Archives of Medical Research 50 (2019) 518e526

REVIEW ARTICLE
Endocannabinoids as Therapeutic Targets
Oscar Prospero-Garcıa,a Alejandra E. Ruiz Contreras,b Alette Ortega G
omez,c Andrea Herrera-Solıs,d
Monica Mendez-Dıaz,a and Grupo de Neurociencias de la Universidad Nacional Autonoma de Mexico
a
Departamento de Fisiologıa, Laboratorio de Canabinoides, Facultad de Medicina, Universidad Nacional Autonoma de Mexico, Ciudad de Mexico, Mexico
b
Laboratorio de Neurogenomica Cognitiva, Facultad de Psicologıa, Universidad Nacional Autonoma de Mexico, Ciudad de Mexico, Mexico
c
Laboratorio de Medicina Traslacional, Instituto Nacional de Cancerologıa, Ciudad de Mexico, Mexico
d
Laboratorio Efectos Terapeuticos de los Canabinoides, Subdireccion de Investigacion Biomedica, Hospital General Dr. Manuel Gea Gonzalez, Ciudad de
Mexico, Mexico
Received for publication April 30, 2019; accepted September 30, 2019 (ARCMED_2019_385).

Most of the drugs of abuse affect the brain by interacting with naturally expressed mo-
lecular receptors. Marihuana affects a series of receptors including cannabinoid receptor
1 (CB1R) and CB2R, among others. Endogenous molecules with cannabinoid activity
interact with these receptors naturally. Receptors, ligands, synthesizing and degrading en-
zymes, as well as transporters, have been described. This endocannabinoid system mod-
ulates behaviors and physiological processes, i.e. food intake, the sleep-waking cycle,
learning and memory, motivation, and pain perception, among others. The rather broad
distribution of endocannabinoids in the brain explains the different effects marihuana in-
duces in its users. However, this very same anatomical and physiological distribution
makes this system a useful target for therapeutic endeavors. In this review, we briefly
discuss the potential of small molecules that target the endocannabinoids as therapeutic
tools to improve behaviors and treat illnesses. We believe that under medical supervision,
endocannabinoid targets offer new advantages for patients for controlling multiple med-
ical disorders. Ó 2019 IMSS. Published by Elsevier Inc.
Key Words: Cannabinoids, Endocannabinoids, Therapeutic properties, Sleep, Epilepsy, Pain,
Learning and memory.

Marihuana affects the brain by interacting with a series of
naturally expressed receptors including cannabinoid recep-
tor 1 (CB1R) and CB2R. Endogenous molecules with
cannabinoid activity interact with these receptors naturally.
Similarly, receptors, ligands, synthesizing and degrading
enzymes, as well as transporters, have been described. This
endocannabinoid (eCB) system modulates behaviors and
physiological processes, that is food intake, the sleep-
waking cycle, learning and memory, motivation, and pain
perception, among others. The rather broad distribution of
endocannabinoids in the brain explains the different effects
marihuana induces in its users. This anatomical distribution
and physiological effects make this system a useful target
for therapeutic endeavors. In this review, we briefly discuss
Address reprint requests to: Oscar Prospero-Garcıa, Departamento de
Fisiologıa, Facultad de Medicina, Universidad Nacional Autonoma de
Mexico, Apdo. Postal 70-250, Ciudad de Mexico, 04510 Mexico; Phone:
(þ52) 55 255 623 2509; FAX: (þ52) 55 2585 5623 2241.; E-mail: opg@
unam.mx
how some molecules that target the eCB system under med-
ical supervision are potential therapeutic tools to improve
behaviors and treat illnesses.
Since the isolation and structural description of D9-
tetrahydrocannabinol (THC), the main psychoactive
component of marihuana (Cannabis sativa) in 1964 (1),
knowledge on how marihuana causes its effects in the user
has expanded exponentially. Howlett’s suggestion of the ex-
istence of a receptor to which THC binds (2), ignited the
search for endogenous molecules. In 1992, Mechoulam’s
group isolated anandamide (AEA) from pig brain (3). In
1994, oleamide (ODA), another endocannabinoid was iso-
lated from the cerebrospinal fluid of sleep-deprived cats
(4). In the same year, Mechoulam’s group isolated 2 arach-
ydonoylglycerol (2-AG) from dog intestine (5) (Table 1).
Few years after CB1R was cloned (6), CB2R were charac-
terized (6,7). Enzymes that participate in the synthesis and
breakdown of endocannabinoids have also been identified,
and the existence of an endocannabinoid transporter has
been suggested (8). All this information has led to

0188-4409/$ - see front matter. Copyright Ó 2019 IMSS. Published by Elsevier Inc.
https://doi.org/10.1016/j.arcmed.2019.09.005
 Cannabinoids and Medicine 519

Table 1. Endogenous cannabinoids (endocannabinoids) and related compounds

Endocannabinoids and related compounds Common name Functional properties at cannabinoid receptors

N-arachidonylethanolamine Anandamide Partial CB1R agonist, Weak CB2R agonist. Sleep and food intake inducer
2-arachidonoyl-glycerol 2-AG Full CB1R and CB2R agonist. Sleep and food intake inducer
Cis-9,10 octadecenamide Oleamide Weak CB1R, CB2R agonist. Sleep and food intake inducer
N-palmitoyl ethanolamine PEA PPAR-a agonist It inhibits the expression of FAAH
N-oleoyl ethanolamine OEA TRPV1 agonist PPARa agonist. Waking and anorexia inducer
2-Arachidonoylglyceryl ether Noladin ether CB1R agonist
O-arachidonoylethanolamine Virodhamine Partial CB2R agonist and CB1R antagonist
N-Arachidonoyl-Dopamine NADA CB1R agonist and potent TRPV1 agonist

expectations of cannabinoid-based therapies for treatment
of several illnesses and drug-dependence (Table 2).
In the following section, we discuss some evidence sup-
porting the potential use of the facilitation or blockade of
endocannabinoids to improve behaviors and illnesses.
Therapeutic Properties
Ritual use of marihuana have been suggested by remains of
seeds and leaves found in China next to a human skeleton
which was estimated to be 10 thousand years old (9). It
has been speculated that marihuana has been used to cure
or control several diseases such as inflammation and pain,
anxiety, depression and psychosis, fatigue and insomnia,
loss of appetite and digestive disorders, such as: nausea,
diarrhea, and constipation, among others (10). Both mari-
huana and THC have been used to lower elevated intraoc-
ular pressure (glaucoma) (11). Similarly, the manipulation
of endogenous cannabinoids may be useful for the control
of drug addiction (12). THC has been useful in asthma
and as an analgesic (13). Many of these alleged effects
are still under investigation. Comparably, Cannabidiol
(CBD) seems to have properties to control epilepsy (14),
and in combination with THC to control pain (15).
Marihuana is classified as a schedule I substance by the
U.S. Drug Enforcement Administration (DEA), indicating
that marihuana is a drug with high potential for abuse.
However, THC and a synthetic analog of THC (Dronabinol)
have been approved by the Food and Drug Administration
(FDA) for patients suffering from serious, chronic, or debil-
itating medical conditions. THC itself or THC analogs, as
Dronabinol, are approved for treatment of the severe nausea
and vomiting associated with cancer chemotherapy (16);
weight loss associated with debilitating illnesses, such as
HIV infection or cancer (17); spasticity associated with
neurological diseases, such as multiple sclerosis and dis-
eases accompanied by intense pain and glaucoma (18).
Otherwise, any physician prescribing marihuana for dis-
eases different from the above mentioned is committing a
crime in the USA and in other countries. In Mexico, the
law is so permissive that those physicians that are prescrib-
ing raw marijuana extracts to treat patients do not have to
face legal charges. In the vast majority of countries, it is
definitely illegal to even suggest marihuana use. On the
other hand, the information indicating that California,
USA, has an estimated 100,000 users of medical marihuana
is absolutely fascinating. Some of them claim to use mari-
huana for medical conditions, but they may be faking the
disease to obtain marihuana for recreational purposes.

Table 2. Synthetic cannabinoids

Compound Characteristics

CP-55940 CB1R agonist. Highly psychoactive. 40 times more potent than THC
HU-210 CB1R full agonist. 100 times more potent than THC
WIN55,212-2 CB1R agonist
JWH-133 CB2R agonist
URB597 (KDS-4103) FAAH selective inhibitor
AM251 CB1R antagonist. Potential anti-hypersomnia aid
AM404 Endogenous cannabinoid reuptake inhibitor, Vanilloid receptor agonist.
SR144528 CB2R antagonist

Therapeutic Compound Use

Dronabinol (Marinol)
Nabilone (Cesament)
Rimonabant (SR141716A, Complain,
Riobant, Slimona)
Sativex
THC analog. Prescribed as an appetite stimulant for patients with AIDS, chemotherapy and gastric bypass patients.
Antiemetic. Potential sleep inducer and pain killer
THC analog. Antiemetic and analgesic. Potential sleep inducer and pain killer
CB1R Inverse agonist. Anorectic anti-obesity. Prescribed for patients with body mass index greater than 30 kg/m2
or 27 kg/m2 associated to risk factor. Potential anti-hypersomnia aid
THC and CBD analog, used for neuropathic pain of multiple sclerosis
520 Prospero-Garcıa et al./ Archives of Medical Research 50 (2019) 518e526

Addiction and pathology associated with marijuana abuse but of the commercial availability of rimonabant. The main
psychiatric symptoms rimonabant induced, according to the
Some studies indicate that increasing endocannabinoids by
Food and Drug Administration report (2007), were anxiety
inhibiting their breakdown enzymes prevent alcohol, nico-
(more than 3% with 5 mg and more than 6% with 20 mg),
tine or even heroin reinstatement (19e21). In contrast, some
insomnia (almost 3% with 5 mg and more than 5% with
other studies relate endocannabinoids and motivation and
20 mg), depressed mood (almost 3% with 5 mg, almost
drug dependence (12,22), that is it has been observed that
4% with 20 mg), depression (more than 2% with 5 mg
CB1R blockade may prevent development of drug-seeking
and more than 3% with 20 mg), and several other minor
behavior and reinstatement in rats and mice. However,
problems were also observed.
CB1R blockade in humans, may induce negative emotional
CB2R exhibits a role opposite to CB1R role. Some data
effects. Regarding CB2R, its activation inhibits cocaine
support obesity leads to increased expression of the CB2R,
self-administration (23); however, CB2R KO mice do not
in both adipose tissue and liver, in high-fat fed and ob/ob
develop nicotine-induced conditioned place preference
mice (39). While CB2R deficiency prevents body weight
(CPP) (24). These dissimilar effects seem to be parts of the
gain during the feeding of a high-fat diet and obesity-
same puzzle that are, at present time, difficult to conciliate.
associated inflammation, insulin resistance and fatty liver
Further studies will shed light to this contradiction.
(40). It should be noted that unlike CB1R the activation
Regarding the effects of marijuana chronic use, delete-
of CB2R reduces VTA DA-neurons firing, suggesting that
rious effects have been consistently reported. Therefore,
these receptors may be a therapeutic target in obesity
the Diagnostic and Statistical Manual of Mental Disorders
without affecting hedonism.
V (DSM, American Psychiatric Association, APA, 2013)
includes a description of marijuana dependence syndrome
(25). Marijuana tolerance and dependence (26) includes
anxiety, irritability, insomnia, hyporexia, restlessness, and eCB System also Regulate Food Intake
an intense desire for consuming marijuana (craving), after
ODA, AEA and 2-AG increase food intake in rats (41e43),
24e74 h of abstinence. In addition, marijuana users have
By acting on brain structures like the hypothalamus and the
several brain structural changes, that is reduction in the hip-
nucleus accumbens (44e46). Rats exhibit CPP induced by
pocampus, amygdala, nucleus accumbens and prefrontal
regular Lab Chow food, but CPP is stronger when they are
cortex, and a reduction of their connections, when they
under the effect of OLE or AEA. Such CPP is prevented by
consume it before they were 20 years of age (27e29). Simi-
CB1 inverse agonist AM251, suggesting that OLE and
larly, some studies have suggested a reduction in the Intel-
AEA increase the food palatability (47). Hence, CB1R
ligence Quotient (IQ) (30,31), while other studies revealed
seems to mediate in part the liking phase of reward. More-
that marijuana induces the first psychotic or bipolar
over, endocannabinoids increase its levels in a close rela-
outbreak in susceptible users (32). Due to these consider-
tionship with feeding (48). AEA, AA5HT (FAAH
ations, although marijuana derivatives may have some me-
inhibitor) and OMDM-1 (AEA reuptake inhibitor) increase
dicinal properties, it is advisable that their use must be
AEA and 2-AG levels in the NAc, while inducing hypotha-
subjected to strict medical supervision.
lamic nuclei activation and food intake (46). All these ef-
fects were prevented by AM251 (46). This study opens a
potential avenue to target endocannabinoid-breakdown
molecules for treatment of eating disorders.
Food Intake
Two or three marihuana joints increase average daily
caloric intake, mostly as in between-meal snacks that cause
Sleep
an increase in meal size per se. An increase in body weight
was also observed (33,34). THC increases food intake in Users report, anecdotally, that marihuana induces drowsi-
satiated rats (35); however, they consume sweet more than ness or sleepiness. Babor TF, et al. (49) observed that mod-
less palatable foods (36). Free-feeding rats receiving THC erate to heavy marihuana use induced better sleep during
increase their high-fat and high-fat sweetened food intake the days following the consumption. Regrettably, heavy
(37). Complementary, SR141716A (rimonabant, a CB1R use of marihuana may trigger anxiety crises, and psychotic
antagonist) induces anorectic effects (38). Hence, cannabi- outbreaks, complicating its use to induce sleep (50). Both
noids effects on food intake occur through the activation of ODA and AEA increase sleep, particularly REM sleep, in
the CB1R. This finding opens the possibility to use these rats. One single dose of either systemic ODA or intra lateral
kinds of drugs as pharmacological tools in the treatment hypothalamus 2-AG increases REM sleep. Intracerebroven-
of obesity, see rimonabant in obesity (RIO) study by Van tricular infusion of either ODA or 2-AG increases REM
Gaal (38). Volunteers in this study developed psychiatric sleep after one single dose or after 15 d of daily administra-
symptoms that led to the suspension, not only of the study, tion, see review (51). Moreover, both ODA and 2-AG
 Cannabinoids and Medicine
increase NREM and REM sleep in a rodent model of
insomnia (52,53). Congruently, Santucci V, et al. (54) re-
ported that SR141716A increases wakefulness. Similarly,
fatty-acid amide hydrolase (FAAH)-knockout (KO) mice
(FAAH hydrolyzes AEA and ODA) exhibit more NREM
sleep compared to their wild type (WT) littermates (55).
While CB1R-KO mice spent more time in W than their
WT littermates (56,57). In humans, the FDA meta-
analysis (2007) of the RIO Europe study (38) emphasized
that more than 5% of the volunteers receiving rimonabant
(20 mg) developed insomnia. These findings complement
those obtained in animal models, and further support the
notion that the facilitation of the eCB system may improve
sleep in insomniac patients.
Regarding Cannabidiol (CBD), it is one of the main
components of Cannabis sativa, that antagonizes the bind-
ing of CB1 and CB2 receptor agonists (58). At first, it
was reported that CBD decreased the latency to sleep onset,
while increasing duration of non-rapid-eye-movement
(NREM) sleep (59). Chagas MH, et al. 2013 (60), reported
an increase in the total amount of sleep in rats during the
light phase. Conversely, some other studies reported that
CBD increased waking and decreased REM sleep, leaving
NREM sleep unchanged (61,62). Some studies have re-
ported that CBD (600 mg) induced sedative effects in
healthy volunteers (63); while some others have shown
that low doses of CBD (15 mg/d) combined with THC
(15 mg/d) increased wakefulness while reducing NREM
sleep stage 3 (64). An absence of effects have also been re-
ported in healthy subjects with 300 mg of 99% pure CBD
(65). Unfortunately, the experimental evidence do not sup-
port CBD sleep inducer.
As an additional note, Nabilone, a synthetic CB1R agonist,
has exhibited sleep-promoting effects in patients suffering
from fibromyalgia, very possible by reducing pain (66).
Learning and Memory
The effect of marihuana and endocannabinoids on learning
and memory has been studied intensively (67e69). Hence,
it is now accepted that endocannabinoids play a crucial role
in the modulation of cognitive processes (70).
The CB1R mediates the impairing effect induced by
cannabinoids on memory. CB1R is widely expressed in
memory systems, such as in the hippocampus (71). Rats un-
der THC effects performed worse than vehicle rats in a
working memory (WM) task (72). CB1R agonists reduce
hippocampal neurons firing rate during encoding and delay
period in WM in rats (73). In contrast, CB1R knock-out
mice were able to learn the Morris water maze, albeit
increasing perseverance errors after the platform position
was changed (69), suggesting that CB1R participates in ex-
tinguishing memories and updating new information in
WM. Congruently, SR141716A prevents THC-induced
521
deficits on working and short-term memory in rats and mice
(74). Terranova JP, et al. (75) described that SR141716A fa-
cilitates memory formation (76), and delays the extinction
of fear conditioning (77).
Cannabis users have shown an impairment in memory
tasks performance (78,79). THC induces WM deficiency
while reducing the activity of the dorsolateral prefrontal
cortex, posterior parietal cortex, anterior cingulate and tem-
poral cortices (80). Moreover, a reduction of BOLD signal
at the posterior parietal cortex was detected in adults with
early onset of cannabis use when performing a working
memory task, even if subjects smoked only a few times,
as long as it was at early age (81).
Contrasting studies have failed to document memory
deficiency in cannabis users (82,83), promoting controversy
regarding cannabis effects on memory (84,85). It should be
considered that THC negative effect on memory can be
attenuated by CBD (86). Studies in rats have suggested that
cannabis effect in memory in humans could depend on
doses (87), that is THC low doses (3 mg/kg) disrupts
WM performance, whereas high doses (10 mg/kg) affects
spatial reference memory in mice (88). In rats, a
semichronic (7d) and chronic (21d) THC administration
induced hippocampal neurogenesis and upregulation of
brain-derived neurotrophic factor, while inducing a better
performance in short-term and long-term memory novel-
recognition tasks (89). Subjects genetic variation on cogni-
tive performance should be considered, too (90e92), that is
polymorphisms of the CNR1, gene which codes for CB1R,
have been associated with differential efficiency in WM
and attentional control in healthy subjects (90,91). It is
possible that some genotypes are less vulnerable to the
deleterious effect on memory when cannabis is consumed.
Endocannabinoids also participate in memory processes.
In 1998, our group reported the memory-modulating prop-
erties of AEA (93). AEA impairs memory consolidation in
rats in an inhibitory avoidance task, further supporting that
cannabinoids regulate memory acquisition or retrieve (94).
However, it is also possible that endocannabinoids modu-
late learning and memory by regulating the use of different
strategies to solve a memory task (95).
However, one eCB system important role in memory
regulation is in memory extinction. For example, CB1R
knockout mice exhibit a significant deficit in solving a
spatial task, that is the water maze (69). The principal
deficit observed in these mice is in memory extinction, that
has been interpreted as an inability to substitute old strate-
gies with newer and more adaptive ones. CB1R activation
in the amygdala promotes aversive memories extinction
(96) and prevents the development of post-traumatic stress
disorder (PTSD)-like in rats, such as enhancement of corti-
costerone levels and the startle response generated by a
single-prolonged stress (97). Furthermore, stressed mice in-
crease the endocannabinoids levels in the basolateral amyg-
dala during the extinction process, and if they are treated
522 Prospero-Garcıa et al./ Archives of Medical Research 50 (2019) 518e526
with SR141716A the aversive memory extinction is de-
layed (74). In addition, it has been shown that CBD pre-
vented the consolidation of aversive memories in a fear
conditioning task when it is given immediately after the
acquisition (98).
Another line of therapeutic target that is an open window
of research opportunity is cognitive function in ageing.
Some studies have revealed that the systemic administra-
tion of low doses of THC (3 mg/kg) during 28 d improved
learning and memory in mature (12 m) and old mice
(18 m), behaving like young vehicle animals. In these aged
animals, also, several synaptic, spine density and synaptic
formation proteins increased (99).
With all, proper doses of THC or CBD must be precisely
determined to prevent adverse effects in memory, and in
other cognitive functions, such as attention, perception, ex-
ecutive functions, and decision making (78,100).
Pain
Activation of the eCB system appears to reduce neuropathic
pain (101e103). Several studies have documented a reduc-
tion in the perception of nociceptive stimuli in animal
models (104) and pain in humans. Although results are very
consistent, some controversies have arisen since the advan-
tages of using CB1R agonists over already commercially
available drugs are dubious. Since some cannabinoids, that
is nabilone, marinol, have efficacy as pain relievers as some
data in the clinic have shown, and may target neuropathic
pain, as with opioids, the challenge remains to find pain
relieving endocannabinoid modulating molecules that do
not have abuse potential (66).
Cancer
The involvement of metabolic changes in the eCB system
associated with cancer has been documented. Regrettably,
poor prognosis through CB1R receptor up-regulation in
malignant tissues has been describe until now (105,106).
CB1R was considered a potential clinical target using direct
or inverse agonists; however, as we have abovementioned
these treatments interfere with normal cognitive function
(107). Therefore, new indirect agonists have been devel-
oped for specific actions mediated by the activity of cata-
lytic enzymes and/or allosteric positive modulation of
endocannabinoids activity (108e110).
Munson AE, et al. reported anti-proliferative actions of
phytocannabinoids in animal models, documenting THC
and CBD inhibition of tumor growth, long before the dis-
covery of cannabinoid receptors and endocannabinoids
(111). Nowadays, it is known that phytocannabinoids, en-
docannabinoids and synthetic cannabinoids exert inhibitory
effects on cancer growth and spreading, in diverse cancer
cell lines and animal models, albeit findings from pre-
clinic studies remain under debate. The inhibition of
tumoral pathways in which cannabinoids exert anti-
proliferative effects and cell death comprise: inhibition of
mitogenic proteins, sustained stimulation of ceramide and
inhibition of RAS-MAPK pathway, through pro-apoptotic
proteins such as BCL-2 (112,113). It is already known that
somatic or hereditary mutations on cancer, like KRAS or
PI3K act like active mitogenic proteins (114,115). This ge-
netic heterogeneity among tumoral tissues is associated to a
wide range of effects through cannabinoids actions. In this
context, we speculate that cannabinoids interact directly
with active mutations exerting cytotoxic effects, inhibiting
proliferation, migration or activating apoptotic mechanisms
by increasing caspase-3 and PARP activation (116).
Cannabinoids promote different cell death mechanisms
as their anti-proliferative cancer actions. AEA induces late
apoptosis/necrosis in different tumors; while synthetic ana-
logs such as Meth-Anandamide induce early apoptosis and
CP,55-940 induces necrosis (117). Hence, cannabinoids
activate selective mechanisms that induce different patterns
of cell death in different tumor cells. Further studies will
clarify the utility of these findings.
Phytocannabinoids, synthetic cannabinoids and endo-
cannabinoids exert their anti-tumoral effects by a negative
cross-talk between GPR55 and CB2 receptors, and a bidi-
rectional cross-antagonism between both receptors (118).
These molecular mechanisms highlight the importance of
inhibiting endocannabinoids synthesizing and degrading
enzymes as anti-proliferative actions demand (118e120).
Epilepsy
Although a wide variety of medication is available to treat epi-
lepsy, at least one-third of patients are drug-resistant (121), that
is, the current medication cannot control their seizures. Several
cultures have used cannabis to treat seizures, including the Su-
merians around 1800 BCE and the Arabians in the 12th century
(122,123). In the 18th century, O’Shaughnessy and Gowers re-
ported the use cannabis to treat medication-resistant epileptics
(124,125). The effects of marijuana compounds have been stud-
ied more consistently in recent times.
Mounting evidence supports the anti-seizure effects of
THC, CBD, cannabidavarin (CBDV), endocannabinoids,
and synthetic cannabinoid receptor agonists in animal
models (126). Although THC has anti-seizure effects, it
can also promote them. Again, as marijuana psychotropic
effects that can result in tolerance and addiction, we have
to consider its therapeutic limitations.
In this context, the case of Charlotte has captured the
attention of the general population. Charlotte, who has Dra-
vet syndrome, had nearly 50 seizures per day. After she
began to use a CBD: THC extract, along with her pre-
scribed antiepileptic drugs, her seizures decreased to 2 or
3 nocturnal convulsions per month (127).
CBD in combination with prescribed antiepileptic drugs
has exhibited anticonvulsive effects. One double-blind
 Cannabinoids and Medicine
clinical trial compared CBD (200e300 mg) daily versus pla-
cebo, for 4 months, in patients suffering from generalized
epilepsy secondary to a temporal focus, reported that 4 out
of 8 patients had virtually no convulsions during CBD treat-
ment, while 3 experienced partial improvements. One pa-
tient did not improve (128). The first open-label
interventional trial was conducted with 162 patients (chil-
dren and adults) suffering from Dravet and Lennox-
Gastaut syndrome. CBD (Epidiolex) 2e5 mg/kg/d for
12 weeks reduced seizures by 36% (129). Another study
used CBD (Epidiolex) 20 mg/kg/d to treat 120 children
and young adults with Dravet syndrome and drug-resistant
seizures, decreasing the frequency of convulsive seizures
per month from 12.4e5.9, and 5% of patients became
seizure-free during the treatment (130). One study more,
included 171 children and middle-aged patients suffering
from Lennox-Gastaut syndrome. CBD (20 mg/kg/d) reduced
the median percentage of seizures per month to 43.9%. More
studies have been conducted (131), all of them supported
CBD anti-seizure effects. Regarding adverse effects, they
have been somnolence, diarrhea, decreased appetite, leth-
argy, fatigue, vomiting, and even convulsions that became
severe (129e132). Elevated transaminase was common for
patients using valproate medication and high doses of
CBD (133). Based on reports from the clinical trials, the
FDA approved Epidiolex as a first-line CBD medication
for Dravet and Lennox-Gastaut syndrome (133).
Conclusion
In this context, it is clear that the eCB system can be a target to
control some debilitating diseases, that is insomnia and hyper-
somnia, learning and memory, anxiety, cancer and epilepsy. In
the meantime, we believe marijuana’s derivatives may improve
the quality of life for many people suffering a terminal disease.
Although cannabinoids induce dependence, see above, we
believe in terminal diseases this issue should not be a concern.
In other types of diseases, such as insomnia or anorexia, or pain,
molecules that target the eCB system and that have no abuse po-
tential may prove to be efficacious medical treatments.
Acknowledgment
This work received support from Grant IN215218, IN217918,
IA205218 from DGAPA-UNAM to OPG, AERC and MMD,
respectively. The authors are grateful to Edith Monroy for review-
ing the language of the manuscript. We thank Dr. George Koob,
Professor, The Scripps Research Institute for his critique of an
early draft of the manuscript.
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