![Cannabidiol (CBD) mechanism of action. The main action of CBD is to increase CB 1 and CB 2 signaling by preventing N-arachidonylethanolamine (AEA) degradation. This constrains the stress response and its manifestations both via its inhibition of the stress response and (independently) inhibition of some manifestations such as the anxiety, neuroinflammation, and GIT dysfunction. For example, CB 1 signaling inhibits stress-associated anxiety by both constraining the stress response and by CB 1 activity on forebrain glutamatergic neurons [41-43]. CBD also acts independently of CB 1 /CB 2 signaling by increasing serotonergic 5HT 1A signaling, increasing PPARγ signaling and desensitizing TPRV1, which inhibit stress-associated anxiety, neuroinflammation and GIT dysfunction, respectively.](https://www.researchgate.net/publication/357029985/figure/fig1/AS:1100962794086402@1639501393968/Cannabidiol-CBD-mechanism-of-action-The-main-action-of-CBD-is-to-increase-CB-1-and-CB_Q320.jpg)
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Journal of
Clinical Medicine
Review
Enhancing Endocannabinoid Control of Stress
with Cannabidiol
Jeremy D. Henson 1, 2, * , Luis Vitetta 1,3 , Michelle Quezada 2and Sean Hall 2
Citation: Henson, J.D.; Vitetta, L.;
Quezada, M.; Hall, S. Enhancing
Endocannabinoid Control of Stress
with Cannabidiol. J. Clin. Med. 2021,
10, 5852.
https://doi.org/10.3390/jcm10245852
Academic Editor: Timm B. Poeppl
Received: 30 November 2021
Accepted: 8 December 2021
Published: 14 December 2021
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
Copyright: © 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
1
Prince of Wales Clinical School, University of NSW, Sydney, NSW 2052, Australia; luis.vitetta@sydney.edu.au
2Medlab Clinical Ltd., Sydney, NSW 2015, Australia; michelle_quezada@medlab.co (M.Q.);
sean_hall@medlab.co (S.H.)
3Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia
*Correspondence: j.henson@unsw.edu.au
Abstract:
The stress response is a well-defined physiological function activated frequently by life
events. However, sometimes the stress response can be inappropriate, excessive, or prolonged; in
which case, it can hinder rather than help in coping with the stressor, impair normal functioning, and
increase the risk of somatic and mental health disorders. There is a need for a more effective and
safe pharmacological treatment that can dampen maladaptive stress responses. The endocannabi-
noid system is one of the main regulators of the stress response. A basal endocannabinoid tone
inhibits the stress response, modulation of this tone permits/curtails an active stress response, and
chronic deficiency in the endocannabinoid tone is associated with the pathological complications
of chronic stress. Cannabidiol is a safe exogenous cannabinoid enhancer of the endocannabinoid
system that could be a useful treatment for stress. There have been seven double-blind placebo
controlled clinical trials of CBD for stress on a combined total of 232 participants and one partially
controlled study on 120 participants. All showed that CBD was effective in significantly reduc-
ing the stress response and was non-inferior to pharmaceutical comparators, when included. The
clinical trial results are supported by the established mechanisms of action of CBD (including in-
creased N-arachidonylethanolamine levels) and extensive real-world and preclinical evidence of the
effectiveness of CBD for treating stress.
Keywords:
stress; hypothalamus–pituitary–adrenal axis; endocannabinoid; N-arachidonylethanolam-
ine; AEA; cannabidiol; CBD
1. The Stress Response
1.1. Physiology and Pathology of the Stress Response
The stress response has two arms: (i) the hypothalamus–pituitary–adrenal (HPA) axis
secretion of cortisol and (ii) the sympathetic nervous system (SNS) release of noradrenaline
and adrenaline. The HPA axis and SNS are interconnected and act in parallel to increase
the ability to cope with the immediate stress and avoid similar threats in future [
1
–
3
].
The “fight or flight” reaction is part of the acute stress response that mobilizes glucose
and increases blood flow to the muscles. Mentally, attention to the threat is increased by
facilitating arousal, increasing focus on the threat, and increasing awake time. Distraction
from the threat is reduced by increasing analgesia and inhibiting immediately unhelpful
behaviors/processes such as feeding, reproduction, and growth. Memory consolidation is
also facilitated so that the threat can be identified in future [
2
–
5
]. Some aspects of the stress
response may not be appropriate for modern-day stressors that do not require increased
physical activity to be dealt with.
Fear, anxiety, and depressive behaviors are normal physiological aspects of the stress
response, can be beneficial, and are not pathological states [
4
,
6
]. Fear is an unpleasant
emotional response to an immediate threat that can enhance mental functions, including
attention. Anxiety is also an unpleasant emotional response that can enhance mental
J. Clin. Med. 2021,10, 5852. https://doi.org/10.3390/jcm10245852 https://www.mdpi.com/journal/jcm
J. Clin. Med. 2021,10, 5852 2 of 15
functions; however, it is in response to a future (not immediate) threat. Anxiety creates
hypervigilance in anticipation of the future threat to help individuals prepare for dangers
and facilitates memory consolidation for alerting to repeated occurrences [
6
]. Depressive
behaviors, such as anhedonia, may help reduce distraction from the threat. Fear, anxiety,
and depressive behaviors are only diagnosed as mental disorders when they are both
(i) persistent or are elicited by non-threatening stimuli and (ii) hinder the ability to function
normally [6].
Stress can cause considerable harm. While the acute stress response improves survival,
if it is excessive or chronic, stress can be a causative factor for or exacerbate numerous
somatic and mental illnesses. In order to prioritize relevant activities for dealing with
the immediate threat, the stress response changes key processes in the cardiorespiratory,
gastrointestinal, and immune systems; growth, sex, and thyroid hormone axes; and ex-
ecutive, cognitive, fear, anger, reward, and wake–sleep centers of the brain, as well as
increasing inflammatory cytokine levels [
2
]. If excessive or persistent, these changes can
lead to substantial pathology. For example, stress can promote (i) inflammatory diseases
such as asthma, eczema or urticaria, rheumatoid arthritis, ulcerative colitis, and sickness
syndrome; (ii) pain disorders such as headaches and abdominal, pelvic, and lower back
pain; (iii) gastrointestinal dysfunction such as diarrhea, constipation, and peptic ulcers;
(iv) mental illnesses such as anxiety, depression, psychosis, cognitive dysfunction, and
insomnia; (v) metabolic diseases such as diabetes mellitus, hypercholesterolemia, vis-
ceral obesity, and sarcopenia; (vi) ischemic heart disease; (vii) neurodegenerative diseases;
and (viii) osteopenia and osteoporosis [
2
–
4
,
7
–
10
]. Chronic or repeated stress is especially
harmful and is a major factor in precipitating or exacerbating mental illnesses such as
anxiety disorders and depression [
9
]. In some systems, the appropriate intensity and
duration of the stress response can improve functioning and health; however, an excessive
or prolonged stress response reduces it. For example, acute stress can improve immune
system functioning, whereas excessive or chronic stress suppresses the immune response
to bacterial and viral infections, vaccinations, and cancer [
2
,
11
,
12
]. Similarly, acute stress
increases analgesia, whereas chronic stress can cause hyperalgesia.
Habituation or adaptation of the stress response is important for minimizing the
adverse effects from a repeated stress response [
13
,
14
]. With habituation, the stress response
decreases in intensity with repeated events of the same stressor. For example, when a
person starts living next to a railway line, the sound of a train hurtling past may induce a
substantial stress response; however, the intensity dwindles over time. This habituation is
important for reducing what can be thought of as the wear and tear load on the mind and
body from an ongoing stress response [15,16].
1.2. Measures of the Stress Response
The stress response can be measured clinically by assessing either or both of its two
arms. The HPA axis is usually measured by assessing cortisol levels, which are increased
with acute stress. Cortisol levels in healthy individuals have a diurnal pattern, peaking in
the early morning and having their low point early in the night-time. Chronic stress can
cause a flattening of the diurnal pattern, lowering the early morning peak and elevating
the low night-time levels [
9
]. The sympathetic nervous system (SNS) arm of the stress
response causes an increase in circulating catecholamines, increased heart rate, decreased
heart rate variability (especially decreased high-frequency heart rate variability), and raised
salivary alpha-amylase [
9
,
17
–
20
]. Symptoms of the stress response should also be assessed
using validated questionnaires such as the Subclinical Stress Symptom Questionnaire-25
(SSQ-25) [
21
] or the Perceived Stress Scale-10 (PSS-10) [
22
]. For specifically measuring
occupational stress, the Psychological Strain Questionnaire (PSQ) can be used, which is part
of the larger Occupational Stress Inventory—Revised (OSI-R) [
23
]. Some validated anxiety
questionnaires also assess stress, e.g., the Depression Anxiety Stress Scales (DASS) [24].
J. Clin. Med. 2021,10, 5852 3 of 15
1.3. Impact and Current Treatment Options for Stress
Stress can be defined as an event that is perceived to threaten homeostasis [
2
]. The
common types of life stressors and their average stress response intensity with respect to
causing illness are listed in the Social Readjustment Rating Scale (SRRS; also known as
the Holmes and Rahe Stress Scale) [
25
]. While occupational issues do not rate as highly
as changes in personal relationships, health problems, and legal issues, occupational
stress provides an insight into the substantial impact stress has on the individual and the
economy. In Australia, in 2015, 91% of workers’ compensation claims involving a mental
health condition were linked to occupational stress. The claims caused by occupational
stress, comprised 5.5% of all workers’ compensation claims and 16% of all payouts and
caused 17% of all time off work due to compensation claims [
26
]. Apart from increasing the
number of sick and personal leave days, occupational stress also reduces productivity and
work quality when employees are at work by causing an increased rate of accidents, poor
communication, increased conflict, reduced job satisfaction and morale, reduced client
satisfaction, and increased staff turnover [12,14].
There is a need for interventions in the stress response to prevent health disorders
from eventuating and to reduce unhelpful symptoms. Treatments to reduce stress re-
sponses include pharmacological and psychological approaches. Many of the medications
that are used for stress relief are addictive, and all have the potential for serious adverse
reactions and drug interactions. In addition, many can take several weeks before their
effects are experienced, and medications that only inhibit one arm of the stress response
can be undermined by a compensatory increase in the other [1]. Prescription medications
used for stress and its manifestations include beta blockers [
1
], benzodiazepines [
27
,
28
],
selective serotonin reuptake inhibitors [
27
], and bupropion [
29
]. Psychological methods
for treating occupational stress include meditation, relaxation, biofeedback, and cognitive
and behavioral therapy. Meditation and relaxation techniques, such as thought reduc-
tion (mental silence) or progressive muscle relaxation, are used to reduce physiological
symptoms of the stress response and, thereby, reduce the reactivity of the individual to
occupational stressors [
23
]. Biofeedback techniques aim to reduce reactivity by training
people on how to gain conscious control over stress processes such as heart rate and brain
wave patterns. Cognitive behavioral techniques include changing the way the person
appraises the stressful situations and an individual’s own perceived ability to deal with
the situation, as well as improving coping techniques [
14
]. When individuals believe that
they can manage a stressor, they experience a less intense stress response [23].
2. The Endocannabinoid System
The endocannabinoid signaling system is one of the key regulators of the stress
response and is important for proper return to the non-stressed state. The endocannabinoid
system constrains the magnitude of the stress response, promotes return of the HPA axis
to non-stressed levels, and facilitates habituation of the stress response to repeated or
ongoing stress. It also directly inhibits stress-associated processes such as fear, anxiety,
depressive behaviors, inflammation, and hyperalgesia and promotes behaviors inhibited
by the stress response such as feeding and sleep. The effect of the endocannabinoid
system can be summarized as promoting a cool, calm, collected, fat, and happy state [
13
].
Furthermore, resilience to stress-related disease and dysfunction may depend on the
satisfactory functioning of the endocannabinoid system [4,30–33].
The endocannabinoid system is an evolutionarily conserved signaling system that was
discovered in the 1990s after the identification of the primary targets of tetrahydrocannabi-
nol (THC) and the cannabinoid receptors type 1 (CB
1
) and type 2 (CB
2
). CB
1
are one of
the most abundant G-protein coupled receptors in the central nervous system and are
located on presynaptic terminals where they suppress neurotransmitter release, mostly on
excitatory glutamatergic neurons and inhibitory gamma-aminobutyric acid (GABA)ergic
interneurons, and to a lesser extent serotonergic, noradrenergic, and dopaminergic neu-
rons [
15
]. CB
2
are mostly located in immune cells (include microglia) and modulate
J. Clin. Med. 2021,10, 5852 4 of 15
immune cell migration and cytokine release. There is also evidence that CB
2
are present on
neurons in stress-associated areas of the brain and regulate the release of GABA, dopamine,
and glutamate [
34
–
36
]. The two main endogenous cannabinoids (endocannabinoids),
N-arachidonylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG), are
synthesized in response to neuronal depolarization and/or Ca
+2
influx, via cleavage of
membrane phospholipids. In the nervous system, this occurs in the postsynaptic mem-
brane and the endocannabinoids feedback in a retrograde manner to CB
1/2
on presynaptic
terminals, thus inhibiting afferent neurotransmitter release (Figure 1) [
15
,
37
]. AEA and
2-AG are hydrophobic, and it is not known how they cross the aqueous synaptic space;
however, AEA produced by microglia cells may be transported to presynaptic CB
1
via mi-
crovesicles [
38
]. AEA also binds peroxisome proliferator-activated receptor-
γ
and transient
receptor potential vanilloid member 1 [13].
J.Clin.Med.2021,10,xFORPEERREVIEW4of15
CB1areoneofthemostabundantG‐proteincoupledreceptorsinthecentralnervous
systemandarelocatedonpresynapticterminalswheretheysuppressneurotransmitter
release,mostlyonexcitatoryglutamatergicneuronsandinhibitorygamma‐aminobutyric
acid(GABA)ergicinterneurons,andtoalesserextentserotonergic,noradrenergic,and
dopaminergicneurons[15].CB2aremostlylocatedinimmunecells(includemicroglia)
andmodulateimmunecellmigrationandcytokinerelease.ThereisalsoevidencethatCB2
arepresentonneuronsinstress‐associatedareasofthebrainandregulatethereleaseof
GABA,dopamine,andglutamate[34–36].Thetwomainendogenouscannabinoids
(endocannabinoids),N‐arachidonylethanolamine(anandamide;AEA)and2‐
arachidonoylglycerol(2‐AG),aresynthesizedinresponsetoneuronaldepolarization
and/orCa+2influx,viacleavageofmembranephospholipids.Inthenervoussystem,this
occursinthepostsynapticmembraneandtheendocannabinoidsfeedbackinaretrograde
mannertoCB1/2onpresynapticterminals,thusinhibitingafferentneurotransmitter
release(Figure1)[15,37].AEAand2‐AGarehydrophobic,anditisnotknownhowthey
crosstheaqueoussynapticspace;however,AEAproducedbymicrogliacellsmaybe
transportedtopresynapticCB1viamicrovesicles[38].AEAalsobindsperoxisome
proliferator‐activatedreceptor‐γandtransientreceptorpotentialvanilloidmember1[13].
Figure1.CB1/2signalinginthenervoussystem.Thetwomainendocannabinoids,AEAand2‐AG,
aresynthesizedinresponsetoneuronaldepolarizationand/orCa+2influx,viacleavageofmembrane
phospholipids,suchasphosphatidylethanolamine(PE),inthepostsynapticmembrane.ForAEA,
Ca+2‐dependentN‐acyltransferase(NAT)firstproducesN‐arachidonoylPE(NAPE),whichisthen
hydrolyzedbyphospholipaseD(NAPE‐PLD).For2‐AG,Ca+2influxand/orcortisolstimulates
phospholipaseC(PLC),whichhydrolyzesphosphatidylinositol(PI)intodiacylglycerol(DAG),
whichishydrolyzedbydiacylglycerollipase(DGL).AEAand2‐AGfeedbackinaretrograde
mannertoCB1/2receptorsonpresynapticterminals.CB1/2arecoupledtoGi/o‐proteinsthatfunction
toinhibitadenylylcyclaseandvoltage‐gatedcalciumchannelsandactivatepotassiumchannels,
thus,suppressingafferentneurotransmitterrelease.Inthebrain,CB1/2signalinghasabasaltonethat
dependsonAEAproductioninresponsetoneuronalactivity.Thistonecanberapidlyreduced,by
increasedhydrolyzationofAEAtoarachidonicacid(AA)andethanolamine(EA)byFAAHthatis
inthepost‐synapticendoplasmicreticulum.ThemainactionofCBDistocompetitivelyinhibit
bindingofAEAtoitsaqueoustransporter,fattyacidbindingprotein(FABP),therebyinhibitingthe
Figure 1.
CB
1/2
signaling in the nervous system. The two main endocannabinoids, AEA and 2-AG,
are synthesized in response to neuronal depolarization and/or Ca
+2
influx, via cleavage of membrane
phospholipids, such as phosphatidylethanolamine (PE), in the postsynaptic membrane. For AEA,
Ca
+2
-dependent N-acyltransferase (NAT) first produces N-arachidonoyl PE (NAPE), which is then
hydrolyzed by phospholipase D (NAPE-PLD). For 2-AG, Ca
+2
influx and/or cortisol stimulates
phospholipase C (PLC), which hydrolyzes phosphatidylinositol (PI) into diacylglycerol (DAG),
which is hydrolyzed by diacylglycerol lipase (DGL). AEA and 2-AG feedback in a retrograde manner
to CB
1/2
receptors on presynaptic terminals. CB
1/2
are coupled to G
i/o
-proteins that function to
inhibit adenylyl cyclase and voltage-gated calcium channels and activate potassium channels, thus,
suppressing afferent neurotransmitter release. In the brain, CB
1/2
signaling has a basal tone that
depends on AEA production in response to neuronal activity. This tone can be rapidly reduced, by
increased hydrolyzation of AEA to arachidonic acid (AA) and ethanolamine (EA) by FAAH that
is in the post-synaptic endoplasmic reticulum. The main action of CBD is to competitively inhibit
binding of AEA to its aqueous transporter, fatty acid binding protein (FABP), thereby inhibiting the
degradation of AEA by FAAH and increasing CB
1/2
receptor signaling tone. Moreover, 2-AG is not
degraded by FAAH but by monoacylglycerol lipase (MAGL), which is located near CB
1/2
on the
pre-synaptic membrane [15,39].
J. Clin. Med. 2021,10, 5852 5 of 15
In the brain, CB
1/2
signaling has a basal tone that depends on AEA production in
response to neuronal activity. This tone can be rapidly reduced by increased degradation
of AEA by fatty acid amide hydrolase (FAAH) that is located in post-synaptic endoplasmic
reticulum (Figure 1) [
15
,
39
]. CB
1/2
signaling is increased by increasing the levels of 2-AG
production by phospholipase C [
40
]. Phospholipase C is activated by Ca
+2
influx secondary
to neuronal depolarization and cortisol [3]. Furthermore, 2-AG is not degraded by FAAH
but by monoacylglycerol lipase (MAGL), which is located near CB
1/2
on the pre-synaptic
membrane (Figure 1) [
15
]. In addition to their respective primary degradative enzymes,
AEA and 2-AG can also be oxygenated by cyclooxygenase 2 (COX-2) to form bioactive
prostaglandin derivatives [15].
3. Regulation of the Stress Response by the Endocannabinoid System
CB
1
expression is especially high in the cortico-limbic brain regions associated with the
stress response, and CB
1
signaling constrains the stress response centrally via both its HPA
axis and sympathetic nervous system arms [
9
,
30
–
32
]. Both CB
1
and CB
2
signaling are also
involved in mediating the central and peripheral manifestations of the stress response [
13
].
Most research and understanding of the role of the endocannabinoid system in stress has
come from animal (rodent) studies that employ unconditioned stressors and then monitor
changes in the balance between exploration and avoidance behaviors [
31
,
32
]. Human
studies correlating circulating AEA and 2-AG levels with aspects of the stress response and
studies investigating the stress response effects of CB
1
inhibition (by rimonabant) have
supported that the animal model data can be extrapolated to humans [15].
Although CB
1
signaling is known to inhibit noradrenalin release by the SNS [
9
], more
is known about how it regulates the HPA axis. There is tonic inhibition of the HPA axis’s
stress response by CB1signaling, which can be modified in the following ways (Figure 2):
1.
Stress response induction and maintenance: Acute exposure to stress rapidly increases
corticotropin-releasing hormone signaling in limbic structures, which increases the
enzymatic activity of FAAH, resulting in a rapid decrease of the inhibitory tone of
AEA (and CB
1
signaling) on the HPA axis [
13
,
15
,
32
]. This mechanism continues to
maintain low AEA levels as long as the stressor remains [13].
2.
Stress response termination: Increased levels of cortisol following induction of the
stress response stimulates production of 2-AG in the hypothalamus and other stress
centers of the brain, increasing CB1signaling. This applies negative-feedback inhibi-
tion of the HPA axis and can facilitate termination of the stress response [15].
3.
Habituation of the stress response: Upon repeated presentation of the same stressor,
2-AG levels are progressively enhanced within forebrain stress centers, increasing
CB
1
signaling and HPA axis habituation [
4
,
15
]. This increase in 2-AG may be due to a
reduction in MAGL expression.
4.
Chronic dysfunction: Exposure to chronic stress causes decreased CB
1
expression
in the stress centers of the brain due to epigenetic changes [
15
,
40
]. This results in
less feedback inhibition on the HPA axis and contributes to continued high levels of
cortisol following chronic stress [5].
In addition to regulating the stress response, decreased levels of CB
1
and CB
2
signaling
also have direct effects on the manifestations and complications of the stress response,
which makes CB
1
and CB
2
signaling a good target for reducing many undesirable effects
of acute and chronic stress. CB
1
signaling on forebrain glutamatergic neurons reduces
anxiety specifically under stressful or aversive situations [
41
–
43
]. Chronic stress induces
neuroinflammation and activates microglia (the brain-resident macrophages), which can
facilitate anxiety and depressive behaviors and contribute to the development of affective
disorders. Both CB
1
and CB
2
signaling can prevent the activation of microglia, cytokine
signaling, and stress-induced recruitment of monocytes to the brain’s neurovascular space,
which may help constrain neuroinflammation [
4
,
9
,
15
,
36
]. CB
1
and possibly CB
2
are present
in the enteric nervous system, and CB
2
is also expressed on immune and epithelial cells
of the gastrointestinal tract (GIT). CB
1
and CB
2
signaling opposes the increased GIT pain
J. Clin. Med. 2021,10, 5852 6 of 15
sensitivity, motility, inflammation, immune activation, and permeability caused by acute
and/or chronic stress [
13
,
40
]. Chronic impairments in CB
1
and CB
2
signaling may also
directly contribute to long-term complications of chronic stress, such as learning and mem-
ory deficits, changes in coping behaviors, post-traumatic stress disorder, anxiety disorders,
depression, psychosis, and pain syndromes [
15
,
16
,
44
]. For example, CB
1
signaling extin-
guishes fear and can prevent persistence of aversive memories, which if impaired may
promote post-traumatic stress disorder (PTSD) and phobias [
3
,
4
,
44
]. Administration of
medicines such as FAAH inhibitors or endocannabinoid reuptake inhibitors have been
shown to ward off the development of adverse effects of chronic stress [3,4,15,44].
J.Clin.Med.2021,10,xFORPEERREVIEW6of15
Figure2.Endocannabinoidregulationofthestressresponse.Withoutastressor(NoStress)basal
AEAtonemaintainsCB1signalingconstraintofthestressresponseandacool,calm,collected,and
happystate.Acutepresentationofastressor(AcuteStress)elevatesFAAHhydrolysisofAEA,
reducingCB1signalingandpermittingactivationofthestressresponse[13,15,32,39].Secretionof
cortisolbythestressresponseprovidesNegativeFeedbackbyincreasing2‐AGproduction,which
increasesCB1signalingandterminatesthestressresponse[15].Repeatedpresentationofthesame
stressorprogressivelyincreases2‐AGlevels,possiblybyreducedMAGLexpressionand
degradationof2‐AG,whichcausesprogressivelyhigherCB1signalingandHabituationtothestress
response[4,15].ChronicStresscausesadownregulationofCB1thatimpairsfeedbackinhibitionand
facilitatespersistenceofthestressresponseandhighcortisollevels,whichprecipitatesor
exacerbatesillness(complications)[5,15,40].
Inadditiontoregulatingthestressresponse,decreasedlevelsofCB1andCB2
signalingalsohavedirecteffectsonthemanifestationsandcomplicationsofthestress
response,whichmakesCB1andCB2signalingagoodtargetforreducingmany
undesirableeffectsofacuteandchronicstress.CB1signalingonforebrainglutamatergic
neuronsreducesanxietyspecificallyunderstressfuloraversivesituations[41–43].
Chronicstressinducesneuroinflammationandactivatesmicroglia(thebrain‐resident
Figure 2.
Endocannabinoid regulation of the stress response. Without a stressor (No Stress) basal AEA
tone maintains CB
1
signaling constraint of the stress response and a cool, calm, collected, and happy
state. Acute presentation of a stressor (Acute Stress) elevates FAAH hydrolysis of AEA, reducing
CB
1
signaling and permitting activation of the stress response [
13
,
15
,
32
,
39
]. Secretion of cortisol by
the stress response provides Negative Feedback by increasing 2-AG production, which increases
CB
1
signaling and terminates the stress response [
15
]. Repeated presentation of the same stressor
progressively increases 2-AG levels, possibly by reduced MAGL expression and degradation of
2-AG, which causes progressively higher CB
1
signaling and Habituation to the stress response [
4
,
15
].
Chronic Stress causes a downregulation of CB
1
that impairs feedback inhibition and facilitates
persistence of the stress response and high cortisol levels, which precipitates or exacerbates illness
(complications) [5,15,40].
J. Clin. Med. 2021,10, 5852 7 of 15
4. Cannabidiol (CBD) as a Treatment for Stress
Cannabis has been used medicinally for thousands of years in various societies
around the world to reduce the physiological and psychological consequences of stress
and
fear [13,45]
. Of the two main components of cannabis, cannabidiol (CBD) and tetrahy-
drocannabinol (THC), CBD appears to be the component responsible for these effects.
Although THC is a weak partial agonist of CB
1
and CB
2
, as far as the stress response is con-
cerned, THC appears to act as a competitive inhibitor of AEA and 2-AG at CB1, and THC
increases basal- and stress-induced glucocorticoids [
13
]. CBD products (edibles, tinctures,
and vapes) are commonly used around the world to treat stress, as well as self-perceived
anxiety and insomnia, which often may be symptoms of stress [
46
,
47
]. Because CBD acts
on several synergistic targets, it may be more effective (as well as safer) for constraining
the stress response than molecules designed to target specific endocannabinoid receptors
or degradative enzymes [31,32].
4.1. Real-World Evidence
In the UK, over 10% of adults have tried CBD [
46
] and, in the USA, in one month,
there were over 6 million internet searchers for CBD [
48
]. Between 35% and 65% of people
using CBD for medicinal purposes in the UK, USA, Denmark, and New Zealand were
found to be administering it for stress [
46
,
47
], and over 90% reported feeling less stressed
with CBD, with no respondents reporting feeling more stressed [
46
]. For stress and its
manifestations of mild anxiety and insomnia, CBD is usually administered at low doses
and mostly from online suppliers, with less than 1% being prescribed by a doctor and less
than 5% purchased from a pharmacy [46].
4.2. Mechanism of Action
CBD increases CB
1
and CB
2
signaling by increasing AEA levels. CBD increases
AEA levels in rodents (usual animal model for stress) by inhibiting the enzymatic activ-
ity of FAAH. In humans, CBD does not enzymatically inhibit FAAH but inhibits AEA
degradation by FAAH indirectly—by preventing transport of AEA from the post-synaptic
membrane to FAAH, which is mainly located in the post-synaptic endoplasmic reticulum.
CBD competitively inhibits AEA binding to fatty acid binding proteins that transport
hydrophobic AEA across the aqueous space between the plasma membrane and the endo-
plasmic reticulum (Figure 1) [
39
]. CBD treatment has been shown to increase AEA levels in
the serum of schizophrenia patients [49].
CBD also acts to reduce stress and its manifestations by non-endocannabinoid re-
ceptors (Figure 3). Even at low doses, CBD acts as an agonist at serotoninergic 5-HT
1A
receptors and blocks stress-induced changes in 5-HT
1A
receptor gene expression, which
reduces anxiety associated with the stress response [
50
–
52
]. CBD also activates peroxisome
proliferator-activated receptor gamma (PPAR
γ
) that reduces neuroinflammation and exci-
totoxicity that is associated with the stress response [
53
]. It is possible that CBD could also
reduce the stress response via binding the transient receptor potential vanilloid member
1 (TRPV1), because CBD is known to desensitize TRPV1 [
54
] and TRPV1 is a mediator
of the stress response [
31
,
32
,
55
]. The differential expression and differential sensitivity
to modulation of CB
1
on different types of neurons may also be important for the net
effect of CBD [
56
–
59
]. CBD can act as a negative allosteric modulator of CB
1
[
60
,
61
] and
CB
2
[
62
] (
in vitro
), thereby acting as a non-competitive antagonist of the actions of THC
and endogenous CB
1/2
agonists. Although CBD does antagonize some actions of THC,
CBD does not have the same effects as CB
1/2
antagonists (such as recombinant) [
61
], and
CBD largely regulates the stress response by increasing CB1/2 signaling [37,63,64].
J. Clin. Med. 2021,10, 5852 8 of 15
J.Clin.Med.2021,10,xFORPEERREVIEW8of15
receptorsandblocksstress‐inducedchangesin5‐HT1Areceptorgeneexpression,which
reducesanxietyassociatedwiththestressresponse[50–52].CBDalsoactivates
peroxisomeproliferator‐activatedreceptorgamma(PPARγ)thatreduces
neuroinflammationandexcitotoxicitythatisassociatedwiththestressresponse[53].Itis
possiblethatCBDcouldalsoreducethestressresponseviabindingthetransientreceptor
potentialvanilloidmember1(TRPV1),becauseCBDisknowntodesensitizeTRPV1[54]
andTRPV1isamediatorofthestressresponse[31,32,55].Thedifferentialexpressionand
differentialsensitivitytomodulationofCB1ondifferenttypesofneuronsmayalsobe
importantfortheneteffectofCBD[56–59].CBDcanactasanegativeallostericmodulator
ofCB1[60,61]andCB2[62](invitro),therebyactingasanon‐competitiveantagonistofthe
actionsofTHCandendogenousCB1/2agonists.AlthoughCBDdoesantagonizesome
actionsofTHC,CBDdoesnothavethesameeffectsasCB1/2antagonists(suchas
recombinant)[61],andCBDlargelyregulatesthestressresponsebyincreasingCB1/2
signaling[37,63,64].
Figure3.Cannabidiol(CBD)mechanismofaction.ThemainactionofCBDistoincreaseCB1and
CB2signalingbypreventingN‐arachidonylethanolamine(AEA)degradation.Thisconstrainsthe
stressresponseanditsmanifestationsbothviaitsinhibitionofthestressresponseand
(independently)inhibitionofsomemanifestationssuchastheanxiety,neuroinflammation,andGIT
dysfunction.Forexample,CB1signalinginhibitsstress‐associatedanxietybybothconstrainingthe
stressresponseandbyCB1activityonforebrainglutamatergicneurons[41–43].CBDalsoacts
independentlyofCB1/CB2signalingbyincreasingserotonergic5HT1Asignaling,increasingPPARγ
signalinganddesensitizingTPRV1,whichinhibitstress‐associatedanxiety,neuroinflammationand
GITdysfunction,respectively.
4.3.Safety,Tolerability,andPharmacokinetics
Low‐doseCBDthatappearseffectiveforstressanditsmanifestations[46]hasagood
safetyandtolerabilityprofile,withfewadverseeffects[65–69].UnlikeTHC,CBDisnot
psychomimeticanddoesnotcauseintoxication,euphoria,addiction,psychomotor
impairment,orcognitiveimpairment[70–72].Importantly,low‐doseCBD(lessthan150
mg/day)doesnotcausethehepatocellularinjuryobservedforhigherdoseCBD(>600
mg/day)[73–76].Reviewsof49clinicaltrialsofCBD,includingintravenous,inhalation,
andoralroutesofadministrationandoraldoserangesof10–1500mgperday,foundthat
CBDwaswelltoleratedwithagoodsafetyprofile[65,77].CBDhasalsobeenshownto
havenopotentialforabuseordependenceinhumans[78–81].High‐doseCBDhasdrug–
druginteractionswithmedicinesmetabolizedbythecytochromeP450pathways[82],and
theextenttowhichthisoccurswithlow‐doseCBDisnotyetknown.Thereisapossibility
ofmilddrowsinessandfatiguewiththelow‐doseCBD[82].
Figure 3.
Cannabidiol (CBD) mechanism of action. The main action of CBD is to increase CB
1
and CB
2
signaling by preventing N-arachidonylethanolamine (AEA) degradation. This constrains the stress
response and its manifestations both via its inhibition of the stress response and (independently)
inhibition of some manifestations such as the anxiety, neuroinflammation, and GIT dysfunction. For
example, CB
1
signaling inhibits stress-associated anxiety by both constraining the stress response and
by CB
1
activity on forebrain glutamatergic neurons [
41
–
43
]. CBD also acts independently of CB
1
/CB
2
signaling by increasing serotonergic 5HT
1A
signaling, increasing PPAR
γ
signaling and desensitizing
TPRV1, which inhibit stress-associated anxiety, neuroinflammation and GIT dysfunction, respectively.
4.3. Safety, Tolerability, and Pharmacokinetics
Low-dose CBD that appears effective for stress and its manifestations [
46
] has a good
safety and tolerability profile, with few adverse effects [
65
–
69
]. Unlike THC, CBD is not psy-
chomimetic and does not cause intoxication, euphoria, addiction, psychomotor impairment,
or cognitive impairment [
70
–
72
]. Importantly, low-dose CBD (less than 150 mg/day) does
not cause the hepatocellular injury observed for higher dose CBD
(>600 mg/day) [73–76]
.
Reviews of 49 clinical trials of CBD, including intravenous, inhalation, and oral routes
of administration and oral dose ranges of 10–1500 mg per day, found that CBD was well
tolerated with a good safety profile [
65
,
77
]. CBD has also been shown to have no potential
for abuse or dependence in humans [
78
–
81
]. High-dose CBD has drug–drug interactions
with medicines metabolized by the cytochrome P450 pathways [
82
], and the extent to
which this occurs with low-dose CBD is not yet known. There is a possibility of mild
drowsiness and fatigue with the low-dose CBD [82].
CBD is currently delivered per-orally (ingested), by absorption across the oral mucous
membranes or by inhalation [
83
–
87
]. Because CBD is poorly water soluble, ingestion
provides poor absorption, and most of the CBD that is absorbed undergoes first-pass
metabolism, which results in a bioavailability of only 6% [
84
,
88
]. Systemic exposure to
CBD is increased four-fold by ingestion with a high-fat meal [
86
] and five-fold with severe
hepatic impairment [
89
]. The main reason for the large increase in absorption with a
high-fat meal is that micelles are naturally formed in the small intestine by the mixing
of bile salts with fatty acids from the high-fat meal (or an oil-based CBD formulation),
and these micelles carry CBD into intestinal epithelial cells and the portal circulation [
90
].
First-pass metabolism may be bypassed by the delivery of CBD across the oral mucous
membrane; however, many CBD sublingual drops still result in high levels of first-pass
metabolites, which indicates that mucous membrane absorption is inefficient [
91
]. Oral
mucous membrane absorption could be improved by mimicking the carriage of CBD in
natural intestinal micelles, by formulating CBD in synthetic nano-micelles [
87
]. Inhaling
CBD by smoking or vaping provides the most rapid method of administration, with a time-
to-peak-plasma-concentration (T
max
)
≤
5 min and a bioavailability of 31% [
92
]; however,
J. Clin. Med. 2021,10, 5852 9 of 15
the higher peak level from inhalation is associated with increased adverse effects [
91
], and
the high temperatures involved produce toxic oxidation products [93].
The single-dose half-life of CBD is around 3 h; however, CBD accumulates in tissues,
including adipose tissues due to its lipophilicity, and after repeated doses, its half-life is
2–5 days [
84
]. CBD is also binds to proteins and blood cells and has a high apparent volume
of distribution of 32 L/kg [
88
,
92
]. Low-dose CBD administration provides serum CBD
levels in the order of 1–10 ng/mL [
83
–
85
,
87
,
91
]. CBD is mainly metabolized in the liver
by CYP3A- and CYP2C-dependent phase I metabolism to its active metabolite 7-OH-CBD,
which is then metabolized and excreted in feces and urine after phase II metabolism by
uridine 50-diphospho-glucuronosyltransferase (UGT) enzymes [84,88].
4.4. Preclinical Evidence of Efficacy
CBD attenuates the effects of experimentally induced acute and chronic stress in
animal models (rodents) by increasing both CB
1
and CB
2
signaling and by facilitating 5-
HT
1A
receptor-mediated neurotransmission. Increased CB
1
and CB
2
signaling due to FAAH
inhibition by CBD attenuated stress-associated anxiety behaviors, prevented the chronic
stress-associated decrease in hippocampal neurogenesis, and prevented the persistence of
fear [
37
,
64
]. The anxiolytic effect of CBD was not seen in unstressed animals, indicating that
CBD induced anti-stress rather than anxiolytic effects [
64
]. Moreover, dependent on CB
1
and CB2activation, CBD treatment has been shown to prevent the chronic stress-induced
decrease in total dendritic length, number of branches, spine density of neurons, and
expression of synaptic proteins in the hypothalamus and other limbic structures [
63
,
64
].
CBD has also been shown to act in 5-HT
1A
-receptor-dependent ways to reduce stress-
associated anxiety behaviors, heart rate, blood pressure, and fear expression. Again, the
anxiolytic effects were only seen after stress (acute or chronic) [37,52].
4.5. Clinical Evidence of Efficacy
The first clinical evidence that CBD reduces the stress response was from the studies
of CBD’s ability to reduce the adverse effects of THC in healthy volunteers [
94
,
95
]. THC
is known to induce stress in healthy people as demonstrated by an increase in cortisol
and transient anxiety-like behavior in people with no anxiety disorders [
13
]. Karniol
et al. reported that a single dose of CBD of 15–60 mg significantly reduced THC-induced
anxiety, and CBD doses of 30–60 mg significantly reduced THC-induced tachycardia, which
like anxiety is part of the stress response [
94
]. These results were supported by Zuardi
et al. (1982), who showed that a single CBD dose of 1 mg/kg (50–80 mg; average of
67 mg) significantly lowered THC-induced anxiety as measured by the State-Trait Anxiety
Inventory (STAI) [
95
]. In both studies, CBD alone did not change the pulse rate or anxiety
levels, indicating that its effects were stress specific [94,95].
CBD has also been shown to reduce stress-response-associated anxiety caused by
public speaking and radiological tests. Zuardi et al. (1993) exposed healthy subjects
(without any psychiatric diagnosis) to the acutely stressful situation of a simulated public
speaking test and measured the anxiety component of the stress response after treatment
with placebo, 300 mg CBD, 10 mg diazepam, or 5 mg ipsapirone (5-HT
1A
agonist). CBD
treatment significantly constrained the stress-induced increase in the STAI and Visual
Analog Mood Scale (VAMS) measures of anxiety by a similar magnitude to diazepam and
ipsapirone, without the sedation associated with diazepam. Again, the actions of CBD
were stress specific with no effect seen on anxiety measures before the stress response [
27
].
The same group confirmed these results in 2017, demonstrating that 300 mg of CBD had
comparable efficacy to 1 mg of clonazepam in lowering stress-induced anxiety and heart
rate [
28
]. This time, the healthy participants (no current or prior psychiatric disorders)
underwent a test of public speaking and stress-induced anxiety measured with the VAMS
showed that CBD had a U-shaped efficacy curve, with less efficacy reported for 100 and
900 mg doses of CBD [28]. Crippa et al. used a different stressor, single positron emission
computed tomography (SPECT) scanning, which included intravenous cannula insertion
J. Clin. Med. 2021,10, 5852 10 of 15
and tracer injection [
96
]. In healthy subjects with no current, past, or family (immediate
family) history of psychiatric disorders, 400 mg CBD (dissolved in corn oil) significantly
lowered stress-induced anxiety (as measured by VAMS) relative to placebo [
96
]; however,
this time some mental sedation from CBD was reported. The stressor, SPECT scanning, was
also used to demonstrate that the stress-associated anxiolytic action of CBD was associated
with reduced blood flow to the cortical limbic and paralimbic brain areas suggesting that
the effect of CBD involved these areas of the brain, which are known to be involved in the
stress response and its behavioral manifestation of anxiety [96].
CBD may be helpful in not only reducing acute stress-associated anxiety but also
normalizing abnormal stress responses. Appiah-Kusi et al. studied the effects of 600 mg
CBD on Trier Social Stress Test (TSST)–induced anxiety and cortisol level changes in
participants who had no history of mental health disorder; however, these participants
were judged at high risk of developing psychosis based on the Comprehensive Assessment
of At-Risk Mental States (CAARMS) questionnaire. These participants were found to have
decreased rather than increased cortisol levels in response to acute stress. CBD treatment
attenuated the abnormal cortisol response and reduced the acute stress-associated increase
in anxiety, as measured by the STAI [8].
Another behavioral manifestation of stress is fear. CB
1
signaling is important for
extinguishing fear after stress, and lack of fear extinction following stress is thought to
be a major contributor to the development of fear and anxiety disorders [
3
,
4
,
37
,
44
]. Das
et al. studied the persistence of fear and aversive memories due to electric shock in healthy
volunteers and found that 32 mg CBD was effective in enhancing fear and aversive memory
extinction [97].
Crippa et al. (2021) studied the effectiveness of 150 mg CBD twice a day on 120 health-
care workers with burnout syndrome [
98
]. Burnout syndrome is a manifestation of chronic
stress that has been described and is only defined for workplace (occupational) stress and
is not considered a mental health disorder [
99
]. Burnout syndrome is characterized by
(i) feelings of energy depletion or exhaustion; (ii) increased mental distance from one’s job
or feelings of negativism or cynicism related to one’s job; and (iii) a sense of ineffectiveness
and lack of accomplishment [
99
,
100
]. This study was not fully blinded or placebo con-
trolled for ethical reasons; however, it did show that by 14 days, CBD treatment provided
significant decreases in the emotional exhaustion from burnout syndrome and associated
symptoms of anxiety and depression and had a medium effect size for treating burnout
syndrome [98].
Although the ability to reduce anxiety caused by anxiety disorders is not necessarily
predictive of ability to treat physiological stress-induced anxiety, CBD has been studied in
people with anxiety disorders. There have been two clinical trials of CBD in social anxiety
disorder (SAD). The first study used the Simulation Public Speaking Test in individuals
diagnosed with SAD, to show that a 400–600 mg single dose of CBD significantly reduced
subjective symptoms of anxiety, cognitive impairment, and performance discomfort, rela-
tive to the placebo group [
77
,
101
]. A recent double-blind study on teenagers (18–19 years
old) with SAD and avoidant personality disorder showed that 300 mg/day CBD for four
weeks significantly decreased anxiety compared to placebo [
102
]. Low-dose CBD has been
studied in a recent clinical trial of CBD for patients with any anxiety disorder, which found
25 mg/day CBD to be effective [75].
5. Conclusions
In summary, the stress response is in need of a safe, rapid, effective treatment to pre-
vent associated morbidities and economic losses. There is substantial clinical evidence that
CBD safely and effectively constrains the stress response. There have been seven double-
blind placebo controlled clinical trials of CBD for stress [
8
,
27
,
28
,
94
–
97
] on a combined total
of 232 participants and one partially controlled study on 120 participants. All showed
that CBD was effective in significantly reducing the stress response and its manifestations
(anxiety, fear, depression, and burnout). Two clinical trials [
27
,
28
] included a comparator
J. Clin. Med. 2021,10, 5852 11 of 15
(benzodiazepines and/or 5HT
1A
agonists) arm, and both showed that the CBD effect was
non-inferior to that of the pharmaceutical drug. The clinical trial results are supported by
the common (unregulated) use of CBD by over 10% of the population, of which 1/3–2/3 use
it to relieve stress and 90% find effective, and by the established mechanism of action and
extensive preclinical evidence of the effectiveness of CBD for treating stress. Maladaptive
stress responses and the endocannabinoid system as a therapeutic target both deserve more
attention from clinicians and researchers, and CBD may be a good solution to both.
Author Contributions:
Writing—original draft preparation, J.D.H.; writing—review and editing,
L.V., M.Q., and S.H. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest:
The authors declare no conflict of interest. Medlab Clinical Ltd. (Sydney,
Australia) funded the publication costs and had no role in the design of the review; in the collection,
analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish.
Search Strategy and Selection Criteria:
References for this review were identified through searches
of PubMed for articles published from January 2000 to June 2021, by use of the terms “stress”,
“endocannabinoid”, and “cannabidiol” and through searches in the authors’ personal files. Articles
resulting from these searches and relevant references cited in those articles were reviewed.
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