitrophenylacetate were obtained from Cayman Chemical Company (Ann
Arbor, MI, USA). For the FAAH inhibition assay, the recombinant FAAH was
diluted with Tris-HCl buffer (125 mM, pH 9.0) containing 1 mM EDTA. Noni
juice samples were added in varying volumes to separate wells of a black plastic
96-well microplate, with deionized water also being added to make up a total
volume of 10 μL. Vehicle control (no inhibitor) wells did not receive noni juice,
only water. Inhibitor (noni juice) and control wells received 10 μL FAAH solu-
tion as well as additional 170 μL of buffer. Background fluorescence wells, to
which no FAAH was added, received 180 μL buffer. The microplate was then
incubated for five minutes at 37˚C. Ten μL of AMC-AA solution was then added
to each well with a final concentration of 20 μM. The microplate was then incu-
bated again at 37˚C for 30 minutes. Following incubation, the fluorescence in-
tensity of each well was measured in a Synergy™ HT microplate reader (BioTek
Instruments, Winooski, VT, USA) with 360 ± 40 nm excitation and 460 ± 40 nm
emission. All samples and the control were evaluated in triplicate. The relative
increase in fluorescence intensity was determined by the ratio of the intensities
of the inhibitor well and its corresponding background well. Percent FAAH in-
hibition was calculated from the difference between the relative increase in fluo-
rescence intensity of the vehicle control and the sample divided by that of the ve-
hicle control alone. DAA, the major phytochemical constituent of noni fruit, was
also evaluated in this assay but with DMSO as the solvent and vehicle control.
In the MAGL inhibition assay, the recombinant MAGL was diluted with
Tris-HCl buffer (10 mM, pH 7.2) containing 1 mM EDTA. Noni juice samples
were added in varying volumes to separate wells of a clear plastic 96-well micro-
plate, with deionized water added to make up a total volume of 10 μL. As in the
previous assay, vehicle control (no inhibitor) wells only received water. Inhibitor
(noni juice) and control wells received 10 μL MAGL solution as well as
additional 150 μL of buffer. Background absorbance wells, with no MAGL, re-
ceived 160 μL buffer. The microplate was then incubated at room temperature
for five minutes. Enzymatic reactions were then begun by the addition of 10 μL
of 4-nitrophenylacetate in ethanol (236 μM in final reaction solution), which
proceeded at room temperature for 10 minutes. Absorbance at 405 nm was then
read with an ELX800 microplate reader (BioTek Instruments, Winooski, VT,
USA). All samples and the control were evaluated in triplicate. Absorbance val-
ues were corrected by subtracting background well values from those of corres-
ponding sample wells. Percent MAGL inhibition was calculated from the differ-
ence between control and sample absorbance divided by that of the absorbance
of just the control. Mean results, as well as standard deviations, were calculated
for each set of replicate samples in both the FAAH and MAGL inhibition assays.
3. Results and Discussion
HPLC analyses revealed that our noni juice samples contained phytochemical
B. J. West et al.
10.4236/jbm.2019.77003 26
Journal of Biosciences and Medicines
constituents that are present in a commercial source of authentic noni juice that
has been reported to protect lymphocyte DNA, improve serum lipid profiles,
and reduce high-sensitivity C-reactive protein (hs-CRP) and homocysteine levels
of cigarette smokers [21] [22]. The concentrations (mean ± standard deviation)
of DAA, AA, scopoletin, rutin, and quercetin were, respectively, 1.3827 ± 0.0170,
0.4033 ± 0.0057, 0.0463 ± 0.0006, 0.0136 ± 0.0005 and 0.0014 ± 0.0001 mg/mL.
Scandoside, which is reported here for the first time in noni fruit or juice, was
present at 0.0823 ± 0.0153 mg/mL. The total polyphenol content was 0.8903 ±
0.0243 mg GAE/mL.
Noni juice inhibited FAAH activity in a concentration dependent manner,
Figure 1. Between 2.50 and 8.33 μ/mL, inhibition vs. noni juice concentration is
linear—reducing AMC-AA hydrolysis by (mean ± standard deviation) 25.22% ±
5.43% to 68.75% ± 5.03%. But above this range, the incremental decrease in
FAAH activity is much less, with suppression of 82.55% ± 0.55% enzyme activity
at 16.66 μL/mL. There was also a concentration-dependent suppression of
MAGL activity by noni juice, Figure 2. The lowest concentration, 2.78 μ/mL,
reduced hydrolysis of 4-nitrophenylacetate by 32.88% ± 3.62%. MAGL activity is
Figure 1. Inhibition of fatty acid amide hydrolase (FAAH) by increasing concentrations
of noni juice. Note: % inhibition by vehicle control (water) is zero.
Figure 2. Inhibition of monoacylglycerol lipase (MAGL) by increasing concentrations of
noni juice. Note: % inhibition by vehicle control (water) is zero.
B. J. West et al.
10.4236/jbm.2019.77003 27
Journal of Biosciences and Medicines
reduced by 55.71% ± 4.40% with 5.56 μL/mL and continues to decline until it is
completed prevented with 18.52 μL noni juice/mL.
These enzyme inhibition assays reveal that noni juice has the potential to in-
fluence AEA and 2-AG levels or prolong their interactions with CB1, CB2, and
the orphan G-protein receptors. This maintenance of endocannabinoid tone, or
levels, likely contributes to pain management since endocannabinoids accumu-
late at sites of injury and inflammation where they interact with cannabinoid re-
ceptors, transient receptor potential vanilloid 1 (TRPV1) ion channels and G
protein-coupled GPR55 receptors to produce analgesia and anti-inflammatory
effects [23] [24] [25]. Mice with a genetic deletion for FAAH had increased pain
tolerance in the tail flick test and the formalin and carrageenan models of in-
flammation [26]. A selective FAAH inhibitor, URB597, reduced neuropathic
pain in Sprague-Dawley rats. This analgesic effect was reduced when CB1 re-
ceptor and peroxisome proliferator-activated receptor alpha (PPAR alpha) an-
tagonists were administered before URB597 [27].
Selective MAGL inhibitors significantly reduced neuropathic pain (allodynia)
resulting from chronic constriction injury of the sciatic nerve [28]. The dual
FAAH/MAGL inhibitor JZL195 reduce allydonia, motor incoordination, and
catalepsy in C57BL/6 mice subjected to chronic constriction injury [29]. The
reduction in neuropathic pain in these animals was greater with the dual
FAAH/MAGL inhibitor than with selective FAAH or MAGL inhibitors alone.
This suggests that substances which impact both AEA and 2-AG levels are more
effective in treating pain and can do so at much lower doses, thus reducing the
potential for side effects.
The antinociceptive properties of noni juice have been demonstrated in mul-
tiple in vivo studies and in human clinical trials. Mice fed noni fruit puree for
four days experience reduced pain sensitivity; an effect comparable to the central
analgesic drug tramadol [30]. This was only partial reversed by naloxone, re-
vealing the involvement of other non-opioid mechanisms. The authors of this
study also reported that a noni fruit extract reduced matrix metalloproteinase-9
(MMP-9) from human monocytes following lipopolysaccharide (LPS) stimula-
tion and suggested that this is one immunomodulating mechanism responsible
for the analgesic and anti-inflammatory action of noni. Interestingly, MMP-9
levels in CB2 knockout mice reached significantly higher levels following LPS
challenge than those in normal mice [31]. This provides supportive in vivo evi-
dence for noni’s potential MAGL and FAAH inhibitor activities since 2-AG is
the principle ligand for CB2.
Clinical trials of noni juice have also been conducted in patients with os-
teoarthritic conditions in which MMP-9 expression has a contributing role [32]
[33]. The first of two open-label clinical trials to demonstrate the potential joint
health benefits of noni juice reported pain reduction and improved range of mo-
tion (flexion, extension, lateral flexion, and rotation) in patients suffering from
cervical spondylosis after four weeks [34]. In this study, 90 patients were ran-
B. J. West et al.
10.4236/jbm.2019.77003 28
Journal of Biosciences and Medicines
domly assigned to either a standard physiotherapy treatment group (positive
control), a noni juice treatment group, or a combined treatment group (physio-
therapy plus noni juice). Measurements of pain intensity and neck flexibility
(cervical range of motion) were compared among the treatment groups. Before
the trial, all subjects in the noni juice group fell within the 5 - 7 (moderate to se-
vere) pain intensity range. But the pain intensity range of this group decreased to
0 - 4 (none to very moderate) after four weeks, with complete relief of neck pain
in 60% of patients. The combined treatment group also experienced significant
reduction in pain symptoms, experiencing even greater reduction in pain inten-
sity. Range of motion improved among all three treatment groups. Lateral flex-
ion and rotation doubled in the noni juice group.
In the second open label intervention study, 82 osteoarthritis (hip and/or
knee) patients drank 88.5 mL noni juice daily for 90 days [35]. Arthritis Impact
Measurement Scales (AIMS2) were used to measure pain/discomfort levels. The
Short Form-36, version 2 (SF-36 V2) was used to measure patient quality of life.
Noni juice ingestion significantly improved mean quality of life measurements.
These included reduced duration of arthritis pain, including a 23.7% decrease in
the frequency of severe pain, and a 16.4% decrease in pain severity. Improve-
ments in average mobility and patient psychological state also occurred. Satisfac-
tion with personal health increased by approximately 19%. The improved
symptoms observed in these two human studies provide further support for the
MAGL and FAAH inhibitory effect of noni juice, since compelling evidence
points to the active involvement of the ECS in mitigating the progress osteoarth-
ritis [36].
The ECS is an important regulator of stress and mental health [37]. As men-
tioned briefly above, noni juice ingestion significantly improved AIMS2 mental
health scores of patients in the 90-day osteoarthritis trial, especially those that rate
anxiety levels and overall mood. A similar effect was reported in post-menopausal
women in a three-month placebo-controlled pilot study [38]. When compared
to the placebo group, drinking 59 mL noni juice twice per day significantly im-
proved the average SF-36 mental health subgroup score.
Feeding of noni juice from Tahiti to rabbits for four weeks resulted in in-
creased sleep duration after receiving general anesthesia as well as improved
basal heart and respiration rates [39]. Further, sponteneous movements were
reduced while under anesthesia, and animals receiving noni juice had smoother
inductions and smoother recoveries. The authors of this study reported that no-
ni juice increased calmness, muscle relaxation, and reduced anxiety in the anes-
thetized rabbits. Another study evaluated the influence of noni juice on
stress-induced impairment of cognitive function of male ICR mice [40]. Those
that had been fed noni juice performed better in a Morris water maze (MWM)
test following chronic restraint stress (CRS). Immunohistochemical analysis re-
vealed that noni juice prevented stress-induced reduction in blood vessel density
in the dentate gyrus of the hippocampus, but the underlying mechanism of ac-
B. J. West et al.
10.4236/jbm.2019.77003 29
Journal of Biosciences and Medicines
tion for this was not elucidated. Even so, CRS increases FAAH activity and low-
ers AEA concentrations in the amygdalas of C57/Bl6 mice, as well as causes
changes in amygdalar structure and increases anxiety-like behavior. But these
changes are absent in FAAH deficient mice [41]. Further, testing with MAGL
knockout mice in hippocampus-dependent learning paradigms indicate that
2-AG signaling is important for learning and memory [42]. Therefore, the inhi-
bition of FAAH and MAGL by noni juice may also be responsible for improved
MWM performance following CRS.
In our study, DAA inhibited FAAH activity modestly at 28.26% ± 4.61%.
Other compounds may also have contributed to the activity of noni juice in our
assays. Quercetin is reported to be a weak FAAH inhibitor, although kaempferol
is reportedly more active [43]. Both of these compounds are in noni fruit and
inhibit 5- and 15-lipoxygenases, with quercetin also weakly inhibiting cycloox-
ygenase-2 (COX-2) [44]. It is worth noting that COX-2 and lipoxygenases de-
grade AEA and 2-AG [45]. Noni fruit juice inhibited these enzymes
in vitro
dramatically reduced the expression of COX-2 in neonatal foals, thereby revealing
another set of pathways by which noni juice may influence endocannabinoid levels
[46] [47]. An extract from noni fruit significantly reduced time-to-recovery fol-
lowing epileptic seizures in Wistar albino rats, with accompanying restoration of
serotonin, dopamine and noradrenaline levels in the forebrain [48]. Similar an-
ti-epileptic effects have been reported for cannabidiol, a known FAAH inhibitor,
in human clinical trials [49] [50]. However, no such phytocannabinoid com-
pounds occur in any part of the noni plant. Further, cannabidiol is reported to be
an ineffective MAGL inhibitor [51]. Therefore, the phytochemical constituents in
noni juice modulate endocannabinoid levels in a different manner with dual
FAAH/MAGL inhibition. Noni fruit juice is a source of polyphenols and con-
tains many other biologically active compounds [52]. So, any number of these
may contribute to FAAH and MAGL inhibition, including the lignans [53].
Therefore, additional phytochemical studies are needed to determine which
compounds in noni fruit are responsible for inhibiting endocannabinoid hydro-
lysis enzymes.
4. Conclusion
The results of this study provide another possible explanation as to why noni
juice has been observed to have such a broad range of therapeutic effects. The
ability of noni juice to reduce FAAH and MAGL activity
in vitro
indicates the
possibility that ingesting it may subsequently elevate AEA and 2-AG levels or
prolong their interactions with CB1, CB2, and orphan G-protein receptors. The
increased opportunity for receptor agonism by these endocannabinoids elicits
physiological responses that have also occurred with repeated daily noni juice
consumption. The presence of phytochemicals with FAAH and MAGL inhibito-
ry potential lends further credence to the hypothesis that noni juice promotes
health and wellbeing by interacting with the body’s ECS. However, further
in vi-
B. J. West et al.
10.4236/jbm.2019.77003 30
Journal of Biosciences and Medicines
research should be conducted to confirm this.
Conflicts of Interest
The authors declare no conflicts of interest regarding the publication of this paper.
[1] Pacher, P., Bátkai, S. and Kunos G. (2006) The Endocannabinoid System as an
Emerging Target of Pharmacotherapy.
Pharmacological Reviews
, 58, 389-462.
[2] Bab, I. and Zimmer, A. (2008) Cannabinoid Receptors and the Regulation of Bone
British Journal of Pharmacology
, 153, 182-188.
[3] Borowska, M., Czarnywojtek, A., Sawicka-Gutaj, N., Woliński, K., Płazińska, M.T.,
Mikołajczak, P. and Ruchała, M. (2018) The Effects of Cannabinoids on the Endo-
crine System.
, 69, 705-719.
[4] Eid, B.G. (2019) Cannabinoids for Treating Cardiovascular Disorders: Putting To-
gether a Complex Puzzle.
Journal of Microscopy and Ultrastructure
, 6, 171-176.
[5] Lu, H.C. and Mackie, K. (2016) An Introduction to the Endogenous Cannabinoid
Biological Psychiatry
, 79, 516-525.
[6] Howlett, A.C. and Abood, M.E. (2017) CB1 and CB2 Receptor Pharmacology.
vances in Pharmacology
, 80, 169-206.
[7] West, B.J., Jensen, C.J., Westendorf, J. and White, L.D. (2006) A Safety Review of
Noni Fruit Juice.
Journal of Food Science
, 71, R100-R106.
[8] Morton, J. (1992) The Ocean-Going Noni, or Indian Mulberry (
Morinda citrifolia
Rubiaceae) and Some of Its “Colorful” Relatives.
Economic Botany
, 46, 241-256.
[9] Whistler, W.A. (1992) Polynesian Herbal Medicine. National Tropical Botanical
Garden, Hong Kong.
[10] Petard, P. (1986) Quelques Plantes Utiles de Polynesie Francaise et Raau Tahiti.
Editions Haere Po No Tahiti, Papeete.
[11] Brown, F.B.H. (1935) Flora of Southeastern Polynesia. III. Dicotyledons. Bishop
Museum, Honolulu, HI.
[12] Girardi, C., Butaud, J.F., Ollier, C., Ingert, N., Weniger, B., Raharivelomanana, P.
and Moretti, C. (2015) Herbal Medicine in the Marquesas Islands.
Journal of Eth-
, 161, 200-213.
[13] West, B.J., Deng, S., Isami, F., Uwaya, A. and Jensen, C.J. (2018) The Potential
Health Benefits of Noni Juice: A Review of Human Intervention Studies.
, 7,
[14] Palu, A.K., Kim, A.H., West, B.J., Deng, S., Jensen, J. and White, L. (2008) The Ef-
fects of
Morinda citrifolia
L. (Noni) on the Immune System: Its Molecular Mechan-
isms of Action.
Journal of Ethnopharmacology
, 115, 502-506.
[15] European Commission (2003) Commission Decision of 5 June 2003 Authorising the
B. J. West et al.
10.4236/jbm.2019.77003 31
Journal of Biosciences and Medicines
Placing on the Market of “Noni Juice “(Juice of the Fruit of
Morinda citrifolia
L.) as
a Novel Food Ingredient under Regulation (EC) No 258/97 of the European Parlia-
ment and of the Council.
Official Journal of the European Union L
, 144, 12.
[16] European Commission (2003) Commission Decision of 21 April 2010 Authorising
the Placing on the Market of Puree and Concentrate of the Fruits of
Morinda citri-
as a Novel Food Ingredient under Regulation (EC) No 258/97 of the European
Parliament and of the Council.
Official Journal of the European Union L
, 102,
[17] Deng, S., West, B.J., Palu, A.K. and Jensen, C.J. (2011) Determination and Compar-
ative Analysis of Major Iridoids in Different Parts and Cultivation Sources of
rinda citrifolia
Phytochemical Analysis
, 22, 26-30.
[18] Deng, S., West, B.J. and Jensen, C.J. (2010) A Quantitative Comparison of Phyto-
chemical Components in Global Noni Fruits and Their Commercial Products.
, 122, 267-270.
[19] Yang, J., Paulino, R., Janke-Stedronsky, S. and Abawi, F. (2007) Free Radical Sca-
venging Activity and Total Phenols of Noni (
Morinda citrifolia
L.) Juice and Powd-
er in Processing and Storage.
Food Chemistry
102, 302-308.
[20] El-Alfy, A.T., Joseph, S., Brahmbhatt, A., Akati, S. and Abourashed, E.A. (2016) In-
direct Modulation of the Endocannabinoid System by Specific Fractions of Nutmeg
Total Extract.
Pharmaceutical Biology
, 54, 2933-2938.
[21] Wang, M.Y., Peng, L., Lutfiyya, M.N., Henley, E., Weidenbacher-Hoper, V. and
Anderson, G. (2009)
Morinda citrifolia
) Reduces Cancer Risk in Current
Smokers by Decreasing Aromatic DNA Adducts.
Nutrition and Cancer
, 61,
[22] Wang, M.Y., Peng, L., Weidenbacher-Hoper, V., Deng, S., Anderson, G. and West,
B.J. (2012) Noni Juice Improves Serum Lipid Profiles and Other Risk Markers in
Cigarette Smokers.
Scientific World Journal
, 2012, Article ID: 594657.
[23] Zygmunt, P.M., Ermund, A., Movahed, P., Andersson, D.A., Simonsen, C., Jönsson,
B.A., Blomgren, A., Birnir, B., Bevan, S., Eschalier, A., Mallet, C., Gomis, A. and
Högestätt, E.D. (2013) Monoacylglycerols Activate TRPV1A Link between Phos-
pholipase C and TRPV1.
, 8, e81618.
[24] Piomelli, D. and Sasso, O. (2014) Peripheral Gating of Pain Signals by Endogenous
Analgesic Lipids.
Nature Neuroscience
, 17, 164-174.
[25] Sharir, H. and Abood, M.E. (2010) Pharmacological Characterization of GPR55, a
Putative Cannabinoid Receptor.
Pharmacology & Therapeutics
, 126, 301-313.
[26] Cary, L.M., Slivicki, R.A., Leishman, E., Cornett, B., Mackie, K., Bradshaw, H. and
Hohmann, A.G. (2016) A Pro-Nociceptive Phenotype Unmasked in Mice Lacking
Fatty-Acid Amide Hydrolase.
Molecular Pain
, 12, 1-23.
[27] Kim, M.J., Tanioka, M., Um, S.W., Hong, S.K. and Lee, B.H. (2018) Analgesic Ef-
B. J. West et al.
10.4236/jbm.2019.77003 32
Journal of Biosciences and Medicines
fects of FAAH Inhibitor in the Insular Cortex of Nerve-Injured Rats.
, 14, 1-26.
[28] Ignatowska-Jankowska, B., Wilkerson, J.L., Mustafa, M., Abdullah, R., Niphakis, M.,
Wiley, J.L., Cravatt, B.F. and Lichtman, A.H. (2015) Selective Monoacylglycerol Li-
pase Inhibitors: Antinociceptive versus Cannabimimetic Effects in Mice.
The Jour-
nal of Pharmacology and Experimental Therapeutics
, 353, 424-432.
[29] Adamson Barnes, N.S., Mitchell, V.A., Kazantzis, N.P. and Vaughan, C.W. (2016)
Actions of the Dual FAAH/MAGL Inhibitor JZL195 in a Murine Neuropathic Pain
British Journal of Pharmacology
, 173, 77-87.
[30] Basar, S., Uhlenhut, K., Högger, P., Schöne, F. and Westendorf, J. (2010) Analgesic
and Anti-Inflammatory Activity of
Morinda citrifolia
L. (Noni) Fruit.
, 24, 38-42.
[31] Kapellos, T.S., Recio, C., Greaves, D.R. and Iqbal, A.J. (2017) Cannabinoid Receptor
2 Modulates Neutrophil Recruitment in a Murine Model of Endotoxemia.
tors of Inflammation
, 2017, Article ID: 4315412.
[32] Bian, Q., Wang, Y.J., Liu, S.F. and Li, Y.P. (2012) Osteoarthritis: Genetic Factors,
Animal Models, Mechanisms, and Therapies.
Frontiers in Bioscience
, E4, 74-100.
[33] Karadimas, S.K., Klironomos, G., Papachristou, D.J., Papanikolaou, S., Papadaki, E.
and Gatzounis, G. (2013) Immunohistochemical Profile of NF-κB/p50, NF-κB/p65,
MMP-9, MMP-2, and u-PA in Experimental Cervical Spondylotic Myelopathy.
, 38, 4-10.
[34] Akinbo, S.R.A., Noronha, C.C., Okanlawon, A.O. and Denesi, M.A. (2006) Com-
parative Study of the Effect of
Morinda citrifolia
(Noni) with Selected Physiothera-
py Modalities in the Management of Patients with Cervical Spondylosis.
Journal of Health and Biomedical Sciences
, 5, 6-11.
[35] Wang, M.Y., Lutfiyya, M.N., Weidenbacher-Hoper, V., Peng, L., Lipsky, M.S. and
Anderson, G. (2011)
Morinda citrifolia
L. (Noni) Improves the Quality of Life in
Adults with Osteoarthritis.
Functional Foods in Health & Disease
, 1, 75-90.
[36] La Porta, C., Bura, S.A., Negrete, R. and Maldonado, R. (2014) Involvement of the
Endocannabinoid System in Osteoarthritis Pain.
European Journal of Neuroscience
39, 485-500.
[37] Morena, M., Patel, S., Bains, J.S. and Hill, M.N. (2016) Neurobiological Interactions
Between Stress and the Endocannabinoid System.
, 41,
[38] Langford, J., Doughty, A., Wang, M., Clayton, L. and Babich, M. (2004) Effects of
Morinda citrifolia
on Quality of Life and Auditory Function in Postmenopausal
Journal of Alternative and Complementary Medicine
, 10, 737-739.
[39] Bayo, N.O., Eyarefe, O.D. and Arowolo, R.O.A. (2010) Effects of Tahitian Noni
Juice on Ketamine Anaesthesia in Some Local Rabbits.
British Journal of Pharma-
cology and Toxicology
, 1, 81-84.
[40] Muto, J., Hosung, L., Uwaya, A., Isami, F., Ohno, M. and Mikami, T. (2010)
rinda citrifolia
Fruit Reduces Stress-Induced Impairment of Cognitive Function
Accompanied by Vasculature Improvement in Mice.
Physiology and Behavior
, 101,
B. J. West et al.
10.4236/jbm.2019.77003 33
Journal of Biosciences and Medicines
[41] Hill, M.N., Kumar, S.A., Filipski, S.B., Iverson, M., Stuhr, K.L., Keith, J.M., Cravatt,
B.F., Hillard, C.J., Chattarji, S. and McEwen, B.S. (2013) Disruption of Fatty Acid
Amide Hydrolase Activity Prevents the Effects of Chronic Stress on Anxiety and
Amygdalar Microstructure.
Molecular Psychiatry
, 18, 1125-1135.
[42] Kishimoto, Y., Cagniard, B., Yamazaki, M., Nakayama, J., Sakimura, K., Kirino, Y.
and Kano, M. (2015) Task-Specific Enhancement of Hippocampus-Dependent
Learning in Mice Deficient in Monoacylglycerol Lipase, the Major Hydrolyzing En-
zyme of the Endocannabinoid 2-Arachidonoylglycerol.
Frontiers in Behavioral
, 9, 134.
[43] Thors, L., Belghiti, M. and Fowler, C.J. (2008) Inhibition of Fatty Acid Amide Hy-
drolase by Kaempferol and Related Naturally Occurring Flavonoids.
British Journal
of Pharmacology
, 155, 244-252.
[44] Deng, S., Palu, A.K., West, B.J., Su, C.X., Zhou, B.N. and Jensen, J.C. (2007) Lipox-
ygenase Inhibitory Constituents of the Fruits of Noni (
Morinda citrifolia
) Collected
in Tahiti.
Journal of Natural Products
, 70, 859-862.
[45] Urquhart, P., Nicolaou, A. and Woodward, D.F. (2015) Endocannabinoids and
Their Oxygenation by Cyclo-Oxygenases, Lipoxygenases and Other Oxygenases.
Biochimica et Biophysica Acta
, 1851, 366-376.
[46] Wang, M.Y., West, B.J., Jensen, C.J., Nowicki, D., Su, C., Palu, A.K. and Anderson,
G. (2002)
Morinda citrifolia
(Noni): A Literature Review and Recent Advances in
Noni Research.
Acta Pharmacologica Sinica
, 23, 1127-1141.
[47] Xu, J., McSloy, A.C., Anderson, B.K., Godbee, R.G., Peek, S.F. and Darien, B.J.
(2006) Tahitian Noni® Equine Essentials™: A Novel Anti-Inflammatory and a
COX-2 Inhibitor Which Regulates LPS-Induced Inflammatory Mediator Expression
in Equine Neonatal Monocytes.
Journal of Veterinary Internal Medicine
, 20, 756.
[48] Muralidharan, P. and Srikanth, J. (2010) Anti Epileptic Activity of
Morinda citrifo-
Linn Fruit Extract.
Journal of Chemistry
, 7, 612-616.
[49] Neubauer, D., Perković Benedik, M. and Osredkar, D. (2018) Cannabidiol for
Treatment of Refractory Childhood Epilepsies: Experience from a Single Tertiary
Epilepsy Center in Slovenia.
Epilepsy & Behavior
, 81, 79-85.
[50] Watanabe, K., Ogi, H., Nakamura, S., Kayano, Y., Matsunaga, T., Yoshimura, H.
and Yamamoto, I. (1998) Distribution and Characterization of Anandamide Ami-
dohydrolase in Mouse Brain and Liver.
, 62, 1223-1229.
[51] De Petrocellis, L., Ligresti, A., Moriello, A.S., Allarà, M., Bisogno, T., Petrosino, S.,
Stott, C.G. and Di Marzo, V. (2011) Effects of Cannabinoids and Cannabino-
Extracts on TRP Channels and Endocannabinoid Metabolic
British Journal of Pharmacology
, 163, 1479-1494.
[52] Pawlus, A.D. and Kinghorn, D.A. (2007) Review of the Ethnobotany, Chemistry,
Biological Activity and Safety of the Botanical Dietary Supplement
Morinda citrifo-
The Journal of Pharmacy and Pharmacology
, 59, 1587-1609.
B. J. West et al.
10.4236/jbm.2019.77003 34
Journal of Biosciences and Medicines
[53] Beladjila, K.A., Berrehal, D., De Tommasi, N., Granchi, C., Bononi, G., Braca, A.
and De Leo, M. (2018) New Phenylethanoid Glycosides from
Cistanche phelypaea
and Their Activity as Inhibitors of Monoacylglycerol Lipase (MAGL).
Planta Medi-
, 84, 710-715.
... Therefore, the inhibition of the activity of these enzymes by ascorbic acid and rutin may become the subject of research not only in terms of the protection of skin cells but also in the assessment of therapeutic factors in relation to developing diseases of this organ. So far, plant extracts containing polyphenols, including rutin, have been described as preparations that strongly reduce the activity of FAAH and MAGL [55,56], which has not been previously shown for ascorbic acid. ...
Full-text available
Natural antioxidants effectively counteract changes caused by UV radiation in human skin cells. However, their action is limited due to their lipo/hydrophilicity. Therefore, the aim of this study was to analyze the mutual protective action of hydrophilic ascorbic acid and partially lipophilic rutin against UVA/UVB-induced changes in membranes phospholipid and endocannabinoid system in keratinocytes and fibroblasts. Obtained results clearly showed that, despite the stronger antioxidant properties of ascorbic acid, the lipid membranes were more effectively protected against UV-induced oxidation by rutin, including changes in phospholipid fatty acid levels, prevention against reactive aldehydes formation and endocannabinoids degradation. Ascorbic acid more strongly prevented UV-induced endocannabinoid receptors expression in fibroblasts, especially CB1. However, the combined action of used antioxidants resulted in the greatest cytoprotective effect, which was evident in the inflammatory marker TNFα down-regulation and increased cell viability following cell irradiation. The applied mixture of antioxidants showed a stronger protective in relation to membrane phospholipids in keratinocytes and in the endocannabinoid system in fibroblasts. In conclusion, it can be suggested that combined antioxidant capacities of ascorbic acid and rutin protects against lipid peroxidation but also decreases the UV-induced inflammation by direct interaction with the endocannabinoid system, thus increasing skin cell viability.
... We previously reported that noni juice exhibits CB2 receptor agonist activity, indicating that some phytochemical constituents of noni fruit may exert an influence on the ECS via CB2 receptor binding [14]. We also discovered that processed noni fruit juice inhibits FAAH and MAGL in vitro [15]. Therefore, we sought to further investigate the interactions of various phytochemical constituents of noni fruit with FAAH and MAGL. ...
... Morinda citrifolia is described as a small or medium sized tree that usually grows in tropical lands. It is commonly known as Noni or Indian mulberry which has been used as both food and medicine 1 . Extract of M. citrifolia has been used for generations in traditional therapy 2 . ...
Full-text available
Spray drying is a widely spread technique for drying of liquid products especially fruit juices such as noni juice. However, during the spray drying of noni juice stickiness problem commonly occurs due to low molecular weight sugars (sucrose, glucose and fructose). The aim of the present research was to determine the impact of Teflon surface modification on the yield of spray-dried Nonijuice and deposition flux. The different exposure time of feed spray was undertaken prior to adhesion flux weight determination. Three different sets of inlet temperature (100 °C, 150 °C and 190 °C) and exposure times (of 15 min, 30 min, 60 min, 75 min, 90 min and 115 min) were tested. Samples were evaluated for contact angle, the weight of adhesion flux, hygroscopicity and moisture content. There was a sudden increase in deposition flux (p<0.05) as the temperature increased. At 150 and 190°C, the weight of deposition flux was not significant (p>0.05) for both plate materials. The borosilicate plates (BP) registered up to 80% deposit removal whilst the Teflon plate (TP) recorded only 20%. Physical observation of the Teflon plates showed that some areas of the plate (100 °C) were fully clear from any particles. Nevertheless, for the borosilicate glass plates, the primary adhered particles tend to retain and smeared along with the plates. In addition, there was a substantial negative relationship between the contact angle and adhesion weight, (r =-0,924, p<0.01). The negative connection suggests that by increasing the contact angle, the adhesion weight will decrease and vice versa. The contact angle of the Teflon (PTFE) surface was approximately 117.2 ± 1.4°, which provided an excellent hydrophobic surface. In this research, the powder with the lowest amount of hygroscopicity was gained at 190 °C using the Teflon plate. For that reason, surface modification was indeed amplified the surface hydrophobicity thus decreasing the deposition flux.
Full-text available
Background: Morinda citrifolia Linn (noni), as a “pain killer”, has been used as a traditional medicine by Polynesians for over 2000 years. It was reported to have a broad range of therapeutic effects including analgesic and anti-inflammation. The in-vitro and in vivoanti-inflammatory and analgesic properties of noni juice (NJ) suggest that NJ may be a useful adjunctive treatment for osteoarthritis (OA). In this pilot study we explored whether NJ improves the symptoms and Quality of Life (QoL) for adults with OA. We also sought to evaluate the tolerability and safety of NJ for patients with OA in a primary care setting. Methods: This was an open label three-month intervention pilot study. Data were collected by pre/post intervention survey and laboratory testing. Inclusion criteria were: adults of both sexes aged 40 to 75, with a diagnosis of OA on the hip or knee by x-ray examination provided by their primary care physician, not on prescription medicine for OA, and who were willing to drink 3 oz of NJ a day for 90 days. Results: Of the 64 questions measuring different aspects of QoL asked on the pre/post survey, 49 (77%) had significant pre/post mean scale differences as measured by independent t-test. The OA patients reported being significantly more satisfied with their current health conditions including mobility, walking and bending, hand, finger, and arm functions, household tasks, social activity, arthritis pain, work ability, level of tension, and mood. The study participants were also more positive about their future health and reported taking less over-the-counter (OTC) pain relievers. Pre/post laboratory testing including: lipid panel, liver and kidney functions were in the normal ranges. High Sensitive C Reactive Protein (hsCRP), an inflammatory biomarker, was reduced by 10% after the intervention. Conclusion: As a nutritional supplement, NJ demonstrated a potential therapeutic effect and improved the symptoms and the QoL for adults with OA. A larger, double blinded, and placebo controlled clinical trial study is needed to confirm these benefits. NJ has the potential to become an adjunctive therapy for OA patients. Clinical trial registration number: NCT01070264.Key words: Morinda citrifolia (noni), Noni juice (NJ), Osteoarthritis, Quality of life (QoL), pain scales
Full-text available
Noni juice is a globally popular health beverage originating in the tropics. Traditional Tahitian healers believe the noni plant to be useful for a wide range of maladies, and noni juice consumers throughout the world have similar perceptions. Nevertheless, human clinical trials are necessary for a precise understanding of what the health benefits of noni juice are. A review of published human intervention studies suggests that noni juice may provide protection against tobacco smoke-induced DNA damage, blood lipid and homocysteine elevation as well as systemic inflammation. Human intervention studies also indicate that noni juice may improve joint health, increase physical endurance, increase immune activity, inhibit glycation of proteins, aid weight management, help maintain bone health in women, help maintain normal blood pressure, and improve gum health. Further, these studies point to notable antioxidant activity in noni juice, more so than other fruit juices which served as trial placebos. It is this antioxidant effect and its interaction with the immune system and inflammation pathways that may account for many of the observed health benefits of noni juice. However, the existing evidence does have some limitations as far as its general application to noni juice products; all the peer-reviewed human interventions studies to date have involved only one source of French Polynesian noni juice. Geographical factors and variations in processing methods are known to produce commercial noni juice products with divergent phytochemical and nutrient compositions. Therefore, other sources of noni products may have different toxicological and pharmacological profiles.
Full-text available
The endocannabinoid system consists of endogenous lipid mediators and cannabinoid receptors (CB) 1 and 2. It has previously been demonstrated that activation of the leukocyte-expressed CB 2 has anti-inflammatory effects in vivo . Here, we report its role under baseline conditions and in a model of low-dose endotoxemia by comparing CB 2 knockout to littermate control mice. CB 2 -deficient mice displayed significantly more neutrophils and fewer monocytes in the bone marrow under steady state. In initial validation experiments, administration of 1 mg/kg LPS to male C57BL/6J mice was shown to transiently upregulate systemic proinflammatory mediators (peaked at 2 hours) and mobilise bone marrow neutrophils and monocytes into circulation. In CB 2 knockout mice, the level of the metalloproteinase MMP-9 was significantly elevated by 2 hours and we also observed augmented recruitment of neutrophils to the spleen in addition to increased levels of Ccl2 , Ccl3 , Cxcl10 , and Il6 . Collectively, our data show that the absence of CB 2 receptor increases the levels of innate immune cell populations in the bone marrow under steady state. Furthermore, during an acute systemic inflammatory insult, we observe a highly reproducible and site-specific increase in neutrophil recruitment and proinflammatory chemokine expression in the spleen of CB 2 knockout mice.
Full-text available
Context: Nutmeg [Myristica fragrans Houtt. (Myristicaceae)] has a long-standing reputation of psychoactivity. Anecdotal reports of nutmeg use as a cheap marijuana substitute, coupled to previous studies reporting a cannabimimetic-like action, suggest that nutmeg may interact with the endocannabinoid system. Objective: The study evaluates nutmeg fractions for binding capacity with various CNS receptors and their potential interaction with the endocannabinoid system. Materials and methods: Dichloromethane (DF) and ethyl acetate (EF) fractions were prepared from the methanol extract of powdered whole nutmeg. The HPLC-profiled fractions were assayed by the NIMH Psychoactive Drug Screening Program (PDSP) in a panel of CNS targets at a 10 μg/mL concentration. The fractions were also screened for fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) inhibition, initially at a concentration of 500 μg/mL, then by concentration-dependent inhibition studies. Results: None of the tested fractions showed significant binding to CNS receptors included in the PDSP panel. However, both fractions exerted significant inhibition of the FAAH and MAGL enzymes. The DF fraction inhibited FAAH and MAGL enzymes at IC50 values of 21.06 ± 3.16 and 15.34 ± 1.61 μg/mL, respectively. Similarly, the EF fraction demonstrated FAAH and MAGL inhibition with IC50 values of 15.42 ± 3.09 and 11.37 ± 6.15 μg/mL, respectively. Discussion and conclusion: The study provides the first piece of evidence that nutmeg interacts with the endocannabinoid system via inhibition of the endocannabinoid catabolizing enzymes. This mechanism provides insight into reported cannabis-like action as well as expands the potential therapeutic utility of nutmeg.
Full-text available
Fatty-acid amide hydrolase (FAAH) is the major enzyme responsible for degradation of anandamide, an endocannabinoid. Pharmacological inhibition or genetic deletion of FAAH (FAAH KO) produces antinociception in preclinical pain models that is largely attributed to anandamide-induced activation of cannabinoid receptors. However, FAAH metabolizes a wide range of structurally related, biologically active lipid signaling molecules whose functions remain largely unknown. Some of these endogenous lipids, including anandamide itself, may exert pro-nociceptive effects under certain conditions. In our study, FAAH KO mice exhibited a characteristic analgesic phenotype in the tail flick test and in both formalin and carrageenan models of inflammatory nociception. Nonetheless, intradermal injection of the transient receptor potential channel V1 (TRPV1) agonist capsaicin increased nocifensive behavior as well as mechanical and heat hypersensitivity in FAAH KO relative to wild-type mice. This pro-nociceptive phenotype was accompanied by increases in capsaicin-evoked Fos-like immunoreactive (FLI) cells in spinal dorsal horn regions implicated in nociceptive processing and was attenuated by CB1 (AM251) and TRPV1 (AMG9810) antagonists. When central sensitization was established, FAAH KO mice displayed elevated levels of anandamide, other fatty-acid amides, and endogenous TRPV1 agonists in both paw skin and lumbar spinal cord relative to wild-type mice. Capsaicin decreased spinal cord 2-AG levels and increased arachidonic acid and prostaglandin E2 levels in both spinal cord and paw skin irrespective of genotype. Our studies identify a previously unrecognized pro-nociceptive phenotype in FAAH KO mice that was unmasked by capsaicin challenge. The heightened nociceptive response was mediated by CB1 and TRPV1 receptors and accompanied by enhanced spinal neuronal activation. Moreover, genetic deletion of FAAH has a profound impact on the peripheral and central lipidome. Thus, genetic deletion of FAAH may predispose animals to increased sensitivity to certain types of pain. More work is necessary to determine whether such changes could explain the lack of efficacy of FAAH inhibitors in clinical trials.
Cannabinoids are the derivatives of the cannabis plant, the most potent bioactive component of which is tetrahydrocannabinol (THC). The most commonly used drugs containing cannabinoids are marijuana, hashish, and hashish oil. These compounds exert their effects via interaction with the cannabinoid receptors CB1 and CB2. Type 1 receptors (CB1) are localised mostly in the central nervous system and in the adipose tissue and many visceral organs, including most endocrine organs. Type 2 cannabinoid receptors (CB2) are positioned in the peripheral nervous system (peripheral nerve endings) and on the surface of the immune system cells. Recently, more and more attention has been paid to the role that endogenous ligands play for these receptors, as well as to the role of the receptors themselves. So far, endogenous cannabinoids have been confirmed to participate in the regulation of food intake and energy homeostasis of the body, and have a significant impact on the endocrine system, including the activity of the pituitary gland, adrenal cortex, thyroid gland, pancreas, and gonads. Interrelations between the endocannabinoid system and the activity of the endocrine system may be a therapeutic target for a number of drugs that have been proved effective in the treatment of infertility, obesity, diabetes, and even prevention of diseases associated with the cardiovascular system. � 2018 Endokrynologia Polska. All rights reserved.
Cannabinoids have been increasingly gaining attention for their therapeutic potential in treating various cardiovascular disorders. These disorders include myocardial infarction, hypertension, atherosclerosis, arrhythmias, and metabolic disorders. The aim of this review is to cover the main actions of cannabinoids on the cardiovascular system by examining the most recent advances in this field and major literature reviews. It is well recognized that the actions of cannabinoids are mediated by either cannabinoid 1 or cannabinoid 2 receptors (CB2Rs). Endocannabinoids produce a triphasic response on blood pressure, while synthetic cannabinoids show a tissue-specific and species-specific response. Blocking cannabinoid 1 receptors have been shown to be effective against cardiometabolic disorders, although this should be done peripherally. Blocking CB2Rs may be a useful way to treat atherosclerosis by affecting immune cells. The activation of CB2Rs was reported to be useful in animal studies of myocardial infarction and cardiac arrhythmia. Although cannabinoids show promising effects in animal models, this does not always translate into human studies, and therefore, extensive clinical studies are needed to truly establish their utility in treating cardiovascular disease.
Purpose: Refractory epilepsies in children present a major burden for patients and their families. Cannabidiol (CBD) has been suggested as a potential treatment for refractory epilepsies. The aim of this study was to evaluate the effectiveness of add-on therapy with CBD for the treatment of refractory childhood epilepsies. Method: Patients with childhood-onset refractory epilepsy, treated at the tertiary epilepsy center of the University Children's Hospital Ljubljana, Slovenia, were included in the study. Add-on therapy with CBD was initiated once the child's epilepsy was categorized as pharmacoresistant to other antiepileptic drugs/therapies. The dosage of CBD was gradually increased to at least 8mg/kg/day. The effect of CBD treatment was evaluated by the reduction in seizure burden and presence of side effects (positive and negative). Serial electroencephalography was performed in some children. Results: Sixty-six patients were included in the analysis. Thirty-two (48.5%) patients had a more than 50% improvement regarding seizure burden, 14 of whom (21.2%) became seizure-free. None of the patients reported worsening of seizure frequency, but CBD had no effect in 15 (22.7%) patients. Some patients reported less vigorous seizures, shorter duration of seizures, shorter time to recovery, and other positive side effects of CBD treatment. Adverse effects were reported in 5/66 children. Conclusions: In our cohort of patients, CBD was found to have potential benefits as add-on therapy for refractory childhood epilepsies, mainly by reducing seizure burden.
Four new phenylethanoid glycosides (1–4), 1-β-p-hydroxyphenyl-ethyl-2-O-acetyl-3,6-di-α-l-rhamnopyranosyl-β-d-glucopyranoside (1), 1-β-p-hydroxyphenyl-ethyl-3,6-O-di-α-l-rhamnopyranosyl-β-d-glucopyranoside (2), 1-β-p-hydroxyphenyl-ethyl-2-O-acetyl-3,6-di-α-l-rhamnopyranosyl-4-p-coumaroyl-β-d-glucopyranoside (3), and 1-β-p-hydroxyphenyl-ethyl-3,6-di-α-l-rhamnopyranosyl-4-p-coumaroyl-β-d-glucopyranoside (4), together with three known compounds, were isolated from the n-butanol extract of Cistanche phelypaea aerial parts. The structural characterization of all compounds was performed by spectroscopic analyses, including 1D and 2D NMR, and HRESIMS experiments. The isolated compounds were assayed for their inhibitory activity on two enzymes involved in the peculiar glycolytic or lipidic metabolism of cancer cells, human lactate dehydrogenase (LDH), and monoacylglycerol lipase (MAGL), respectively. All the compounds showed negligible activity on LDH, whereas some of them displayed a certain inhibition activity on MAGL. In particular, compound 1 was the most active on MAGL, showing an IC50 value of 88.0 µM, and modeling studies rationalized the supposed binding mode of 1 in the MAGL active site.
The CB1 and CB2 cannabinoid receptors (CB1R, CB2R) are members of the G protein-coupled receptor (GPCR) family that were identified over 20 years ago. CB1Rs and CB2Rs mediate the effects of Δ⁹-tetrahydrocannabinol (Δ⁹-THC), the principal psychoactive constituent of marijuana, and subsequently identified endogenous cannabinoids (endocannabinoids) anandamide and 2-arachidonoyl glycerol. CB1Rs and CB2Rs have both similarities and differences in their pharmacology. Both receptors recognize multiple classes of agonist and antagonist compounds and produce an array of distinct downstream effects. Natural polymorphisms and alternative splice variants may also contribute to their pharmacological diversity. As our knowledge of the distinct differences grows, we may be able to target select receptor conformations and their corresponding pharmacological responses. This chapter will discuss their pharmacological characterization, distribution, phylogeny, and signaling pathways. In addition, the effects of extended agonist exposure and how that affects signaling and expression patterns of the receptors are considered.