Preclinical Science and Clinical Studies – Review Article

Medical Cannabis
and Cannabinoids Received: April 28, 2023
Med Cannabis Cannabinoids 2023;6:130–137
Accepted: August 30, 2023
DOI: 10.1159/000534007 Published online: October 27, 2023

Neuro-Gastro-Cannabinology: A Novel
Paradigm for Regulating Mood and
Digestive Health
Fabio Turco a Viola Brugnatelli a Raquel Abalo b, c, d

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a
Cannabiscientia SA, Lugano, Switzerland; bDepar High Performance Research Group in Physiopathology and
Pharmacology of the Digestive System NeuGut-URJC, Department of Basic Health Sciences, Faculty of Health
Sciences, Universidad Rey Juan Carlos (URJC), Madrid, Spain; cR & D & I Unit Associated with the Institute of
Medicinal Chemistry (IQM), Spanish National Research-Council (CSIC), Madrid, Spain; dSpanish Pain Society
Working Groups on Basic Sciences in Pain and Analgesia and on Cannabinoids, Madrid, Spain

Keywords cannabinology as a novel and alternative paradigm for

Cannabinoid treatment · Gut-brain axis · Mood disorders · studying and treating GI disorders that affect mood, as well as
Gastroinstestinal disorders · Probiotics · Endocannabinoid mood disorders that imbalance GI physiology. This concept
system suggests the use of prebiotics or probiotics for improving the
tone of the ECS, as well as the use of phytocannabinoids or
endocannabinoid-like molecules, such as palmitoylethanola-
Abstract mide, to restore the normal intestinal microbiota. This ap-
The maintenance of homeostasis in the gastrointestinal (GI) proach may be effective in ameliorating the negative effects of
tract is ensured by the presence of the endocannabinoid GI dysfunctions on mood and/or the effects of mood disorders
system (ECS), which regulates important physiological activi- on digestive health. © 2023 The Author(s).
ties, such as motility, permeability, fluid secretion, immunity, Published by S. Karger AG, Basel

and visceral pain sensation. Beside its direct effects on the GI

system, the ECS in the central nervous system indirectly reg-
ulates GI functions, such as food intake and energy balance. Introduction
Mounting evidence suggests that the ECS may play an im-
portant role in modulating central neurotransmission which Homeostasis is derived from the ancient Greek words
affects GI functioning. It has also been found that the inter- ὅμoιoς and στάσις, meaning “staying the same”. As a
action between the ECS and microbiota affects brain and gut biological concept, it refers to the attitude of living or-
activity in a bidirectional manner, and a number of studies ganisms toward maintaining a steady balance when their
demonstrate that there is a strong relationship between GI conditions are optimal [1]. This can be regarded as a
dysfunctions and mood disorders. Thus, microbiota can reg- natural adaptive process of preservation of nearly constant
ulate the tone of the ECS. Conversely, changes in intestinal ECS conditions in the internal environment. As with other
tone may influence microbiota composition. In this mini- areas of the human body, the maintenance of intestinal
review, we propose the concept of neuro-gastro- homeostasis is fundamentally relevant to health. It is

karger@karger.com © 2023 The Author(s). Correspondence to:

www.karger.com/mca Published by S. Karger AG, Basel Fabio Turco, fabio @ cannabiscientia.com

This article is licensed under the Creative Commons Attribution-

NonCommercial 4.0 International License (CC BY-NC) (http://www.
karger.com/Services/OpenAccessLicense). Usage and distribution for
commercial purposes requires written permission.
crucial that the digestive and defensive functions of the gut physiology [30–32]. Moreover, growing evidence suggests
are integrated and balanced to protect the body against a role of the ECS in regulating the circadian sleep-wake
insults caused, i.e., by indigestion, pathogens, and toxins. cycle, and dysregulation of this circuit can lead to both
Intestinal equilibrium is maintained by a variety of mood and GI disorders [33–35]. The ECS is also involved,
pathways and cells, including immune, epithelial, neu- at least in part, in the induction of placebo effects, es-
ronal, glial, and endocrine cells [2]. Microbiota-gut-brain pecially in placebo analgesia [36]. Bringing all this evi-
interactions also play an important role in this process [3]. dence together, we propose the concept of neuro-gastro-
It is in this context that the endocannabinoid system cannabinology as a novel and alternative paradigm for
(ECS) emerges as a key modulator of intestinal homeo- studying and treating GI disorders that affect mood, as
stasis. Several intestinal physiological processes are reg- well as mood disorders that imbalance GI physiology.
ulated by the ECS, a network of lipid mediators that have
been found ubiquitously throughout the entire gastroin-
testinal (GI) system. The presence of the ECS in the GI Role of the ECS in Mediating Gut and
tract has been extensively described elsewhere [4, 5]. Brain Interactions
Briefly, the gut is home to both cannabinoid (CB) re-

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ceptors, CB1 and CB2, their endogenous ligands, termed In both the peripheral nervous system and the CNS, the
endocannabinoids, such as anandamide and 2- ECS plays a critical role in modulating and fine-tuning
arachidonoylglicerol (2-AG), and the enzymes responsi- synaptic transmission. CB1 and, to a lesser extent, CB2 are
ble for their biosynthesis and degradation. Several non- located in nerve fibers throughout the gut, but their
typical cannabinoid members are also expressed, in- concentration is highest in the myenteric and submucosal
cluding the transient receptor potential (TRP) channels, plexi [37]. Importantly, CB receptors are believed to be
such as TRPV1 and TRPM8, proliferator-activated re- localized only to excitatory nerves in the gut [38]. The
ceptors (PPARs), G protein-coupled receptors (GPRs), endocannabinoids function as retrograde neurotransmit-
and endocannabinoid-like molecules, including palmi- ters since they are synthetized in the postsynaptic cell, then
toylethanolamide (PEA) and oleoylethanolamide (OEA) cross the synapse and activate CB receptors presynaptically
[4, 5]. In the human body, the endocannabinoid signaling [39]. Conversely, CB2 and, to a lesser extent, CB1 are
pathways are involved in regulating a variety of biological mainly expressed in intestinal immune cells, where they
and cognitive processes (such as appetite, pain sensation, are involved in modulating intestinal inflammation as well
and mood) and in mediating the pharmacological effects as abnormal motility, visceral sensitivity, and pain [40].
of cannabis [6–12]. The ECS in the GI tract regulates ECS activation induces an overall inhibitory effect on gut
important physiological activities, such as intestinal cells’ functions, particularly on cholinergic neurons. This
motility, permeability, fluid secretion, immunity, and inhibitory physiological mechanism may be exploited in
visceral pain sensation [12, 13]. Apart from the direct pathological conditions, by enhancing or decreasing the
effects on the GI system, the ECS in the central nervous ECS tone; indeed, the ECS affects motility, pain, secretion,
system (CNS) indirectly controls intestinal functions, such and inflammation; moreover, the brain and the GI system
as food intake and energy balance [10, 14, 15]. It is now are intimately connected. Accumulating evidence is sug-
well established that the brain and gut communicate gestive of the ECS linking gut microbiota to CNS path-
bidirectionally to control a variety of physiological pro- ophysiology (shown in Fig. 1) [20, 41]. Besides helping to
cesses, through the gut-brain axis. Evidence suggests that digest nutrients and protect against pathogenic bacteria,
the ECS may play an important role in modulating central the gut microbiota has a significant impact on the activities
neurotransmission which affects GI functioning [3, of the CNS, particularly mood. There is a strong rela-
16–19]. It has also been found that the interaction between tionship between GI dysfunctions and mood disorders
the ECS and microbiome affects brain and gut activity in a [42]; both functional and chronic inflammatory GI dis-
bidirectional manner [20–22]. The ECS plays a role in orders, such as irritable bowel syndrome (IBS) and in-
modulating both emotional and non-emotional behavior flammatory bowel disease (IBD), are often associated with
[23–26]. Signals originating from the ECS are known to affective ailments, such as depression, anxiety, panic, and
influence the hypothalamic-pituitary-adrenocortical post-traumatic stress disorder (PTSD) [43]. Conversely,
(HPA) axis, which is the mammals’ primary stress re- mood disorders can lead to the development of GI diseases,
sponse system [27–29]. It has been demonstrated that such as functional dyspepsia and gastric ulcer [44, 45]. A
dysbiosis and/or altered endocannabinoid tone contribute possible link between gut and brain disorders may be
to mood changes and that mood disorders affect gut represented by the crosstalk between the gut microbiota

Neuro-Gastro-Cannabinology and Mood/ Med Cannabis Cannabinoids 2023;6:130–137 131

Digestive Health DOI: 10.1159/000534007
Fig. 1. Alteration of the endocannabinoid
system (ECS) in mood and gastrointestinal
(GI) disorders. The interaction between the
gut and the brain can be mediated either by
the vagus nerve or by circulating metabo-
lites. Alterations in the composition of the
microbiota can modulate the tone of the

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ECS, leading to central modifications that
influence mood. Conversely, mood disor-
ders can modify the tone of the ECS, which
in turn can alter the composition of the
microbiota, potentially resulting in the
development of GI disorders. IBS, irritable
bowel syndrome; IBD, inflammatory bowel
disease; PTSD, post-traumatic stress
disorder.

and the ECS. A study in 2007 reported that the commensal composition induced by dysbiosis are correlated with
bacterium Lactobacillus acidophilus increased intestinal hippocampal and gut alterations in some members of the
epithelial CB2 expression when administered orally to ECS [48]. Interestingly, probiotic supplementation re-
mice and rats [46]. Changes in gut microbiota also affect duced gut inflammation and decreased depression-like
the levels of fatty acid amide hydrolase (FAAH), mono- behavior by normalizing gut microbiota and reversing
acylglycerol lipase (MAGL), and CB1 mRNA [47, 48]. By biochemical and functional changes in the hippocampus
treating mice with the commensal bacterium Akkermansia [48]. Dysbiosis-induced changes in the ECS tone can also
muciniphila, levels of endocannabinoids in the gut are induce pain, which can be reverted with PEA supplements
increased, and the metabolic dysregulation caused by a that restore the microbiota and endocannabinoid tone to
high-fat diet can be reversed [49]. Also, in obese mice, CB1 normal [55]. Intriguingly, a significant increase in Ak-
antagonist SR141716A increases Akkermansia muciniphila kermansia muciniphila, Eubacterium, and Enter-
levels and decreases Lachnospiraceae and Erysipelo- obacteriaceae is observed following PEA administration,
trichaceae levels, which are implicated in gaining weight suggesting that PEA has anti-inflammatory properties as
and induction of metabolic syndrome [50]. A common well as the ability to regulate gut dysbiosis [56]. Fecal
feature of GI diseases, such as IBS, IBD, and functional microbiota transplantation from mildly stressed mice, a
dyspepsia, is dysbiosis, a disturbance in gut microbial mouse model of depression, caused depression-like be-
composition and function caused by both environmental havior in recipient mice [57]. There were significant
and internal factors. Dysbiosis has been repeatedly asso- molecular and behavioral alterations in the recipient mice
ciated with chronic GI disorders and metabolic disorders, associated with reduced serum lipid precursors for the
such as IBD, obesity, diabetes mellitus, cancer, and car- production of ECS ligands, as well as a decrease in brain
diovascular diseases [51–53]. Furthermore, dysbiosis, as endocannabinoids levels, supporting the hypothesis that
well as intestinal inflammation and loss of gut integrity, is stress causes a lower endocannabinoid tone, where gut
also linked to mood disorders, such as anxiety and de- microbial composition imbalance might be a factor. Other
pression, as well as more severe psychiatric and neurologic studies have shown dramatic changes in the intestinal ECS
conditions, such as schizophrenia, autism, or neurode- in germ-free mice, including reduced gene expression of
generative diseases [54, 55]. Changes in microbiota CB1, GPR55, and PPARα in the gut, and fecal transplants

132 Med Cannabis Cannabinoids 2023;6:130–137 Turco/Brugnatelli/Abalo

DOI: 10.1159/000534007
partially reversed these changes, suggesting that micro- normal microbiota or improving the ECS tone may be
biota composition profoundly affects the intestinal effective in counteracting the negative effects of stress on
endocannabinoid tone [58]. Human studies have shown mood or digestive health.
that dysbiosis triggers gut-microbial alterations that con-
tribute to anhedonia and amotivation via the ECS, espe-
cially through changes in PEA serum levels [59]. Taken Potential Interventions Targeting the ECS in GI and
these data together, it seems that the ECS is implied in the Mood-Related Disorders
CNS consequences of gut dysbiosis. One explanation may
be that commensal microorganisms affect ECS signaling by A number of studies have described the use of prebiotics,
directly producing endocannabinoid-like molecules able to probiotics, or both in treating anxiety and depression both
bind the receptors of the ECS [52]. Furthermore, as CB1 is in animal and human studies [47, 65–70]. Notably, in
expressed in vagal afferents that innervate various regions vagotomized mice, probiotic-related effects on neuro-
of the GI tract, the ECS may also modulate vagus nerve chemical changes as well as on behavior were abolished,
transmission, which is crucial for controlling food intake, again suggesting a role of the vagus nerve in these beneficial
hedonic feeding, visceral pain, aversion, and emotions by reactions [65]. In light of these findings, our review suggests

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modulating the microbiota-gut-brain axis [47]. Studies the modulation of the microbiota composition as a first-line
using germ-free mice further confirm the relationship treatment or an adjuvant to psychiatric intervention for
between the microbiota, ECS, and brain. As reported in a anxiety and depression, using prebiotics or probiotics
2017 paper, the alterations in gut microbiota composition (shown in Fig. 2). Such treatments may be especially
affect both brain and gut levels of endocannabinoids [60]. beneficial to patients who suffer from GI co-morbidities,
This study suggests that the endocannabinoid-like com- such as IBS or dyspepsia [71]. Additionally, phytocanna-
pound OEA, through its binding to GRP111 receptors, binoids can also be used to improve the composition of the
influences the secretion of the satiating hormone GLP-1, microbiota. The chronic treatment of obese rodents with
thus improving cognitive functions in patients with mood tetrahydrocannabinol (THC) caused an altered microbiota
disorders [60]; therefore, microbiota have the potential to with a higher Firmicutes:Bacteroidetes ratio, an increase in
regulate the tone of the ECS. On the other hand, alterations Akkermansia muciniphila abundance, and reduced obesity
in the intestinal ECS tone could also have an impact on the concurrently [72]. Capsaicin, a TRPV1 agonist, increased
composition of the microbiota. An altered intestinal ECS butyrate-producing Ruminococcaceae and Lachnospiraceae
modifies microbiota composition and may contribute to in obese rodents while decreasing LPS production [73].
chronic abdominal pain, a common symptom of anxiety Fecal microbiota transplant into germ-free mice revealed
and depression, as well as GI disorders [56]. Intestinal that capsaicin-induced obesity resistance was transferrable,
permeability and metabolic endotoxemia are reduced by a demonstrating the importance of the microbiota [73].
CB1 antagonist, which also induces an imbalance in gut Researchers examined the gut microbiome of mice treated
microbiota composition and a decrease in inflammation with cannabidiol (CBD)-enriched cannabis extracts as well
and macrophage levels in the adipose tissue of diet-induced as the associated histomorphological and molecular changes
obese mice. Conversely, a probiotic strain of Escherichia coli in their gut mucosa [73]. There was a significant increase in
engineered to produce endocannabinoids can reduce ad- Akkermansia muciniphila relative abundance; nevertheless,
iposity in mice on a high-fat diet by suppressing food the colon tissue had increased levels of pro-inflammatory
intake, improving insulin sensitivity, and reducing liver cytokines and chemokines, and gut integrity was decreased.
fibrosis [61]. Thus, by using engineered bacteria, it may be As a result, questions have been raised about the potential
possible to manipulate gut ECS signaling to provide long-term effects on the microbiome of therapeutic CBD
therapeutic benefits. Numerous studies have demonstrated application in humans. Interestingly, the mice used in this
the interaction between the gut microbiota and the HPA study were not pathological, so the situation may have
axis, indicating that stress-induced activation of this neu- differed if an induced pathological state, such as obesity or
roendocrine system may be affected by the composition of gut inflammation, had been present [74]. In addition to
the gut microbiota [62, 63]. There is also evidence sug- phytocannabinoids, endocannabinoid-like molecules, such
gesting that stress reduces the levels of endocannabinoids, as PEA and OEA, by restoring microbiota normal com-
especially 2-AG, which may lead to GI issues [64]. It is position and counteracting central and peripheral neuro-
unclear whether stress-induced microbiota modification inflammatory responses, may be beneficial in improving
affects the ECS tone or if the effect of stress on the ECS both brain and gut health simultaneously (shown in Fig. 2)
changes microbiota composition. However, restoring [56, 60, 75]. Furthermore, because mood disorders, such as

Neuro-Gastro-Cannabinology and Mood/ Med Cannabis Cannabinoids 2023;6:130–137 133

Digestive Health DOI: 10.1159/000534007
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Fig. 2. Restoring normal brain and gastrointestinal (GI) (THC) and cannabidiol (CBD), endocannabinoid-like mol-
functions by improving the endocannabinoid system (ECS) ecules such as palmitoylethanolamide (PEA) and oleoyle-
tone. Mood and GI disorders can alter the tone of the ECS. A thanolamide (OEA), or compounds that modify the levels of
normal ECS tone can be restored by using prebiotics, pro- endocannabinoids which, in turn, promote GI health and
biotics, phytocanbinoids such as tetrahydrocannabinol brain function.

depression, are preceded by patterns of poor appetite and Several mechanisms may be involved here, including in-
skipping meals, improving the ECS tone (with prebiotics, testinal barrier regulation, immune modulation, enter-
probiotics, phytocannabinoids, endocannabinoids, oendocrine system influence, mediators from the micro-
endocannabinoids-like molecules, and compounds that biome entering the body, and modulation of the vagus
modify the levels of endocannabinoids) may have a nerve. Therefore, approaches that promote the growth of
beneficial effect as it positively affects food intake and “beneficial” bacteria could be favorable in conferring re-
eating habits [15, 76, 77]. Mood and digestive disorders silience against mood disorders. There were, however,
may be related to altered circadian rhythms, which can be differences between strains of probiotic, the dose, and the
disrupted by stress [33, 34]. Microbiota composition and duration of treatment in the analyzed studies, and further
abundance also follow circadian rhythms [35]; when research studies are needed to determine the optimal
stress-related alterations of the circadian rhythm occur treatment regime. Nonetheless, this review claims for a
because of the effects of the ECS on the sleep-wake cycle, consideration of administration of prebiotics and pro-
restoring the microbiota’s normal composition and biotics for the treatment of patients with mood disorders,
enanchiong the endocannabinoid tone with phytocanna- such as anxiety, depression, and cognitive impairment,
binoids or compounds that enhance endocannabinoids particularly those that are able to modulate the ECS in a
activity may provide benefits (shown in Fig. 2). beneficial manner. In addition to prebiotics and probiotics,
endocannabinoid-like compounds, such as PEA and OEA,
or compounds that increase the levels of endocannabi-
Conclusion noids (i.e., through metabolic enzyme inhibitors), may be
considered for patients with mood and GI disorders, and
ECS signaling and gut microbiota have reciprocal in- because of their ability to modulate neuroinflammation as
teractions, which, in turn, influence the organism response well as microbiota composition, they may also be useful
via the gut-brain axis and may contribute to the protection supplements that support both gut and brain health at the
from stress-related diseases and mood alterations, as well same time [56, 60, 71, 75]. In particular, the use of
as from GI disorders. This is consistent with the fact that cannabis-derived compounds that decrease the impact of
the ECS facilitates the homeostatic state of the organism stress, regulate circadian rhythm, and improve mood may
and responds both to internal and external challenges [78]. represent a winning strategy in case of functional GI

134 Med Cannabis Cannabinoids 2023;6:130–137 Turco/Brugnatelli/Abalo

DOI: 10.1159/000534007
diseases. Co-morbidities between mood and GI health Funding Sources
might benefit from treatments with prebiotics or probiotics
and/or with compounds that modify the ECS tone to a more No funding was received.
substantial degree. Overall, neuro-gastro-cannabinology
represents a new clinical and research paradigm that fo-
cuses on the complex interactions between the CNS, the gut, Author Contributions
and the ECS and investigates novel treatments for GI and
mood disorders. F.T.: conceptualization (equal), methodology (lead),
writing – original draft (lead), and writing – review and editing
(equal). V.B.: conceptualization (equal), methodology (support-
ing), writing – original draft (supporting), and writing – review
Conflict of Interest Statement and editing (equal). R.A.: methodology (supporting),
writing – original draft (supporting), and writing – review and
The authors have no conflicts of interest to declare. editing (equal).

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Digestive Health DOI: 10.1159/000534007