ArticlePDF Available

New Perspectives on the Use of Cannabis in the Treatment of Psychiatric Disorders

Authors:

Abstract

Following the discovery of the endocannabinoid system and its potential as a therapeutic target for various pathological conditions, growing interest led researchers to investigate the role of cannabis and its derivatives for medical purposes. The compounds Δ9-tetrahydrocannabinol and cannabidiol are the most abundant phytocannabinoids found in cannabis extracts, as well as the most studied. The present review aims to provide an overview of the current evidence for their beneficial effects in treating psychiatric disorders, including schizophrenia, anxiety, and depression. Nevertheless, further investigations are required to clarify many pending issues, especially those relative to the assessment of benefits and risks when using cannabis for therapeutic purposes, thereby also helping national and federal jurisdictions to remain updated.
medicines
Review
New Perspectives on the Use of Cannabis in the
Treatment of Psychiatric Disorders
Maria Scherma 1, Paolo Masia 1, Matteo Deidda 1, Walter Fratta 1, Gianluigi Tanda 2
and Paola Fadda 1,3,4,5,*
1Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology,
University of Cagliari, 09042 Monserrato, Italy; mscherma@unica.it (M.S.); paolo.masia@unica.it (P.M.);
matteo.deidda@unica.it (M.D.); wfratta@unica.it (W.F.)
2Medication Development program, NIDA-IRP, NIH/DHHS, NIDA suite 3301, Baltimore, MD 21224, USA;
gtanda@intra.nida.nih.gov
3Centre of Excellence “Neurobiology of Dependence”, University of Cagliari, 09042 Monserrato, Italy
4CNR Institute of Neuroscience – Cagliari, National Research Council, 09042 Monserrato, Italy
5National Institute of Neuroscience (INN), University of Cagliari, 09042 Monserrato, Italy
*Correspondence: pfadda@unica.it
Received: 7 August 2018; Accepted: 30 September 2018; Published: 2 October 2018


Abstract:
Following the discovery of the endocannabinoid system and its potential as a therapeutic
target for various pathological conditions, growing interest led researchers to investigate the role of
cannabis and its derivatives for medical purposes. The compounds
9-tetrahydrocannabinol and
cannabidiol are the most abundant phytocannabinoids found in cannabis extracts, as well as the
most studied. The present review aims to provide an overview of the current evidence for their
beneficial effects in treating psychiatric disorders, including schizophrenia, anxiety, and depression.
Nevertheless, further investigations are required to clarify many pending issues, especially those
relative to the assessment of benefits and risks when using cannabis for therapeutic purposes, thereby
also helping national and federal jurisdictions to remain updated.
Keywords: phytocannabinoids; 9-tetrahydrocannabinol; cannabidiol; psychiatric disorders
1. Introduction
Evidence of the consumption of cannabis for therapeutic uses is prevalent throughout
history. The first indication of use dates back to 2700 before Christ (BC), in the world’s oldest
Chinese pharmacopeia, the Pen-ts’ao ching, which recommended cannabis for the treatment of
constipation, malaria, gout, rheumatism, and painful menstruation, among others [
1
]. Around the
year 1000 BC, the presence of cannabis was widespread throughout India, where its medical uses were
numerous, owing to its analgesic, anti-inflammatory, anticonvulsant, appetite-stimulant, tranquilizing,
and diuretic properties [
2
]. Subsequently, the plant gradually spread across the world. Cannabis use
in Western medicine dates back to the first half of the 19th century, when Irish physician William
Brooke O’Shaughnessy recommended it for a great variety of therapeutic purposes, including muscle
spasms, menstrual cramps, and rheumatism, as well as convulsions of tetanus, rabies, and epilepsy [
3
].
Moreover, French psychiatrist Jean-Jacques Moreau de Tours experimented with the therapeutic use of
cannabis in mental disorders, and described the plant as hypnotic, analgesic, and anticonvulsant [
4
].
In the second half of the 19th century, over 100 scientific articles were published regarding the
therapeutic value of the plant, and cannabis extracts were listed for sedative and anticonvulsant
effects in the British, and later United States (US), pharmacopeia [
5
]. However, the first few decades
of the 20th century were characterized by decreased attention to the medical use of cannabis due
Medicines 2018,5, 107; doi:10.3390/medicines5040107 www.mdpi.com/journal/medicines
Medicines 2018,5, 107 2 of 17
to the social impact of increased drug consumption for recreational purposes, as well as to the fact
that the effects were difficult to predict and standardize because of the variable composition of plant
extracts. In the following years, cases of the medical use of cannabis completely subsided until the first
decades of the 21st century, during which it returned to being considered for therapeutic purposes,
despite its use being highly restricted [
2
]. The cannabis plant contains a total of 483 compounds,
among which more than 120 are bioactive constituents, collectively known as phytocannabinoids [
6
].
Among them, the most important and studied are
9-tetrahydricannabinol (
9-THC) and cannabidiol
(CBD), which also represent the major constituents found in the plant. CBD was first isolated in 1940,
but it was not until 1963 that its structure was clarified [
7
,
8
]. On the other hand,
9-THC was isolated
in 1964, and was soon thereafter synthesized and found to be the primary psychoactive constituent
of cannabis [
9
,
10
]. Primarily, the pharmacological effects of cannabis were attributed to the ability
of
9-THC to alter specific membrane properties due to its high lipophilicity [
11
]. Nevertheless,
evidence of it being able to inhibit the formation of adenylate cyclase [
12
] instigated researchers to
hypothesize on the existence of a specific receptor for this compound. This receptor, named CB1
(CB1R), was cloned for the first time, in 1990, from a rat cerebral-cortex complementary DNA (cDNA)
library [
13
], and it represents the most abundant G-protein-coupled receptor in the brain [
14
]. Later
on, a second cannabinoid receptor, named CB2 (CB2R), derived from human promyelocytic leukemic
cells (HL-60 cells), was cloned [
15
]. CB2R also belongs to the family of G-protein-coupled receptors,
and it is mainly expressed in the immune system, while also being identified in some areas of the
brain [
16
]. Recent studies suggest the existence of other cannabinoid receptors, including the orphan
G-protein-coupled receptor, GPR55 [
17
]. Moreover, a growing body of evidence identified other
receptors as cannabinoid targets, including the type 1 vanilloid receptor (TRPV1) and peroxisome
proliferator-activated receptor [
18
]. The discovery of cannabinoid receptors prompted researchers
to find endogenous ligands that activate them. The first endocannabinoid to be isolated, in 1992,
was anandamide (AEA) [
19
]. Three years later, 2-arachidonoylglycerol (2-AG) became the second
endocannabinoid to be identified [
20
]. In addition to AEA and 2-AG, several other compounds with
endocannabinoid-like activity were isolated, including 2-arachidonylglyceryl ether (2-AGE, noladin),
O-arachidonylethanolamine (virodhamine), and N-arachidonyldopamine (NADA) [
21
]. Soon after,
the biochemical processes responsible for endocannabinoid synthesis and degradation were also
identified [
22
]. AEA and 2-AG are synthesized upon demand in a Ca
2+
-dependent manner after
cellular depolarization from lipid precursors, which are components of the cell membrane. AEA is
derived mainly from the cleavage of N-arachidonoylphosphatidylethanolamine (NAPE), which is
then specifically hydrolyzed by phospholipase D (NAPE-PLD); 2-AG is primarily formed from the
hydrolysis of 1,2-diacylglycerol (DAG) by the phospholipase C/diacylglycerol lipase pathway [
23
].
Once synthesized, AEA and 2-AG are immediately released by the postsynaptic terminal and
activate cannabinoid receptors (CBRs) in the presynaptic membrane, inhibiting neurotransmission
release by activating presynaptic K
+
channels and inhibiting N- and P/Q-type Ca
2+
channels [
23
].
Endocannabinoid signaling is terminated by rapid metabolic deactivation via specific enzymes after
being taken up into the cell. AEA is primarily metabolized by the intracellular enzyme, fatty-acid
amide hydrolase (FAAH), which breaks it down into free arachidonic acid. Ethanolamine, as well
as the pharmacological blockade and genetic deletion of this enzyme, not only enhances AEA levels,
but also amplifies its effects [
24
,
25
]. The compound 2-AG is metabolized into arachidonic acid and
glycerol mainly by the enzyme monoacylglycerol lipase (MAGL) [
23
]. These metabolic pathways
represent the key points in the regulation of endocannabinoid tissue levels. Altogether, these elements
are part of the endocannabinoid system representing important lipid signaling, which was recently
recognized as a modulator of a large variety of physiological processes, as well as of emotional
responses and cognitive function [
26
] (Figure 1). Abnormalities in emotion and cognitive deficits
are characteristic of several neuropsychiatric conditions; thus, a defect in endocannabinoid signaling
might play a role in the pathophysiology of these disorders [
27
,
28
]. The present review addresses
the current literature on the endocannabinoid system in the neurobiology of psychiatric disorders,
Medicines 2018,5, 107 3 of 17
specifically schizophrenia and mood disorders (anxiety and depression), and current evidence for the
beneficial effects of phytocannabinoids in treating them.
Medicines 2018, 5, x FOR PEER REVIEW 3 of 17
Figure 1. Schematic representation of the main elements of the endocannabinoid system at the
synaptic level: endocannabinoids are produced upon demand after cellular depolarization from lipid
precursors. AEA is derived mainly from NAPE by a specific phospholipase D; 2-AG is primarily
formed from the hydrolysis of DAG. Once released from postsynaptic terminal, AEA and 2-AG
activate CBRs in the presynaptic terminal, inhibiting neurotransmission release by activating
presynaptic K+ channels and inhibiting Ca2+ channels. Endocannabinoid signaling is terminated by
metabolic degradation by specific enzymes. AEA: anandamide; 2-AG: 2-arachidonoylglycerol;
FAAH: fatty acid amide hydrolase; MGL: monoacylglycerol lipase; DAG: diacylglycerol; NAPE:
N-acyl-phosphatidylethanolamine; NAPE-PLD: N-acyl-phosphatidylethanolamine phospholipase D;
CBR: cannabinoid receptor; Gi/o: G protein; Ca2+: calcium; K+: potassium.
2. Search Methods
A PubMed database search was performed using the combination of keywords: ‘‘Cannabis”,
“phytocannabinoids”, “∆9-tetrahydrocannabinol”, “cannabidiol”, “endocannabinoid system”,
‘‘psychiatric disorders”, “psychosis”, Schizophrenia”, “anxiety disorders”, and “depression”. The
search was carried out considering both human and animal studies articles. Clinical trials in healthy
subjects were also considered.
3. Therapeutic Potential of Cannabis Extracts on Psychiatric Disorders
3.1. Schizophrenia
Schizophrenia (SCZ) is a severe psychiatric disorder whose clinical features fall into three
categories: positive symptoms that include hallucinations, delusions, disorganized speech, and
catatonia; negative symptoms indicating disruption in the expression of emotions or difficulty in
beginning and sustaining activities (e.g., depression, anhedonia, and blunted affection); and
cognitive deficits in working and verbal memory, as well as in executive function and attention [29].
The more severe the negative symptoms and cognitive deficits are, the more marked the disability is
[30]. SCZ affects around 0.51% of the population worldwide and tends to be chronic, with a
substantial impact on quality of life [31]. Antipsychotic medications, which represent the main
treatment for SCZ, reduce psychotic symptoms, but are not effective in all patients: 3060% of them
are refractory to all current treatments. Moreover, these drugs cause several adverse effects [32,33].
Figure 1.
Schematic representation of the main elements of the endocannabinoid system at the synaptic
level: endocannabinoids are produced upon demand after cellular depolarization from lipid precursors.
AEA is derived mainly from NAPE by a specific phospholipase D; 2-AG is primarily formed from
the hydrolysis of DAG. Once released from postsynaptic terminal, AEA and 2-AG activate CBRs in
the presynaptic terminal, inhibiting neurotransmission release by activating presynaptic K
+
channels
and inhibiting Ca
2+
channels. Endocannabinoid signaling is terminated by metabolic degradation by
specific enzymes. AEA: anandamide; 2-AG: 2-arachidonoylglycerol; FAAH: fatty acid amide hydrolase;
MGL: monoacylglycerol lipase; DAG: diacylglycerol; NAPE: N-acyl-phosphatidylethanolamine;
NAPE-PLD: N-acyl-phosphatidylethanolamine phospholipase D; CBR: cannabinoid receptor; Gi/o: G
protein; Ca2+: calcium; K+: potassium.
2. Search Methods
A PubMed database search was performed using the combination of keywords: “Cannabis”,
“phytocannabinoids”, “
9-tetrahydrocannabinol”, “cannabidiol”, “endocannabinoid system”,
“psychiatric disorders”, “psychosis”, “Schizophrenia”, “anxiety disorders”, and “depression”.
The search was carried out considering both human and animal studies articles. Clinical trials in
healthy subjects were also considered.
3. Therapeutic Potential of Cannabis Extracts on Psychiatric Disorders
3.1. Schizophrenia
Schizophrenia (SCZ) is a severe psychiatric disorder whose clinical features fall into three
categories: positive symptoms that include hallucinations, delusions, disorganized speech,
and catatonia; negative symptoms indicating disruption in the expression of emotions or difficulty in
beginning and sustaining activities (e.g., depression, anhedonia, and blunted affection); and cognitive
deficits in working and verbal memory, as well as in executive function and attention [
29
]. The more
severe the negative symptoms and cognitive deficits are, the more marked the disability is [
30
]. SCZ
affects around 0.5–1% of the population worldwide and tends to be chronic, with a substantial impact
Medicines 2018,5, 107 4 of 17
on quality of life [
31
]. Antipsychotic medications, which represent the main treatment for SCZ, reduce
psychotic symptoms, but are not effective in all patients: 30–60% of them are refractory to all current
treatments. Moreover, these drugs cause several adverse effects [
32
,
33
]. Thus, the discovery of new
molecular targets for the development of novel medication is of critical importance. In the last few
years, a cannabinoid hypothesis of SCZ was postulated, and the pharmacological modulation of the
endocannabinoid system could be considered a potential therapeutic tool for SCZ treatment [34].
3.1.1. Human Studies
Clinical studies showed altered endocannabinoid signaling in schizophrenic patients [
35
].
For instance, elevated levels of AEA were found in the blood and cerebrospinal fluid of schizophrenic
patients that were normalized by antipsychotic treatment [
36
39
]. Furthermore, increased cerebrospinal
fluid levels of AEA seem to be negatively correlated with psychotic symptoms, and this increase may
represent a protective role against psychosis [
38
]. Altered CB1R densities in schizophrenic patients
were also reported, even though results were not entirely consistent across studies. Accordingly,
an increase [
40
42
], decrease [
43
,
44
], or even lack of alteration [
45
] in CB1R density was found in
cortical regions that are thought to be linked to SCZ, such as the dorsolateral prefrontal cortex and
the anterior cingulate cortex. Since CB1R changes were investigated using radioligand binding and
quantitative autoradiography in postmortem tissue, the variation in techniques used could account
for the discrepancies obtained in these studies. Moreover, inconsistent results may also be related
to the use of antipsychotic treatment [
46
] or cannabis consumption [
40
]. On the other hand,
in vivo
brain-imaging techniques in schizophrenic patients reported elevated CB1R binding in the pons,
nucleus accumbens, cingulate, and insular cortex [
47
49
]. Recent clinical evidence also supports a
role for CB2R. Indeed, reduced expression of CB2R was found in peripheral blood mononuclear cells
of untreated schizophrenic patients with first-episode psychosis [
50
], as well as in patients following
treatment with olanzapine [
37
]. Finally, genetic polymorphisms in the CB1R gene (CN1R) were
implicated in susceptibility to SCZ; however, other studies showed no association [5154]. Moreover,
a correlation between single-nucleotide polymorphisms in the CB2R gene (CNR2) and increased risk of
SCZ were reported [51]. In addition to an alteration of the endocannabinoid system, epidemiological
evidence suggests that cannabis use is linked to an increased risk of developing SCZ in genetically
predisposed people, as well as to precipitate psychotic symptoms in schizophrenic patients [
55
]. Early
onset of use greatly increases the risk: meta-analysis studies indicated that adolescent cannabis use
may account for 8–14% of SCZ cases [
55
,
56
]. On the other hand, the high rate of cannabis use in
several schizophrenic patients was interpreted as an attempt to self-medicate negative symptoms or to
overcome the feeling of depression and anxiety associated with these symptoms [
57
]. As mentioned
earlier,
9-THC is the main psychoactive component of cannabis, and it is the active ingredient
responsible for psychotic outcomes. Indeed, acute
9-THC administration elicits both positive
and negative symptoms, as well as cognitive deficits in healthy individuals, while also inducing
a transient exacerbation in psychotic symptoms and cognitive deficits in schizophrenic patients [
58
,
59
].
Neuroimaging studies showed that
9-THC-induced psychotic symptoms are associated with the
altered activity of several brain areas affected by SCZ, including the prefrontal cortex (PFC), anterior
cingulate cortex, amygdala, and ventral striatum [
60
,
61
]. By contrast, despite the lack of evidence
supporting
9-THC-based medical treatments for SCZ, a recent study reported that three out of six
treatment-resistant patients improved their schizophrenic symptoms following treatment with the
synthetic form of
9-THC (dronabinol) [
62
]. Unlike
9-THC, CBD represents the most abundant
non-psychoactive component of cannabis; it shows low CBR binding and partly antagonizes the
actions of
9-THC and other synthetic CB1R agonists like WIN-55212 and CP-55940 [
63
]. Moreover,
CBD inhibits AEA hydrolysis, stimulates vanilloid receptors like TRPV1, activates 5-HT1A receptors,
and also exerts partial agonist activity on dopamine D2 receptors [
64
,
65
]. Recently, CBD received
growing attention for its antipsychotic properties; thus, it could be considered a promising new agent
in the treatment of SCZ [
66
,
67
]. Firstly, in healthy subjects, CBD blocked the psychotic symptoms
Medicines 2018,5, 107 5 of 17
induced by
9-THC [
68
]. Moreover, randomized clinical trials (RCTs) evaluating the clinical efficacy
of CBD in psychosis found that it was able to improve both positive and negative symptoms in
schizophrenic patients [
32
,
69
71
]. Furthermore, the clinical efficacy of CBD was comparable with that
of amisulpride, but with fewer side effects [
72
]. Although the mechanism through which CBD exerts its
antipsychotic effects is still to be clarified, the majority of studies have focused on its ability to directly
inhibit the reuptake of AEA. In agreement, in the RCT carried out by Leweke et al. [
72
], CBD increased
AEA serum levels, and this increase was associated with a reduction in psychotic symptoms. However,
other molecular targets were proposed. The partial agonist activity on dopamine D2 receptors might,
at least in part, account for CBD’s antipsychotic effects, and other authors suggested that it might
act via 5-HT1A or TRPV1 receptors [
66
]. It is important to note that CBD is characterized by a more
favorable safety profile, with only a few minor side effects, such as tiredness, diarrhea, and changes in
appetite/weight [66].
3.1.2. Animal Studies
Consistent with clinical observations, preclinical data also showed an involvement of the
endocannabinoid system in the pathophysiology of SCZ. For example, the pharmacological blockade
of AEA degradation improved negative symptoms in both amphetamine- and phencyclidine-treated
rats [
73
,
74
]. CB1R alterations in various animal models of schizophrenia-like disorders were also
found [
28
]. Using the model of social isolation rearing, a decrease in CB1R expression was found in the
caudate putamen and amygdala of phencyclidine-treated rats, whereas an increase was observed in
the ventral tegmental area and amygdala [
75
,
76
]. Moreover, the administration of a CB2R antagonist
exacerbated the MK-801- or methamphetamine-induced disturbance of prepulse inhibition involved in
acoustic startle and hyperactivity in mice [
77
]. Preclinical studies also support the hypothesis that CBD
might have antipsychotic properties. For example, CBD attenuated the amphetamine-disruptive effects
on prepulse inhibition, as well as the hyperlocomotion induced by psychotomimetic drugs [78,79].
3.2. Anxiety Disorders
Anxiety disorders are chronic, disabling conditions, including several syndromes such as
generalized anxiety disorder (GAD), panic disorder (PD), social anxiety disorder (SAD), obsessive–
compulsive disorder (OCD), and post-traumatic stress disorder (PTSD) [
80
]. These disorders represent
the most prevalent mental illnesses in the world, with high societal costs [
81
]. Antidepressants and
benzodiazepines are the main pharmacological treatments; however, 40–60% of patients do not attain
total relief from their impairing symptoms [
82
]. Thus, there is a strong need to develop alternative
treatments. In this regard, there is increasing interest in the endocannabinoid system as an important
component of the complex circuitry involved in the control of responses to anxiety [
83
]. It is well
established that cannabis consumption affects anxiety-related behaviors in a dose-dependent manner,
with low doses being anxiolytic and high doses inducing adverse events, including increased anxiety
and panic [
84
,
85
]. Data from animal tests further support the evidence of the bidirectional effects
observed in humans: low doses of cannabinoids produced anxiolytic-like effects, while high doses
produced anxiogenic-like responses [
85
]. The mechanisms underlying the effects of endocannabinoids
on anxiety-related responses occur through CB1R, which is highly expressed in key structures within
the brain directly involved in the modulation of emotional behavior, such as the PFC, amygdala,
and hippocampus [
86
]. The involvement of CB1R was clarified using CB1-knockout mice. Under basal
conditions, untreated CB1-knockout mice exhibited an increase in basal levels of anxiety-like responses
compared to wild-type animals [
87
89
]. Moreover, CB1 deletion consistently caused anxiety under
aversive conditions [
88
,
90
]. Furthermore, the anxiolytic effects of benzodiazepines appear to be less
efficacious in CB1-knockout mice [
89
]. In contrast, Marsicano et al. (2002) found no alterations in
anxiety-related responses between mutant and wild-type animals [
91
]. Using conditional mutant mice,
the importance of the location of CB1R on specific neuronal subtypes with regards to biphasic effects
was also demonstrated. CB1R located in glutamatergic neurons accounted for the anxiolytic effects of
Medicines 2018,5, 107 6 of 17
low doses, while CB1R located in
γ
-aminobutyric acid (GABA)-ergic neurons seems to be involved in
the anxiogenic consequences of higher doses [
92
,
93
]. Experimental studies in animals showed that
exposure to stress, both acute and chronic, appears to impair endocannabinoid signaling, with reduced
AEA content in several brain regions, such as the PFC, hippocampus, and amygdala [
94
]. FAAH
genetic variation also impacts enzyme expression and activity, thereby increasing AEA levels and
attenuating anxiety-like behaviors in both mice and humans [
95
]. In agreement, the pharmacological
blockade of FAAH was shown to reduce anxiety in a variety of animal models, such as the elevated
plus maze and light–dark box test, and these effects were enhanced under aversive stimuli [
96
98
].
Altogether, these data indicate that the endocannabinoid system is clearly implicated in the modulation
of anxiety, and its dysregulation may result in anxiety disorders. Thus, pharmacological modulation
which enhances its signal was suggested as a target for the treatment of these disorders, and proposed
drugs include 9-THC and CBD, among others [99].
3.2.1. Human Studies
It is well documented that patients with anxiety disorders, as well as subjects with high levels
of anxiety, use cannabis to cope with their symptoms. For example, subjects with SAD seem to
use cannabis as a form of “self-medication” [
100
]. Among returning veterans, the most frequently
endorsed conditions for cannabis use were anxiety/stress and PTSD [101]. Moreover, several studies
reported a strong correlation between PTSD symptom severity and the level of cannabis use [
102
].
When the effects of smoked cannabis were evaluated in PTSD patients, improvements in the Quality
of Life Scale, pain scores, and the Clinician-Administered PTSD Scale (CAPS) were reported [
103
].
In agreement, Roitman et al. [
104
], in an open-label study, showed that, in patients with unremitted
PTSD, treatment with orally absorbable
9-THC had beneficial effects on global symptom severity,
sleep quality, frequency of nightmares, and PTSD hyperarousal symptoms. Importantly, a CB1R
positron-emission tomography imaging study showed increased CB1R expression in the brains of
individuals with PTSD compared to the control group [
105
]. The same authors also demonstrated
that this increase was accompanied by a significant reduction in peripheral AEA concentration.
Under other conditions, significant correlation between cannabis use and the prevalence of anxiety
disorders was well documented [
106
]. As mentioned above, the effects of cannabis on anxiety appear
to be dose-dependent, with low doses producing an anxiolytic effect and higher doses producing
anxiogenic behavior. Accordingly, in healthy subjects,
9-THC was demonstrated to decrease and
increase anxiety levels at low and higher doses, respectively [
84
]. Moreover, neuroimaging studies
showed that, at specific doses,
9-THC could both increase and decrease negative emotional processing
in healthy volunteers [
107
,
108
]. Unlike
9-THC, CBD showed anxiolytic effects in humans without
inducing anxiogenic effects at high doses at baseline [
109
]. When co-administered with
9-THC, CBD
was able to attenuate the anxiogenic effect of high doses of
9-THC [
68
,
110
]. Moreover, CBD was able
to reduce post-stress anxiety in healthy subjects submitted to simulated public speaking (SPS), and this
effect was comparable with that of isapirone, a selective 5-HT1A-receptor partial agonist [
111
]. Using
the same procedure, CBD was also able to reduce an increase in anxiety induced by SPS on subjects with
SAD [
112
]. Neuroimaging studies showed that the anxiolytic effect of CBD was related to functional
changes in brain areas involved in the control of emotional processes. In healthy volunteers, as well as
in patients with SAD, CBD induced a significant decrease in anxiety, as determined by single-photon
emission computed tomography (SPECT), acting predominantly in limbic and paralimbic cortical
areas (amygdala and the hippocampus, as well as the hypothalamus, the left posterior cingulate
gyrus, and the left parahippocampal gyrus), which are usually implicated in the pathophysiology of
anxiety [
113
,
114
]. Finally, CBD enhanced the extinction of fear memories in healthy subjects, acting at
the amygdala and the anterior and posterior cingulate cortex [107].
Medicines 2018,5, 107 7 of 17
3.2.2. Animal Studies
In agreement with the results obtained in clinical studies, preclinical evidence also showed the
anxiolytic effects of CBD in several animal models of anxiety [
109
]. For example, in the elevated
plus maze, CBD showed anxiolytic-like effects similar to diazepam in both rats and mice [
115
,
116
].
In the Vogel test, CBD also induced an anticonflict effect in rats, reducing the suppression of punished
responses [
117
]. The use of these animal models also allowed the determination of the brain areas
and the receptors involved in these effects. Indeed, anxiolytic effects were also found when CBD
was microinjected into specific brain regions relevant to anxiety, including the central nucleus of the
amygdala, the bed nucleus of the stria terminalis, and the dorsal periaqueductal gray [
109
]. Moreover,
activation of the 5-HT1A receptor seems to mediate these effects, as they were attenuated by local
treatment with the 5-HT1A-receptor antagonist, WAY100635 [118].
3.3. Depression
Depression is one of the most debilitating psychiatric disorders, affecting 20% of the population,
characterized by sadness, emptiness, loss of interest or pleasure in everyday activities (anhedonia),
impaired concentration or decision-making, psychomotor agitation or retardation, and insomnia
or hypersomnia [
119
]. Antidepressants represent the first-line treatment prescribed for depression;
however, not all patients achieve full remission, and many are unresponsive [
120
]. Consequently,
depression tends to be chronic with high rates of recurrence and relapse [
121
]. In recent years, both
clinical and preclinical evidence led to the hypothesis of a link between defects in the endocannabinoid
system and depression [122].
3.3.1. Human Studies
A reduction in serum content of the endocannabinoid 2-AG was found in females diagnosed
with major depression, while serum AEA content was not significantly altered [
123
,
124
]. Moreover,
the magnitude of 2-AG reduction strictly correlated with the duration of the depressive episode.
On the other hand, the same authors also showed that exposure to an acute social stressor evoked
a significant increase in serum 2-AG content in both females diagnosed with major depression and
healthy matched controls [
124
]. In human postmortem studies, CB1R density and functionality, as well
as CB1 messenger RNA (mRNA) levels, were found elevated in the dorsolateral prefrontal cortex of
depressed suicides [
125
,
126
]. On the contrary, Eggan et al. [
44
] did not find alterations in CB1R mRNA
and protein levels in the dorsal prefrontal cortex in subjects with major depression. Furthermore,
the expression of CB1R in the anterior cingulate cortex was found to be reduced in depressed patients
treated with serotonin selective reuptake inhibitors [
45
]. Genetic studies demonstrated a link between
polymorphisms in the CNR1 gene and increased vulnerability to developing a depressive episode
following exposure to life stress [
127
], as well as increased risk of antidepressant resistance [
128
]. Both
CNR1 and FAAH gene polymorphisms might also contribute to susceptibility to bipolar disorder and
major depression [
129
]. Finally, genetic variability in the CNR1 gene seems to be involved in the
etiology of major depression and in the clinical response to the selective serotonin reuptake inhibitor
citalopram [
130
]. The evidence hereinbefore emphasizes that deficient endocannabinoid signaling
may be implicated in the pathophysiology of depression; therefore, activation of the endocannabinoid
system could represent a new pharmacological approach to treating patients. Anecdotal reports suggest
that some individuals use cannabis to effectively treat depressive and manic symptoms
[131133]
.
For example, Gruber et al. [
134
] described five cases in which patients reported that cannabis
relieved their depressive symptoms, and that they deliberately used it for this purpose. Moreover,
a cross-sectional study showed that those who consume cannabis occasionally or even daily have lower
levels of depressive symptoms than those who have never tried cannabis [
134
].
Babson et al. [135]
reported that individuals with heightened depression symptoms had more severe problematic cannabis
use because of the beneficial effects of cannabis on perceived sleep quality. Finally, in a recent systematic
Medicines 2018,5, 107 8 of 17
review, the authors identified seven cross-sectional studies in which there was clear evidence of an
amelioration of depressed mood through the use of cannabis for medical purposes [
136
]. In bipolar
disorder, it was found that some patients used cannabis to treat mania, depression, or both [
131
].
They also stated that it was more effective than conventional drugs, or helped relieve the side effects
of those drugs. In agreement, an observational study showed that smoking cannabis acts to alleviate
mood-related symptoms in at least a subset of bipolar patients [
137
]. Furthermore, two studies
showed that cannabis use might be related to improved neurocognition in bipolar disorder [
138
,
139
].
On the other hand, a recent meta-analysis, including several longitudinal studies reporting on the
association between cannabis and depression, concluded that cannabis use, particularly heavy use,
may be associated with an increased risk of developing a depressive disorder [
140
]. Moreover, women
with depressive disorders who used cannabis regularly reported poorer mental-health-related quality
of life [
141
]. Cannabis use might also worsen the occurrence of manic symptoms in those diagnosed
with bipolar disorder, and might also be associated with an increased risk of onset of new manic
symptoms [142].
3.3.2. Animal Studies
Modifications of CB1R and other elements belonging to the endocannabinoid system were
also reported in animal models of depression [
143
]. For example, exposure to chronic mild
stress reduced 2-AG brain tissue concentration in the hippocampus [
144
], but increased it in the
hypothalamus, midbrain [
145
], and thalamus [
146
], whereas AEA content decreased throughout the
brain [
145
] or showed no changes [
146
]. Moreover, exposure to chronic mild stress increased CB1R
density in the prefrontal cortex and decreased CB1R density in the hippocampus, hypothalamus,
and ventral striatum [
145
]. Treatment with the antidepressants tranylcypromine and fluoxetine
increased CB1R-binding density in the PFC and hippocampus, and tranylcypromine also reduced the
tissue content of AEA in the PFC, hippocampus, and hypothalamus, while increasing 2-AG content in
the PFC [
147
]. Nevertheless, the potential antidepressant action of its major constituents,
9-THC and
CBD, was demonstrated in several animal models of behavioral despair, such as the forced-swimming
test or the tail-suspension test [
148
,
149
]. Antidepressant effects were also evident when CBD was
injected in a specific brain area with a key role in emotion, such as the PFC [
150
]. Genetic deletion of
CB1R in mice led to the development of a phenotype characterized by depressive-like and anxiety-like
behaviors, as well as by an anhedonic state and cognitive deficits [143].
4. Conclusions
Despite the growing knowledge base of neuropsychiatric disorder neurobiology, a high percentage
of patients do not respond to first-line therapeutic interventions. Therefore, there is clearly a need
for new, more effective treatments. The endocannabinoid system plays a key role in emotional
responses and cognition function, and both clinical and preclinical studies suggest that dysregulation
of its neuronal signaling may be involved in the pathophysiology of these disorders [
27
,
28
]. Thus,
therapeutic strategies based on drugs that modulate endocannabinoid signaling may be useful in
the treatment of neuropsychiatric disorders. Cannabis has been used for millennia for therapeutic
purposes, and there are several anecdotal reports of its use as a form of self-medication for the
alleviation of neuropsychiatric symptoms (e.g., anxiety, depression, and mania) [
85
,
132
]. On the other
hand, epidemiological studies have consistently demonstrated that heavy cannabis use could be
associated with the occurrence of psychiatric outcomes, especially in people at risk for psychosis or
with mood disorders [
59
,
140
]. Thus, evidence supporting the use of cannabis for the treatment of
neuropsychiatric disorders is equivocal, which is mainly due to the use of the whole plant. As we
know, cannabis contains various phytocannabinoids, among which
9-THC and CBD are the major
constituents. As already mentioned,
9-THC is the main psychoactive component of cannabis, and it
is the active ingredient responsible for both psychotic or affective mental health outcomes [
59
,
107
].
In contrast, CBD represents the non-psychoactive component of the plant and has been found to
Medicines 2018,5, 107 9 of 17
have antipsychotic properties and to be anxiolytic [
67
,
111
,
149
]. The ratio of these two compounds in
smoked cannabis varies, and accordingly, the effects on mental health also vary. For example, the use
of cannabis containing high
9-THC and low CBD concentrations was associated with a higher risk of
a first psychotic episode [
151
]. On the contrary, using cannabis with a high CBD content was associated
with significantly lower degrees of psychotic symptoms [
152
]. In agreement, in healthy volunteers
who smoked cannabis, it was demonstrated that individuals with hair traces of
9-THC only had
higher levels of positive schizophrenia-like symptoms than those with hair traces of both
9-THC and
CBD [
153
]. When RCTs investigated the effects of
9-THC and CBD separately in the management
of psychiatric patients, preliminary results suggested that CBD may have potential efficacy in the
treatment of psychotic and anxiety disorders [
70
,
109
]. Indeed, pretreatment of CBD significantly
improves psychotic symptoms in schizophrenic patients and decreases anxiety in patients diagnosed
with generalized SAD [
71
,
72
,
112
]. Also, CBD was well tolerated with only a few minor side effects [
66
].
Although the studies reviewed here provide clear evidence of the beneficial effects of CBD in the
treatment of psychiatric disorders, RCTs with a small sample size and short duration limit its potential
clinical utility. Moreover, in some cases, CBD was evaluated as an adjunct to traditional treatments [
71
].
Thus, further and larger RCTs will be necessary to confirm the efficacy and safety of CBD, as well as
basic research to understand its potential mechanism of action.
Author Contributions:
M.S. and P.F. conceived the study; P.M. and M.D. formally analyzed and investigated the
literature; P.M. and M.D. first drafted the manuscript; M.S., G.T., W.F. and P.F. reviewed and edited the manuscript.
Funding:
This work was supported in part by funds from the Department of Biomedical Sciences Project
(RICDIP_2012_Fratta_01), University of Cagliari, and in part by Medication Development Program funds, National
Institute on Drug Abuse - Intramural Research Program, National Institutes of Health, Department of Health and
Human Services, to G.T. (ZIA DA000569).
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
Iversen, L.L. The Science of Marijuana, 2nd ed.; Oxford University Press: Oxford, UK, 2007;
ISBN 978-0-19-532824-0.
2.
Zuardi, A.W. History of cannabis as a medicine: A review. Rev. Bras. Psiquiatr.
2006
,28, 153–157. [CrossRef]
[PubMed]
3. O’Shaughnessy, W.B. New Remedy for Tetanus and Other Convulsive Disorders. Boston Med. Surg. J. 1840,
23, 153–155. [CrossRef]
4.
Moreau, J.-J. Du Hachisch et de L’Aliénationmentale, Étudespsychologiques, Par J. Moreau de Tours; Fortin, Masson
et Cie: Paris, France, 1845.
5.
Grinspoon. Marihuana Reconsidered, 2nd ed.; Quick American Archives: Oakland, CA, USA, 1994;
ISBN 978-0-932551-13-9.
6.
Brenneisen, R. Chemistry and Analysis of Phytocannabinoids and Other Cannabis Constituents. In Marijuana
and the Cannabinoids; ElSohly, M.A., Ed.; Humana Press: Totowa, NJ, USA, 2007; pp. 17–49, ISBN
978-1-58829-456-2.
7.
Adams, R.; Hunt, M.; Clark, J.H. Structure of cannabidiol, a product isolated from the marihuana extract of
Minnesota wild hemp. I. J. Am. Chem. Soc. 1940,62, 196–200. [CrossRef]
8.
Mechoulam, R.; Shvo, Y. Hashish—I: The structure of cannabidiol. Tetrahedron
1963
,19, 2073–2078. [CrossRef]
9.
Gaoni, Y.; Mechoulam, R. Isolation, structure, and partial synthesis of an active constituent of hashish. J. Am.
Chem. Soc. 1964,86, 1646–1647. [CrossRef]
10.
Mechoulam, R.; Braun, P.; Gaoni, Y. A stereospecific synthesis of (-)-delta 1- and (-)-delta 1(6)-
tetrahydrocannabinols. J. Am. Chem. Soc. 1967,89, 4552–4554. [CrossRef] [PubMed]
11.
Leuschner, J.T.; Wing, D.R.; Harvey, D.J.; Brent, G.A.; Dempsey, C.E.; Watts, A.; Paton, W.D. The partitioning
of delta 1-tetrahydrocannabinol into erythrocyte membranes
in vivo
and its effect on membrane fluidity.
Experientia 1984,40, 866–868. [CrossRef] [PubMed]
12.
Howlett, A.C.; Scott, D.K.; Wilken, G.H. Regulation of adenylate cyclase by cannabinoid drugs. Insights
based on thermodynamic studies. Biochem. Pharmacol. 1989,38, 3297–3304. [CrossRef]
Medicines 2018,5, 107 10 of 17
13.
Matsuda, L.A.; Lolait, S.J.; Brownstein, M.J.; Young, A.C.; Bonner, T.I. Structure of a cannabinoid receptor
and functional expression of the cloned cDNA. Nature 1990,346, 561–564. [CrossRef] [PubMed]
14.
Mackie, K. Distribution of cannabinoid receptors in the central and peripheral nervous system. Handb. Exp.
Pharmacol. 2005,168, 299–325.
15.
Munro, S.; Thomas, K.L.; Abu-Shaar, M. Molecular characterization of a peripheral receptor for cannabinoids.
Nature 1993,365, 61–65. [CrossRef] [PubMed]
16.
Howlett, A.C. The cannabinoid receptors. Prostaglandins Other Lipid Mediat.
2002
,68–69, 619–631. [CrossRef]
17.
Ryberg, E.; Larsson, N.; Sjögren, S.; Hjorth, S.; Hermansson, N.-O.; Leonova, J.; Elebring, T.; Nilsson, K.;
Drmota, T.; Greasley, P.J. The orphan receptor GPR55 is a novel cannabinoid receptor. Br. J. Pharmacol.
2007
,
152, 1092–1101. [CrossRef] [PubMed]
18.
Pertwee, R.G. Receptors and channels targeted by synthetic cannabinoid receptor agonists and antagonists.
Curr. Med. Chem. 2010,17, 1360–1381. [CrossRef] [PubMed]
19.
Devane, W.A.; Hanus, L.; Breuer, A.; Pertwee, R.G.; Stevenson, L.A.; Griffin, G.; Gibson, D.; Mandelbaum, A.;
Etinger, A.; Mechoulam, R. Isolation and structure of a brain constituent that binds to the cannabinoid
receptor. Science 1992,258, 1946–1949. [CrossRef] [PubMed]
20.
Sugiura, T.; Kondo, S.; Sukagawa, A.; Nakane, S.; Shinoda, A.; Itoh, K.; Yamashita, A.; Waku, K.
2-Arachidonoylglycerol: A possible endogenous cannabinoid receptor ligand in brain. Biochem. Biophys.
Res. Commun. 1995,215, 89–97. [CrossRef] [PubMed]
21.
Marzo, V.D.; Petrocellis, L.D. Why do cannabinoid receptors have more than one endogenous ligand?
Phil. Trans. R. Soc. B 2012,367, 3216–3228. [CrossRef] [PubMed]
22.
Mechoulam, R.; Hanuš, L.O.; Pertwee, R.; Howlett, A.C. Early phytocannabinoid chemistry to
endocannabinoids and beyond. Nat. Rev. Neurosci. 2014,15, 757–764. [CrossRef] [PubMed]
23.
Piomelli, D. The molecular logic of endocannabinoid signalling. Nat. Rev. Neurosci.
2003
,4, 873–884.
[CrossRef] [PubMed]
24.
Cravatt, B.F.; Demarest, K.; Patricelli, M.P.; Bracey, M.H.; Giang, D.K.; Martin, B.R.; Lichtman, A.H.
Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid
amide hydrolase. Proc. Natl. Acad. Sci. USA 2001,98, 9371–9376. [CrossRef] [PubMed]
25.
Fegley, D.; Gaetani, S.; Duranti, A.; Tontini, A.; Mor, M.; Tarzia, G.; Piomelli, D. Characterization of the fatty
acid amide hydrolase inhibitor cyclohexyl carbamic acid 3
0
-carbamoyl-biphenyl-3-yl ester (URB597): Effects
on anandamide and oleoylethanolamide deactivation. J. Pharmacol. Exp. Ther.
2005
,313, 352–358. [CrossRef]
[PubMed]
26.
Katona, I.; Freund, T.F. Multiple functions of endocannabinoid signaling in the brain. Annu. Rev. Neurosci.
2012,35, 529–558. [CrossRef] [PubMed]
27.
Fernández-Ruiz, J.; Hernández, M.; Ramos, J.A. Cannabinoid-dopamine interaction in the pathophysiology
and treatment of CNS disorders. CNS Neurosci. Ther. 2010,16, e72–e91. [CrossRef] [PubMed]
28.
Rubino, T.; Zamberletti, E.; Parolaro, D. Endocannabinoids and mental disorders. Handb. Exp. Pharmacol.
2015,231, 261–283. [CrossRef] [PubMed]
29.
Diagnostic and Statistical Manual of Mental Disorders (DSM–5). Available online: https://www.psychiatry.
org/psychiatrists/practice/dsm (accessed on 30 July 2018).
30.
Harvey, P.D.; Koren, D.; Reichenberg, A.; Bowie, C.R. Negative symptoms and cognitive deficits: What is the
nature of their relationship? Schizophr. Bull. 2006,32, 250–258. [CrossRef] [PubMed]
31.
McGrath, J.; Saha, S.; Chant, D.; Welham, J. Schizophrenia: A concise overview of incidence, prevalence, and
mortality. Epidemiol. Rev. 2008,30, 67–76. [CrossRef] [PubMed]
32.
Leweke, F.M.; Odorfer, T.M.; Bumb, J.M. Medical needs in the treatment of psychotic disorders.
Handb. Exp. Pharmacol. 2012,212, 165–185. [CrossRef]
33.
Patel, K.R.; Cherian, J.; Gohil, K.; Atkinson, D. Schizophrenia: Overview and treatment options. Pharm. Ther.
2014,39, 638–645.
34.
Müller-Vahl, K.R.; Emrich, H.M. Cannabis and schizophrenia: Towards a cannabinoid hypothesis of
schizophrenia. Expert Rev. Neurother. 2008,8, 1037–1048. [CrossRef] [PubMed]
35.
Ferretjans, R.; Moreira, F.A.; Teixeira, A.L.; Salgado, J.V. The endocannabinoid system and its role in
schizophrenia: A systematic review of the literature. Rev. Bras. Psiquiatr.
2012
,34 (Suppl. 2), S163–S177.
[CrossRef] [PubMed]
Medicines 2018,5, 107 11 of 17
36.
Leweke, F.M.; Giuffrida, A.; Wurster, U.; Emrich, H.M.; Piomelli, D. Elevated endogenous cannabinoids in
schizophrenia. Neuroreport 1999,10, 1665–1669. [CrossRef] [PubMed]
37.
De Marchi, N.; De Petrocellis, L.; Orlando, P.; Daniele, F.; Fezza, F.; Di Marzo, V. Endocannabinoid signalling
in the blood of patients with schizophrenia. Lipids Health Dis. 2003,2, 5. [CrossRef] [PubMed]
38.
Giuffrida, A.; Leweke, F.M.; Gerth, C.W.; Schreiber, D.; Koethe, D.; Faulhaber, J.; Klosterkötter, J.; Piomelli, D.
Cerebrospinal anandamide levels are elevated in acute schizophrenia and are inversely correlated with
psychotic symptoms. Neuropsychopharmacology 2004,29, 2108–2114. [CrossRef] [PubMed]
39.
Leweke, F.M.; Giuffrida, A.; Koethe, D.; Schreiber, D.; Nolden, B.M.; Kranaster, L.; Neatby, M.A.;
Schneider, M.; Gerth, C.W.; Hellmich, M.; et al. Anandamide levels in cerebrospinal fluid of first-episode
schizophrenic patients: Impact of cannabis use. Schizophr. Res. 2007,94, 29–36. [CrossRef] [PubMed]
40.
Dean, B.; Sundram, S.; Bradbury, R.; Scarr, E.; Copolov, D. Studies on [3H]CP-55940 binding in the human
central nervous system: Regional specific changes in density of cannabinoid-1 receptors associated with
schizophrenia and cannabis use. Neuroscience 2001,103, 9–15. [CrossRef]
41.
Newell, K.A.; Deng, C.; Huang, X.-F. Increased cannabinoid receptor density in the posterior cingulate cortex
in schizophrenia. Exp. Brain Res. 2006,172, 556–560. [CrossRef] [PubMed]
42.
Zavitsanou, K.; Garrick, T.; Huang, X.F. Selective antagonist [3H]SR141716A binding to cannabinoid
CB1 receptors is increased in the anterior cingulate cortex in schizophrenia. Prog. Neuropsychopharmacol.
Biol. Psychiatry 2004,28, 355–360. [CrossRef] [PubMed]
43.
Eggan, S.M.; Hashimoto, T.; Lewis, D.A. Reduced cortical cannabinoid 1 receptor messenger RNA and
protein expression in schizophrenia. Arch. Gen. Psychiatry 2008,65, 772–784. [CrossRef] [PubMed]
44.
Eggan, S.M.; Stoyak, S.R.; Verrico, C.D.; Lewis, D.A. Cannabinoid CB1 receptor immunoreactivity in the
prefrontal cortex: Comparison of schizophrenia and major depressive disorder. Neuropsychopharmacology
2010,35, 2060–2071. [CrossRef] [PubMed]
45.
Koethe, D.; Llenos, I.C.; Dulay, J.R.; Hoyer, C.; Torrey, E.F.; Leweke, F.M.; Weis, S. Expression of CB1
cannabinoid receptor in the anterior cingulate cortex in schizophrenia, bipolar disorder, and major depression.
J. Neural Transm. 2007,114, 1055–1063. [CrossRef] [PubMed]
46.
Urigüen, L.; García-Fuster, M.J.; Callado, L.F.; Morentin, B.; La Harpe, R.; Casadó, V.; Lluis, C.; Franco, R.;
García-Sevilla, J.A.; Meana, J.J. Immunodensity and mRNA expression of A2A adenosine, D2 dopamine,
and CB1 cannabinoid receptors in postmortem frontal cortex of subjects with schizophrenia: Effect of
antipsychotic treatment. Psychopharmacology 2009,206, 313–324. [CrossRef] [PubMed]
47.
Ceccarini, J.; De Hert, M.; Van Winkel, R.; Peuskens, J.; Bormans, G.; Kranaster, L.; Enning, F.; Koethe, D.;
Leweke, F.M.; Van Laere, K. Increased ventral striatal CB1 receptor binding is related to negative symptoms
in drug-free patients with schizophrenia. NeuroImage 2013,79, 304–312. [CrossRef] [PubMed]
48.
Wong, D.F.; Kuwabara, H.; Horti, A.G.; Raymont, V.; Brasic, J.; Guevara, M.; Ye, W.; Dannals, R.F.; Ravert, H.T.;
Nandi, A.; et al. Quantification of cerebral cannabinoid receptors subtype 1 (CB1) in healthy subjects and
schizophrenia by the novel PET radioligand [
11
C]OMAR. NeuroImage
2010
,52, 1505–1513. [CrossRef]
[PubMed]
49.
Horti, A.G.; Fan, H.; Kuwabara, H.; Hilton, J.; Ravert, H.T.; Holt, D.P.; Alexander, M.; Kumar, A.; Rahmim, A.;
Scheffel, U.; et al.
11
C-JHU75528: A radiotracer for PET imaging of CB1 cannabinoid receptors. J. Nucl. Med.
Off. Publ. Soc. Nucl. Med. 2006,47, 1689–1696.
50.
Bioque, M.; García-Bueno, B.; MacDowell, K.S.; Meseguer, A.; Saiz, P.A.; Parellada, M.; Gonzalez-Pinto, A.;
Rodriguez-Jimenez, R.; Lobo, A.; Leza, J.C.; et al. Peripheral endocannabinoid system dysregulation in
first-episode psychosis. Neuropsychopharmacology 2013,38, 2568–2577. [CrossRef] [PubMed]
51.
Ujike, H.; Morita, Y. New perspectives in the studies on endocannabinoid and cannabis: Cannabinoid
receptors and schizophrenia. J. Pharmacol. Sci. 2004,96, 376–381. [CrossRef] [PubMed]
52.
Chavarría-Siles, I.; Contreras-Rojas, J.; Hare, E.; Walss-Bass, C.; Quezada, P.; Dassori, A.; Contreras, S.;
Medina, R.; Ramírez, M.; Salazar, R.; et al. Cannabinoid receptor 1 gene (CNR1) and susceptibility to a
quantitative phenotype for hebephrenic schizophrenia. Am. J. Med. Genet. Part B
2008
,147B, 279–284.
[CrossRef] [PubMed]
53.
Tsai, S.J.; Wang, Y.C.; Hong, C.J. Association study of a cannabinoid receptor gene (CNR1) polymorphism
and schizophrenia. Psychiatr. Genet. 2000,10, 149–151. [CrossRef] [PubMed]
54.
Seifert, J.; Ossege, S.; Emrich, H.M.; Schneider, U.; Stuhrmann, M. No association of CNR1 gene variations
with susceptibility to schizophrenia. Neurosci. Lett. 2007,426, 29–33. [CrossRef] [PubMed]
Medicines 2018,5, 107 12 of 17
55. Moore, T.H.M.; Zammit, S.; Lingford-Hughes, A.; Barnes, T.R.E.; Jones, P.B.; Burke, M.; Lewis, G. Cannabis
use and risk of psychotic or affective mental health outcomes: A systematic review. Lancet Lond. Engl.
2007
,
370, 319–328. [CrossRef]
56.
Jiang, S.; Fu, Y.; Williams, J.; Wood, J.; Pandarinathan, L.; Avraham, S.; Makriyannis, A.; Avraham, S.;
Avraham, H.K. Expression and function of cannabinoid receptors CB1 and CB2 and their cognate cannabinoid
ligands in murine embryonic stem cells. PLoS ONE 2007,2, e641. [CrossRef] [PubMed]
57.
Potvin, S.; Joyal, C.C.; Pelletier, J.; Stip, E. Contradictory cognitive capacities among substance-abusing
patients with schizophrenia: A meta-analysis. Schizophr. Res. 2008,100, 242–251. [CrossRef] [PubMed]
58. D’Souza, D.C.; Perry, E.; MacDougall, L.; Ammerman, Y.; Cooper, T.; Wu, Y.-T.; Braley, G.; Gueorguieva, R.;
Krystal, J.H. The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals:
Implications for psychosis. Neuropsychopharmacology 2004,29, 1558–1572. [CrossRef] [PubMed]
59.
D’Souza, D.C.; Abi-Saab, W.M.; Madonick, S.; Forselius-Bielen, K.; Doersch, A.; Braley, G.; Gueorguieva, R.;
Cooper, T.B.; Krystal, J.H. Delta-9-tetrahydrocannabinol effects in schizophrenia: Implications for cognition,
psychosis, and addiction. Biol. Psychiatry 2005,57, 594–608. [CrossRef] [PubMed]
60.
Bossong, M.G.; Jager, G.; Bhattacharyya, S.; Allen, P. Acute and non-acute effects of cannabis on human
memory function: A critical review of neuroimaging studies. Curr. Pharm. Des.
2014
,20, 2114–2125.
[CrossRef] [PubMed]
61.
Murray, R.M.; Englund, A.; Abi-Dargham, A.; Lewis, D.A.; Di Forti, M.; Davies, C.; Sherif, M.; McGuire, P.;
D’Souza, D.C. Cannabis-associated psychosis: Neural substrate and clinical impact. Neuropharmacology
2017
,
124, 89–104. [CrossRef] [PubMed]
62.
Schwarcz, G.; Karajgi, B.; McCarthy, R. Synthetic delta-9-tetrahydrocannabinol (dronabinol) can improve the
symptoms of schizophrenia. J. Clin. Psychopharmacol. 2009,29, 255–258. [CrossRef] [PubMed]
63.
Pertwee, R.G.; Ross, R.A.; Craib, S.J.; Thomas, A. (
)-Cannabidiol antagonizes cannabinoid receptor agonists
and noradrenaline in the mouse vas deferens. Eur. J. Pharmacol. 2002,456, 99–106. [CrossRef]
64.
Bisogno, T.; Hanus, L.; De Petrocellis, L.; Tchilibon, S.; Ponde, D.E.; Brandi, I.; Moriello, A.S.; Davis, J.B.;
Mechoulam, R.; Di Marzo, V. Molecular targets for cannabidiol and its synthetic analogues: Effect on
vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br. J. Pharmacol.
2001,134, 845–852. [CrossRef] [PubMed]
65.
Seeman, P. Cannabidiol is a partial agonist at dopamine D2High receptors, predicting its antipsychotic
clinical dose. Transl. Psychiatry 2016,6, e920. [CrossRef] [PubMed]
66.
Hahn, B. The potential of cannabidiol treatment for cannabis users with recent-onset psychosis. Schizophr. Bull.
2018,44, 46–53. [CrossRef] [PubMed]
67.
Mandolini, G.M.; Lazzaretti, M.; Pigoni, A.; Oldani, L.; Delvecchio, G.; Brambilla, P. Pharmacological
properties of cannabidiol in the treatment of psychiatric disorders: A critical overview. Epidemiol. Psychiatr.
Sci. 2018,27, 327–335. [CrossRef] [PubMed]
68.
Bhattacharyya, S.; Morrison, P.D.; Fusar-Poli, P.; Martin-Santos, R.; Borgwardt, S.; Winton-Brown, T.;
Nosarti, C.; O’ Carroll, C.M.; Seal, M.; Allen, P.; et al. Opposite effects of delta-9-tetrahydrocannabinol and
cannabidiol on human brain function and psychopathology. Neuropsychopharmacology
2010
,35, 764–774.
[CrossRef] [PubMed]
69.
Zuardi, A.W.; Morais, S.L.; Guimarães, F.S.; Mechoulam, R. Antipsychotic effect of cannabidiol.
J. Clin. Psychiatry 1995,56, 485–486. [PubMed]
70.
Zuardi, A.W.; Crippa, J.A.S.; Hallak, J.E.C.; Moreira, F.A.; Guimarães, F.S. Cannabidiol, a Cannabis sativa
constituent, as an antipsychotic drug. Braz. J. Med. Biol. Res. Rev. 2006,39, 421–429. [CrossRef]
71.
McGuire, P.; Robson, P.; Cubala, W.J.; Vasile, D.; Morrison, P.D.; Barron, R.; Taylor, A.; Wright, S. Cannabidiol
(CBD) as an adjunctive therapy in schizophrenia: A multicenter randomized controlled trial. Am. J. Psychiatry
2018,175, 225–231. [CrossRef] [PubMed]
72.
Leweke, F.M.; Piomelli, D.; Pahlisch, F.; Muhl, D.; Gerth, C.W.; Hoyer, C.; Klosterkötter, J.; Hellmich, M.;
Koethe, D. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia.
Transl. Psychiatry 2012,2, e94. [CrossRef] [PubMed]
73.
Beltramo, M.; de Fonseca, F.R.; Navarro, M.; Calignano, A.; Gorriti, M.A.; Grammatikopoulos, G.; Sadile, A.G.;
Giuffrida, A.; Piomelli, D. Reversal of dopamine D2 receptor responses by an anandamide transport inhibitor.
J. Neurosci. Off. J. Soc. Neurosci. 2000,20, 3401–3407. [CrossRef]
Medicines 2018,5, 107 13 of 17
74.
Seillier, A.; Advani, T.; Cassano, T.; Hensler, J.G.; Giuffrida, A. Inhibition of fatty-acid amide hydrolase and
CB1 receptor antagonism differentially affect behavioural responses in normal and PCP-treated rats. Int. J.
Neuropsychopharmacol. 2010,13, 373–386. [CrossRef] [PubMed]
75.
Malone, D.T.; Kearn, C.S.; Chongue, L.; Mackie, K.; Taylor, D.A. Effect of social isolation on CB1 and D2
receptor and fatty acid amide hydrolase expression in rats. Neuroscience
2008
,152, 265–272. [CrossRef]
[PubMed]
76.
Vigano, D.; Guidali, C.; Petrosino, S.; Realini, N.; Rubino, T.; Di Marzo, V.; Parolaro, D. Involvement of
the endocannabinoid system in phencyclidine-induced cognitive deficits modelling schizophrenia. Int. J.
Neuropsychopharmacol. 2009,12, 599–614. [CrossRef] [PubMed]
77.
Ishiguro, H.; Horiuchi, Y.; Ishikawa, M.; Koga, M.; Imai, K.; Suzuki, Y.; Morikawa, M.; Inada, T.; Watanabe, Y.;
Takahashi, M.; et al. Brain cannabinoid CB2 receptor in schizophrenia. Biol. Psychiatry
2010
,67, 974–982.
[CrossRef] [PubMed]
78.
Pedrazzi, J.F.C.; Issy, A.C.; Gomes, F.V.; Guimarães, F.S.; Del-Bel, E.A. Cannabidiol effects in the prepulse
inhibition disruption induced by amphetamine. Psychopharmacology
2015
,232, 3057–3065. [CrossRef]
[PubMed]
79.
Moreira, F.A.; Guimarães, F.S. Cannabidiol inhibits the hyperlocomotion induced by psychotomimetic drugs
in mice. Eur. J. Pharmacol. 2005,512, 199–205. [CrossRef] [PubMed]
80. Craske, M.G.; Stein, M.B. Anxiety. Lancet 2016,388, 3048–3059. [CrossRef]
81.
Kessler, R.C.; Ruscio, A.M.; Shear, K.; Wittchen, H.-U. Epidemiology of anxiety disorders. Curr. Top.
Behav. Neurosci. 2010,2, 21–35. [PubMed]
82.
Bandelow, B.; Zohar, J.; Hollander, E.; Kasper, S.; Möller, H.-J.; WFSBP Task Force on Treatment Guidelines for
Anxiety Obsessive-Compulsive Post-Traumatic Stress Disoders. World Federation of Societies of Biological
Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and
post-traumatic stress disorders—First revision. World J. Biol. Psychiatry
2008
,9, 248–312. [CrossRef] [PubMed]
83.
Rubino, T.; Guidali, C.; Vigano, D.; Realini, N.; Valenti, M.; Massi, P.; Parolaro, D. CB1 receptor stimulation
in specific brain areas differently modulate anxiety-related behaviour. Neuropharmacology
2008
,54, 151–160.
[CrossRef] [PubMed]
84.
Viveros, M.P.; Marco, E.M.; File, S.E. Endocannabinoid system and stress and anxiety responses. Pharmacol.
Biochem. Behav. 2005,81, 331–342. [CrossRef] [PubMed]
85.
Turna, J.; Patterson, B.; Van Ameringen, M. Is cannabis treatment for anxiety, mood, and related disorders
ready for prime time? Depress. Anxiety 2017,34, 1006–1017. [CrossRef] [PubMed]
86.
Herkenham, M.; Lynn, A.B.; Little, M.D.; Johnson, M.R.; Melvin, L.S.; de Costa, B.R.; Rice, K.C. Cannabinoid
receptor localization in brain. Proc. Natl. Acad. Sci. USA 1990,87, 1932–1936. [CrossRef] [PubMed]
87.
Martin, M.; Ledent, C.; Parmentier, M.; Maldonado, R.; Valverde, O. Involvement of CB1 cannabinoid
receptors in emotional behaviour. Psychopharmacology 2002,159, 379–387. [CrossRef] [PubMed]
88.
Haller, J.; Varga, B.; Ledent, C.; Freund, T.F. CB1 cannabinoid receptors mediate anxiolytic effects: Convergent
genetic and pharmacological evidence with CB1-specific agents. Behav. Pharmacol.
2004
,15, 299–304.
[CrossRef] [PubMed]
89.
Urigüen, L.; Pérez-Rial, S.; Ledent, C.; Palomo, T.; Manzanares, J. Impaired action of anxiolytic drugs in mice
deficient in cannabinoid CB1 receptors. Neuropharmacology 2004,46, 966–973. [CrossRef] [PubMed]
90.
Mikics, E.; Vas, J.; Aliczki, M.; Halasz, J.; Haller, J. Interactions between the anxiogenic effects of CB1 gene
disruption and 5-HT3 neurotransmission. Behav. Pharmacol. 2009,20, 265–272. [CrossRef] [PubMed]
91.
Marsicano, G.; Wotjak, C.T.; Azad, S.C.; Bisogno, T.; Rammes, G.; Cascio, M.G.; Hermann, H.; Tang, J.;
Hofmann, C.; Zieglgänsberger, W.; et al. The endogenous cannabinoid system controls extinction of aversive
memories. Nature 2002,418, 530–534. [CrossRef] [PubMed]
92.
Rey, A.A.; Purrio, M.; Viveros, M.-P.; Lutz, B. Biphasic effects of cannabinoids in anxiety responses:
CB1 and GABA
B
receptors in the balance of GABAergic and glutamatergic neurotransmission.
Neuropsychopharmacology 2012,37, 2624–2634. [CrossRef] [PubMed]
93.
Jacob, W.; Yassouridis, A.; Marsicano, G.; Monory, K.; Lutz, B.; Wotjak, C.T. Endocannabinoids render
exploratory behaviour largely independent of the test aversiveness: Role of glutamatergic transmission.
Genes Brain Behav. 2009,8, 685–698. [CrossRef] [PubMed]
94.
Morena, M.; Patel, S.; Bains, J.S.; Hill, M.N. Neurobiological interactions between stress and the
endocannabinoid system. Neuropsychopharmacology 2016,41, 80–102. [CrossRef] [PubMed]
Medicines 2018,5, 107 14 of 17
95.
Dincheva, I.; Drysdale, A.T.; Hartley, C.A.; Johnson, D.C.; Jing, D.; King, E.C.; Ra, S.; Gray, J.M.; Yang, R.;
DeGruccio, A.M.; et al. FAAH genetic variation enhances fronto-amygdala function in mouse and human.
Nat. Commun. 2015,6, 6395. [CrossRef] [PubMed]
96.
Kathuria, S.; Gaetani, S.; Fegley, D.; Valiño, F.; Duranti, A.; Tontini, A.; Mor, M.; Tarzia, G.; La Rana, G.;
Calignano, A.; et al. Modulation of anxiety through blockade of anandamide hydrolysis. Nat. Med.
2003
,
9, 76–81. [CrossRef] [PubMed]
97.
Scherma, M.; Medalie, J.; Fratta, W.; Vadivel, S.K.; Makriyannis, A.; Piomelli, D.; Mikics, E.; Haller, J.; Yasar, S.;
Tanda, G.; et al. The endogenous cannabinoid anandamide has effects on motivation and anxiety that are
revealed by fatty acid amide hydrolase (FAAH) inhibition. Neuropharmacology
2008
,54, 129–140. [CrossRef]
[PubMed]
98.
Haller, J.; Barna, I.; Barsvari, B.; Gyimesi Pelczer, K.; Yasar, S.; Panlilio, L.V.; Goldberg, S. Interactions between
environmental aversiveness and the anxiolytic effects of enhanced cannabinoid signaling by FAAH inhibition
in rats. Psychopharmacology 2009,204, 607–616. [CrossRef] [PubMed]
99.
Hill, A.J.; Williams, C.M.; Whalley, B.J.; Stephens, G.J. Phytocannabinoids as novel therapeutic agents in CNS
disorders. Pharmacol. Ther. 2012,133, 79–97. [CrossRef] [PubMed]
100.
Buckner, J.D.; Schmidt, N.B.; Lang, A.R.; Small, J.W.; Schlauch, R.C.; Lewinsohn, P.M. Specificity of social
anxiety disorder as a risk factor for alcohol and cannabis dependence. J. Psychiatr. Res.
2008
,42, 230–239.
[CrossRef] [PubMed]
101.
Metrik, J.; Bassett, S.S.; Aston, E.R.; Jackson, K.M.; Borsari, B. Medicinal versus recreational cannabis use
among returning veterans. Transl. Issues Psychol. Sci. 2018,4, 6–20. [CrossRef] [PubMed]
102.
Passie, T.; Emrich, H.M.; Karst, M.; Brandt, S.D.; Halpern, J.H. Mitigation of post-traumatic stress symptoms
by Cannabis resin: A review of the clinical and neurobiological evidence. Drug Test. Anal.
2012
,4, 649–659.
[CrossRef] [PubMed]
103.
Reznik, I. Post-traumatic stress disorder and medical cannabis use: A naturalistic observational study.
Eur. Neuropsychopharmacol. 2012,22, S363–S364. [CrossRef]
104.
Roitman, P.; Mechoulam, R.; Cooper-Kazaz, R.; Shalev, A. Preliminary, open-label, pilot study of add-on oral
9-tetrahydrocannabinol in chronic post-traumatic stress disorder. Clin. Drug Investig.
2014
,34, 587–591.
[CrossRef] [PubMed]
105.
Neumeister, A.; Normandin, M.D.; Pietrzak, R.H.; Piomelli, D.; Zheng, M.Q.; Gujarro-Anton, A.;
Potenza, M.N.; Bailey, C.R.; Lin, S.F.; Najafzadeh, S.; et al. Elevated brain cannabinoid CB1 receptor
availability in post-traumatic stress disorder: A positron emission tomography study. Mol. Psychiatry
2013
,
18, 1034–1040. [CrossRef] [PubMed]
106.
Thomas, H. Psychiatric symptoms in cannabis users. Br. J. Psychiatry
1993
,163, 141–149. [CrossRef] [PubMed]
107.
Fusar-Poli, P.; Crippa, J.A.; Bhattacharyya, S.; Borgwardt, S.J.; Allen, P.; Martin-Santos, R.; Seal, M.;
Surguladze, S.A.; O’Carrol, C.; Atakan, Z.; et al. Distinct effects of
9-tetrahydrocannabinol and cannabidiol
on neural activation during emotional processing. Arch. Gen. Psychiatry
2009
,66, 95–105. [CrossRef]
[PubMed]
108.
Bossong, M.G.; van Hell, H.H.; Jager, G.; Kahn, R.S.; Ramsey, N.F.; Jansma, J.M. The endocannabinoid
system and emotional processing: A pharmacological fMRI study with
9-tetrahydrocannabinol.
Eur. Neuropsychopharmacol. J. Eur. Coll. Neuropsychopharmacol. 2013,23, 1687–1697. [CrossRef] [PubMed]
109.
Blessing, E.M.; Steenkamp, M.M.; Manzanares, J.; Marmar, C.R. Cannabidiol as a potential treatment for
anxiety disorders. Neurother. J. Am. Soc. Exp. Neurother. 2015,12, 825–836. [CrossRef] [PubMed]
110.
Zuardi, A.W.; Shirakawa, I.; Finkelfarb, E.; Karniol, I.G. Action of cannabidiol on the anxiety and other effects
produced by delta 9-THC in normal subjects. Psychopharmacology 1982,76, 245–250. [CrossRef] [PubMed]
111.
Zuardi, A.W.; Cosme, R.A.; Graeff, F.G.; Guimarães, F.S. Effects of ipsapirone and cannabidiol on human
experimental anxiety. J. Psychopharmacol. 1993,7, 82–88. [CrossRef] [PubMed]
112.
Bergamaschi, M.M.; Queiroz, R.H.C.; Chagas, M.H.N.; de Oliveira, D.C.G.; De Martinis, B.S.; Kapczinski, F.;
Quevedo, J.; Roesler, R.; Schröder, N.; Nardi, A.E.; et al. Cannabidiol reduces the anxiety induced
by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology
2011
,
36, 1219–1226. [CrossRef] [PubMed]
113.
Crippa, J.A.; Zuardi, A.W.; Garrido, G.E.J.; Wichert-Ana, L.; Guarnieri, R.; Ferrari, L.; Azevedo-Marques, P.M.;
Hallak, J.E.C.; McGuire, P.K.; Filho Busatto, G. Effects of cannabidiol (CBD) on regional cerebral blood flow.
Neuropsychopharmacology 2004,29, 417–426. [CrossRef] [PubMed]
Medicines 2018,5, 107 15 of 17
114.
Crippa, J.A.S.; Derenusson, G.N.; Ferrari, T.B.; Wichert-Ana, L.; Duran, F.L.S.; Martin-Santos, R.; Simões, M.V.;
Bhattacharyya, S.; Fusar-Poli, P.; Atakan, Z.; et al. Neural basis of anxiolytic effects of cannabidiol (CBD) in
generalized social anxiety disorder: A preliminary report. J. Psychopharmacol.
2011
,25, 121–130. [CrossRef]
[PubMed]
115.
Guimarães, F.S.; Chiaretti, T.M.; Graeff, F.G.; Zuardi, A.W. Antianxiety effect of cannabidiol in the elevated
plus-maze. Psychopharmacology 1990,100, 558–559. [CrossRef] [PubMed]
116.
Onaivi, E.S.; Green, M.R.; Martin, B.R. Pharmacological characterization of cannabinoids in the elevated plus
maze. J. Pharmacol. Exp. Ther. 1990,253, 1002–1009. [PubMed]
117.
Moreira, F.A.; Aguiar, D.C.; Guimarães, F.S. Anxiolytic-like effect of cannabidiol in the rat Vogel conflict test.
Prog. Neuropsychopharmacol. Biol. Psychiatry 2006,30, 1466–1471. [CrossRef] [PubMed]
118.
Campos, A.C.; Guimarães, F.S. Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol
injected into the dorsolateral periaqueductal gray of rats. Psychopharmacology
2008
,199, 223–230. [CrossRef]
[PubMed]
119.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed.; American
Psychiatric Publishing, Inc.: Arlington, VA, USA, 2013; ISBN 978-0-89042-555-8.
120.
Han, M.-H.; Nestler, E.J. Neural substrates of depression and resilience. Neurother. J. Am. Soc. Exp. Neurother.
2017,14, 677–686. [CrossRef] [PubMed]
121.
Hardeveld, F.; Spijker, J.; De Graaf, R.; Hendriks, S.M.; Licht, C.M.M.; Nolen, W.A.; Penninx, B.W.J.H.;
Beekman, A.T.F. Recurrence of major depressive disorder across different treatment settings: Results from
the NESDA study. J. Affect. Disord. 2013,147, 225–231. [CrossRef] [PubMed]
122.
Smaga, I.; Bystrowska, B.; Gawli´nski, D.; Przegali ´nski, E.; Filip, M. The endocannabinoid/endovanilloid
system and depression. Curr. Neuropharmacol. 2014,12, 462–474. [CrossRef] [PubMed]
123.
Hill, M.N.; Miller, G.E.; Ho, W.-S.V.; Gorzalka, B.B.; Hillard, C.J. Serum endocannabinoid content is altered
in females with depressive disorders: A preliminary report. Pharmacopsychiatry
2008
,41, 48–53. [CrossRef]
[PubMed]
124.
Hill, M.N.; Miller, G.E.; Carrier, E.J.; Gorzalka, B.B.; Hillard, C.J. Circulating endocannabinoids and N-acyl
ethanolamines are differentially regulated in major depression and following exposure to social stress.
Psychoneuroendocrinology 2009,34, 1257–1262. [CrossRef] [PubMed]
125.
Hungund, B.L.; Vinod, K.Y.; Kassir, S.A.; Basavarajappa, B.S.; Yalamanchili, R.; Cooper, T.B.; Mann, J.J.;
Arango, V. Upregulation of CB1 receptors and agonist-stimulated [
35
S]GTP
γ
S binding in the prefrontal
cortex of depressed suicide victims. Mol. Psychiatry 2004,9, 184–190. [CrossRef] [PubMed]
126.
Choi, K.; Le, T.; McGuire, J.; Xing, G.; Zhang, L.; Li, H.; Parker, C.C.; Johnson, L.R.; Ursano, R.J. Expression
pattern of the cannabinoid receptor genes in the frontal cortex of mood disorder patients and mice selectively
bred for high and low fear. J. Psychiatr. Res. 2012,46, 882–889. [CrossRef] [PubMed]
127.
Juhasz, G.; Chase, D.; Pegg, E.; Downey, D.; Toth, Z.G.; Stones, K.; Platt, H.; Mekli, K.; Payton, A.; Elliott, R.;
et al. CNR1 gene is associated with high neuroticism and low agreeableness and interacts with recent
negative life events to predict current depressive symptoms. Neuropsychopharmacology
2009
,34, 2019–2027.
[CrossRef] [PubMed]
128.
Domschke, K.; Dannlowski, U.; Ohrmann, P.; Lawford, B.; Bauer, J.; Kugel, H.; Heindel, W.; Young, R.;
Morris, P.; Arolt, V.; et al. Cannabinoid receptor 1 (CNR1) gene: Impact on antidepressant treatment response
and emotion processing in major depression. Eur. Neuropsychopharmacol. J. Eur. Coll. Neuropsychopharmacol.
2008,18, 751–759. [CrossRef] [PubMed]
129.
Monteleone, P.; Bifulco, M.; Maina, G.; Tortorella, A.; Gazzerro, P.; Proto, M.C.; Di Filippo, C.; Monteleone, F.;
Canestrelli, B.; Buonerba, G.; et al. Investigation of CNR1 and FAAH endocannabinoid gene polymorphisms
in bipolar disorder and major depression. Pharmacol. Res. 2010,61, 400–404. [CrossRef] [PubMed]
130.
Mitjans, M.; Serretti, A.; Fabbri, C.; Gastó, C.; Catalán, R.; Fañanás, L.; Arias, B. Screening genetic
variability at the CNR1 gene in both major depression etiology and clinical response to citalopram treatment.
Psychopharmacology 2013,227, 509–519. [CrossRef] [PubMed]
131.
Grinspoon, L.; Bakalar, J.B. The use of cannabis as a mood stabilizer in bipolar disorder: Anecdotal evidence
and the need for clinical research. J. Psychoactive Drugs 1998,30, 171–177. [CrossRef] [PubMed]
132.
Ashton, C.H.; Moore, P.B.; Gallagher, P.; Young, A.H. Cannabinoids in bipolar affective disorder: A review
and discussion of their therapeutic potential. J. Psychopharmacol. 2005,19, 293–300. [CrossRef] [PubMed]
Medicines 2018,5, 107 16 of 17
133.
Gruber, A.J.; Pope, H.G.; Brown, M.E. Do patients use marijuana as an antidepressant? Depression
1996
,
4, 77–80. [CrossRef]
134.
Denson, T.F.; Earleywine, M. Decreased depression in marijuana users. Addict. Behav.
2006
,31, 738–742.
[CrossRef] [PubMed]
135.
Babson, K.A.; Boden, M.T.; Bonn-Miller, M.O. Sleep quality moderates the relation between depression
symptoms and problematic cannabis use among medical cannabis users. Am. J. Drug Alcohol Abuse
2013
,
39, 211–216. [CrossRef] [PubMed]
136.
Walsh, Z.; Gonzalez, R.; Crosby, K.; Thiessen, M.S.; Carroll, C.; Bonn-Miller, M.O. Medical cannabis and
mental health: A guided systematic review. Clin. Psychol. Rev. 2017,51, 15–29. [CrossRef] [PubMed]
137.
Gruber, S.A.; Sagar, K.A.; Dahlgren, M.K.; Olson, D.P.; Centorrino, F.; Lukas, S.E. Marijuana impacts mood in
bipolar disorder: A pilot study. Ment. Health Subst. Use 2012,5, 228–239. [CrossRef]
138.
Ringen, P.A.; Vaskinn, A.; Sundet, K.; Engh, J.A.; Jónsdóttir, H.; Simonsen, C.; Friis, S.; Opjordsmoen, S.;
Melle, I.; Andreassen, O.A. Opposite relationships between cannabis use and neurocognitive functioning in
bipolar disorder and schizophrenia. Psychol. Med. 2010,40, 1337–1347. [CrossRef] [PubMed]
139.
Braga, R.J.; Burdick, K.E.; DeRosse, P.; Malhotra, A.K. Cognitive and clinical outcomes associated with
cannabis use in patients with bipolar I disorder. Psychiatry Res. 2012,200, 242–245. [CrossRef] [PubMed]
140.
Lev-Ran, S.; Roerecke, M.; Le Foll, B.; George, T.P.; McKenzie, K.; Rehm, J. The association between cannabis
use and depression: A systematic review and meta-analysis of longitudinal studies. Psychol. Med.
2014
,
44, 797–810. [CrossRef] [PubMed]
141.
Aspis, I.; Feingold, D.; Weiser, M.; Rehm, J.; Shoval, G.; Lev-Ran, S. Cannabis use and mental health-related
quality of life among individuals with depressive disorders. Psychiatry Res.
2015
,230, 341–349. [CrossRef]
[PubMed]
142.
Gibbs, M.; Winsper, C.; Marwaha, S.; Gilbert, E.; Broome, M.; Singh, S.P. Cannabis use and mania symptoms:
A systematic review and meta-analysis. J. Affect. Disord. 2015,171, 39–47. [CrossRef] [PubMed]
143.
Parolaro, D.; Realini, N.; Vigano, D.; Guidali, C.; Rubino, T. The endocannabinoid system and psychiatric
disorders. Exp. Neurol. 2010,224, 3–14. [CrossRef] [PubMed]
144.
Hill, M.N.; Patel, S.; Carrier, E.J.; Rademacher, D.J.; Ormerod, B.K.; Hillard, C.J.; Gorzalka, B.B.
Downregulation of endocannabinoid signaling in the hippocampus following chronic unpredictable stress.
Neuropsychopharmacology 2005,30, 508–515. [CrossRef] [PubMed]
145.
Hill, M.N.; Carrier, E.J.; McLaughlin, R.J.; Morrish, A.C.; Meier, S.E.; Hillard, C.J.; Gorzalka, B.B. Regional
alterations in the endocannabinoid system in an animal model of depression: Effects of concurrent
antidepressant treatment. J. Neurochem. 2008,106, 2322–2336. [CrossRef] [PubMed]
146.
Bortolato, M.; Mangieri, R.A.; Fu, J.; Kim, J.H.; Arguello, O.; Duranti, A.; Tontini, A.; Mor, M.; Tarzia, G.;
Piomelli, D. Antidepressant-like activity of the fatty acid amide hydrolase inhibitor URB597 in a rat model of
chronic mild stress. Biol. Psychiatry 2007,62, 1103–1110. [CrossRef] [PubMed]
147.
Hill, M.N.; Ho, W.-S.V.; Hillard, C.J.; Gorzalka, B.B. Differential effects of the antidepressants tranylcypromine
and fluoxetine on limbic cannabinoid receptor binding and endocannabinoid contents. J. Neural Transm.
2008,115, 1673–1679. [CrossRef] [PubMed]
148.
Egashira, N.; Matsuda, T.; Koushi, E.; Higashihara, F.; Mishima, K.; Chidori, S.; Hasebe, N.; Iwasaki, K.;
Nishimura, R.; Oishi, R.; et al.
9-tetrahydrocannabinol prolongs the immobility time in the mouse forced
swim test: Involvement of cannabinoid CB1 receptor and serotonergic system. Eur. J. Pharmacol.
2008
,
589, 117–121. [CrossRef] [PubMed]
149.
El-Alfy, A.T.; Ivey, K.; Robinson, K.; Ahmed, S.; Radwan, M.; Slade, D.; Khan, I.; ElSohly, M.; Ross, S.
Antidepressant-like effect of
9-tetrahydrocannabinol and other cannabinoids isolated from
Cannabis sativa L.
Pharmacol. Biochem. Behav. 2010,95, 434–442. [CrossRef] [PubMed]
150.
Sartim, A.G.; Guimarães, F.S.; Joca, S.R.L. Antidepressant-like effect of cannabidiol injection into the ventral
medial prefrontal cortex—Possible involvement of 5-HT1A and CB1 receptors. Behav. Brain Res.
2016
,
303, 218–227. [CrossRef] [PubMed]
151.
Di Forti, M.; Morgan, C.; Dazzan, P.; Pariante, C.; Mondelli, V.; Marques, T.R.; Handley, R.; Luzi, S.; Russo, M.;
Paparelli, A.; et al. High-potency cannabis and the risk of psychosis. Br. J. Psychiatry
2009
,195, 488–491.
[CrossRef] [PubMed]
Medicines 2018,5, 107 17 of 17
152.
Schubart, C.D.; Sommer, I.E.; van Gastel, W.A.; Goetgebuer, R.L.; Kahn, R.S.; Boks, M.P. Cannabis with
high cannabidiol content is associated with fewer psychotic experiences. Schizophr. Res.
2011
,130, 216–221.
[CrossRef] [PubMed]
153.
Morgan, C.J.; Curran, H.V. Eff ects of cannabidiol on schizophrenia like symptoms in people who use
cannabis. Br. J. Psychiatry 2008,192, 306–307. [CrossRef] [PubMed]
©
2018 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 (http://creativecommons.org/licenses/by/4.0/).
... Konoplja se že tisočletja uporablja za zdravljenje različnih bolezni (Baron, 2015;Turna et al., 2017;Noel, 2018;Mouhamed et al., 2018;Scherma et al., 2018). V zadnjem desetletju se je zanimanje za uporabo konoplje še povečalo, zato je postalo raziskovanje endokanabinoidov eno najhitreje rastočih področij v psihofarmakologiji (Atakan, 2012). ...
... V zadnjem desetletju se je zanimanje za uporabo konoplje še povečalo, zato je postalo raziskovanje endokanabinoidov eno najhitreje rastočih področij v psihofarmakologiji (Atakan, 2012). Zaradi premalo zanesljivih dokazov farmakoterapevti še niso odobrili zdravljenja bolezni s konopljo Marshall et al., 2014;Baron, 2015;Ko et al., 2016;Poli et al., 2017;Turna et al., 2017;Noel, 2018;Dariš et al., 2018;Modesto-Lowe et al., 2018;Scherma et al., 2018;Pancer & Dasgupta, 2019). ...
... Varnost uporabe se vsaj v ameriških preizkusih ne more ustrezno oceniti, ker je konoplja, ki jo dobavlja National Institute of Drug Abuse, blažja kot komercialni izdelki (Bonnet & Preuss, 2017;Modesto-Lowe et al., 2018). Crippa et al., 2009;Corey-Bloom et al., 2012;Marshall et al., 2014;Hancox et al., 2015;Self et al., 2016;Turna et al., 2017;Martell et al., 2018;Mojaverrostami et al., 2018;Mouhamed et al., 2018;Poli et al., 2018;Scherma et al., 2018;Stith et al., 2018;Zaheer et al., 2018;Zylla et al., 2018;Neubauer et al., 2019;Pancer & Dasgupta, 2019 Lastnosti konoplje Nezakonito zdravilo -terapevtska uporabafarmakološke in biokemične spojinekratkoročne in dolgoročne poslediceodtegnitveni sindrom -socialna stigmanadaljnje raziskave -endokanabinoidni sistem -stranski učinki -psihozahalucinacije -paranoja -zdravilna rastlina Število kod = 14 Crippa et al., 2009;Atakan, 2012;Marshall et al., 2014;Baron, 2015;Ko et al., 2016;Bonnet & Preuss, 2017;Budney & Borodovsky, 2017;Meier et al., 2017;Dariš et al., 2018 tveganj pri uporabi konoplje v terapevtske namene, s čimer bi pomagali tudi nacionalnim in zveznim oblastem posodobiti zakonodajo na tem področju Atakan, 2012;Scherma et al., 2018;. ...
Article
Full-text available
Uvod: Slovenija je leta 2017 spremenila uredbo o razvrstitvi prepovedanih drog in omogočila uporabo konoplje v medicinske namene. Konoplja ima več kot 140 kanabinoidnih spojin, med katerimi sta najbolj izpostavljeni kanabidiol in tetrahidrokanabinol, saj imata potencial za zdravljenje bolezni. Namen pregleda je raziskati rabo konoplje v medicinske namene. Metode: Izveden je bil integrativni pregled literature v digitalni zbirki podatkov PubMed, spletnem iskalniku Google učenjak in vzajemnemu bibliografskemu sistemu COBISS s pomočjo besednih zvez: »cannabis AND medical use«, »marihuana AND medical use« in »raba konoplje v medicinske namene«. Omejitve iskanja so bile: obdobje objave literature (2008–2019), prost dostop do recenziranih strokovnih in znanstvenih člankov ter literatura v angleškem ali slovenskem jeziku. Za pregled literature je bila uporabljena tematska analiza prebranega gradiva. Rezultati: Za pregled literature je bilo za končno analizo primernih 29 člankov. Identificiranih je bilo 52 kod, združenih v štiri teme: (1) zdravljenje s konopljo, (2) lastnosti konoplje, (3) delovanje kanabidiola, (4) delovanje tetrahidrokanabinola. Diskusija in zaključek: Konoplja se že tisočletja uporablja v medicinske namene. Danes jo v svetu uporabljajo predvsem za zdravljenje naslednjih bolezni: astme, diabetesa, epilepsije, raka, Parkinsonove bolezni, Alzheimerjeve demence, multiple skleroze. V Sloveniji je konoplja odstranjena s seznama najbolj nevarnih drog, a do njene rabe v medicinske namene je zahteven proces.
... Anxiety is recognized as the number one mental illness in the world with associated nancial and personal costs [1]. Anxiety associated with visiting a dentist for routine care or dental procedures is referred to as Dental Anxiety [2] (DA) and the h leading cause of anxiety overall [3]. ...
Article
Full-text available
Cooper DL*, Stephan R and Maygar CW PhytoDental Solutions LLC, Homosassa, Florida, 34446, USA Abstract Background: Dental Anxiety (DA) may produce a vicious cycle where dental problems are not adequately serviced. Chronic non-compliance with prescribed dental care and maintenance is associated ultimately with poor dental health. Current pharmacologic treatments such as benzodiazepines for DA are associated with poor efficacy and significant side effects.The anxiolytic effects of the most studied cannabinoid, cannabidiol (CBD) in the Dual Dosing (AM/PM) Full Spectrum Protocol are detailed here (DDFSP). Materials and methods: Our recently developed PhytoDental Solutions Dental Anxiety Scale (PDSDAS) composed of eight self-reported psychic, somatic and sleep indicators was utilized for scoring a subject’s DA level for three Time Groups (TG): the night before (T0); immediately after (T1); and 24 hours (T2) after a dental procedure or visit. Results: In this series of subjects completing at least one post-dosing time point, the Dual Dosing AM/PM Full Spectrum CBD (DDFSCBD) Protocol significantly reduced both psychic (43% to 67%) and somatic (51%) dental anxiety. Additionally, 87% of study patients reported substantially improved sleep the night before their dental visit. Kruskai-Wallis one-way ANOVA analysis of the three Time Group data sets yielded significant 1-tail statistical differences (p-values< 0.05) with p-values of 0.020 and 0.041 substantiating the role of the DDFSP to modify DA. Further, validation of the PDSDAS as a scoring measure developed for DA was extended by paired t-test comparisons to multiple smaller Paired Data sets across these Time Groups yielding 1-tail p-values of 0.010, 0.050 and 0.024 respectively. Conclusion: Determination of significance by both ANOVA and paired t-tests of PDSDAS scoring strongly suggest the Dual-Dosing (AM/PM) Full Spectrum Protocol is an effective Dental Anxiety anxiolytic. Keywords: Dental anxiety; Cannabinoid; Cannabidiol; Full spectrum; Anxiolytic; T-tests; P-value
... Anxiety is recognized as the number one mental illness in the world with associated financial and personal costs [1]. Anxiety associated with visiting a dentist for routine care or dental procedures is referred to as Dental Anxiety [2] (DA) and the fifth leading cause of anxiety overall [3]. ...
Article
Background: Dental Anxiety (DA) may produce a vicious cycle where dental problems are not adequately serviced. Chronic non-compliance with prescribed dental care and maintenance is associated ultimately with poor dental health. Current pharmacologic treatments such as benzodiazepines for DA are associated with poor efficacy and significant side effects.The anxiolytic effects of the most studied cannabinoid, cannabidiol (CBD) in the Dual Dosing (AM/PM) Full Spectrum Protocol are detailed here (DDFSP). Materials and methods: Our recently developed PhytoDental Solutions Dental Anxiety Scale (PDSDAS) composed of eight self-reported psychic, somatic and sleep indicators was utilized for scoring a subject’s DA level for three Time Groups (TG): the night before (T0); immediately after (T1); and 24 hours (T2) after a dental procedure or visit. Results: In this series of subjects completing at least one post-dosing time point, the Dual Dosing AM/PM Full Spectrum CBD (DDFSCBD) Protocol significantly reduced both psychic (43% to 67%) and somatic (51%) dental anxiety. Additionally, 87% of study patients reported substantially improved sleep the night before their dental visit. Kruskai-Wallis one-way ANOVA analysis of the three Time Group data sets yielded significant 1-tail statistical differences (p-values< 0.05) with p-values of 0.020 and 0.041 substantiating the role of the DDFSP to modify DA. Further, validation of the PDSDAS as a scoring measure developed for DA was extended by paired t-test comparisons to multiple smaller Paired Data sets across these Time Groups yielding 1-tail p-values of 0.010, 0.050 and 0.024 respectively. Conclusion: Determination of significance by both ANOVA and paired t-tests of PDSDAS scoring strongly suggest the Dual-Dosing (AM/PM) Full Spectrum Protocol is an effective Dental Anxiety anxiolytic.
... THC and CBD have demonstrated neuroprotective, immunomodulatory, as well as anti-inflammatory effects (Cameron and Hemingway 2020), leading to their inclusion as adjunctive treatment for malignant brain tumors, Parkinson's disease, Alzheimer's disease, multiple sclerosis, neuropathic pain, and childhood seizure disorders (Maroon and Bost 2018). Experimental studies are being conducted in order to examine anecdotal and preliminary scientific evidence of their benefits in alleviating psychiatric and mood disorders, such as schizophrenia, anxiety, depression, addiction, and post-traumatic stress disorder (Shahbazi et al. 2020;Scherma et al. 2018). While the psychoactivity of THC can be less desirable in some clinical settings, the non-psychoactive CBD, with its anti-inflammatory, anti-convulsive, and anti-emetic effects, is a prime candidate for the development of functional cannabinoid-based nutraceuticals (Parker et al. 2002;Khan et al. 2020). ...
Article
Full-text available
Background This study describes the design, optimization, and stress-testing of a novel phytocannabinoid nanoemulsion generated using high-pressure homogenization. $\text {QNaturale}^{\circledR }$ QNaturale Ⓡ , a plant-derived commercial emulsifier containing quillaja saponin, was used to stabilize the lipid phase droplets in water. Stress-testing was performed on this nanoemulsion in order to evaluate its chemical and colloidal stability under the influence of different environmental factors, encompassing both physical and chemical stressors. Methods Extensive optimization studies were conducted to arrive at an ideal nanoemulsion formulation. A coarse emulsion containing 16.6 wt% CBD-enriched cannabis distillate and 83.4 wt% carrier (soybean) oil dispersed in 10 wt% $\text {QNaturale}^{\circledR }$ QNaturale Ⓡ (1.5 wt% quillaja saponin) solution after 10 homogenization cycles at a pressure of 30,000 psi produced a stable nanoemulsion. This nanoemulsion was then subjected to the stress studies. Results The optimized nanoemulsion had an average droplet diameter of ca. 120 nm and average droplet surface ζ potentials of ca. -30 mV. It was imaged and characterized by a variety of protocols. It proved to be stable to droplet agglomeration and phase separation upon storage under ambient conditions for 6 weeks, as well as under a variety of physical stressors such as heat, cold, dilution, and carbonation. pH values ≤2 and moderately high salt concentrations (> 100 mM), however, destabilized the nanoemulsion, eventually leading to phase separation. Cannabis potency, determined by HPLC, was detrimentally affected by any changes in the nanoemulsion phase stability. Conclusions Quillaja saponin stabilized cannabidiol(CBD)-enriched nanoemulsions are stable, robust systems even at low emulsifier concentrations, and are therefore significant from both a scientific as well as a commercial perspective.
... 31 However, it is higher than the national average for the general population (ganja/ marijuana use-1.2%). 1 The higher prevalence of cannabis use among medical students can be understood in the light that medical UGs often consider it to be an innocuous drug and that cannabis, having the anxiolytic, hypnotic, mood-altering, and appetite-promoting properties, becomes a source for the same. [39][40][41][42] Literature suggests that stress, anxiety, depression (62% students satisfied the criteria of "caseness" by General Health Questionnaire-9 [GHQ-9]), and insomnia are common mental health issues among medical students; 29 cannabis use might represent a form of self-medication for the ongoing Review Article psychological distress. Further, the latest trend of legalization of cannabis in some of the western countries could also portray it as a safer drug. ...
Article
Full-text available
Background Medical students are at an increased risk of developing substance use and related problems (SURP) because of the inherent stress associated with the professional medical course apart from the developmental risk factors. However, this is under-researched. Moreover, a comprehensive review on the prevalence of SURP among the medical undergraduates (UGs) and associated factors is lacking from India. To fill this gap, the current research work is aimed to review the existing literature on the magnitude of the SURP among UGs of India and its determinants. Methods PubMed, Medline, and Google Scholar databases were searched for the original articles studying the prevalence of SURP among medical UGs of India, published from inception till date. Non-original articles, studies on behavioral addictions, and those not directly assessing the prevalence of SURP among the medical UGs were excluded. Results A total of 39 studies were found eligible for the review. Alcohol (current use: 3.2%–43.8%), followed by tobacco (3.7%–28.8%) and cannabis (1.6%–15%), were the common substances used by the medical students. Among the females, an increasing trend of substance use, particularly of nonprescription sedatives (even higher than males), alcohol, and smoking, was seen. Family history, peer pressure, transition from school to college life, and progression in the medical course were important associated factors. Conclusion Sensitizing medical students and college authorities, increasing the duration of training on SURP in medical curricula, and providing psychological support for the students with SURP could address this issue.
... FAAH inhibits AEA signaling via hydrolysis, while Monoacylglycerol Lipase terminates the 2-AG signal Cravatt et al., 2001;Dinh et al., 2002;Gulyas et al., 2004). CB1R, FAAH, and AEA are found in the basolateral amygdala, hippocampus, PFC, and DRN (Burstein et al., 2018;Breivogel and Sim-Selley, 2009;Papagianni and Stevenson, 2019;Russo (2018); Scherma et al., 2018). However, PTSD patients show deficits in CB1R expression and AEA levels in many regions due to elevated FAAH (Neumeister, 2013a(Neumeister, , 2013b. ...
Article
Full-text available
Post-Traumatic Stress Disorder (PTSD), characterized by re-experiencing, avoidance, negative affect, and impaired memory processing, may develop after traumatic events. PTSD is complicated by impaired plasticity and medial prefrontal cortex (mPFC) activity, hyperactivity of the amygdala, and impaired fear extinction. Cannabidiol (CBD) is a promising candidate for treatment due to its multimodal action that enhances plasticity and calms hyperexcitability. CBD’s mechanism in the mPFC of PTSD patients has been explored extensively, but literature on the mechanism in the dorsal raphe nucleus (DRN) is lacking. Following the PRISMA guidelines, we examined current literature regarding CBD in PTSD and overlapping symptomologies to propose a mechanism by which CBD treats PTSD via corticoraphe circuit. Acute CBD inhibits excess 5-HT release from DRN to amygdala and releases anandamide (AEA) onto amygdala inputs. By first reducing amygdala and DRN hyperactivity, CBD begins to ameliorate activity disparity between mPFC and amygdala. Chronic CBD recruits the mPFC, creating harmonious corticoraphe signaling. DRN releases enough 5-HT to ameliorate mPFC hypoactivity, while the mPFC continuously excites DRN 5-HT neurons via glutamate. Meanwhile, AEA regulates corticoraphe activity to stabilize signaling. AEA prevents DRN GABAergic interneurons from inhibiting 5-HT release so the DRN can assist the mPFC in overcoming its hypoactivity. DRN-mediated restoration of mPFC activity underlies CBD’s mechanism on fear extinction and learning of stress coping.
Article
Cannabis use and interest continues to increase among patients with cancer and caregivers. High-quality research remains scant in many areas, causing hesitancy or discomfort among most clinical providers. Although we have limitations on hard outcomes, we can provide some guidance and more proactively engage in conversations with patients and family about cannabis. Several studies support the efficacy of cannabis for various cancer and treatment-related symptoms, such as chemotherapy-induced nausea and cancer pain. Although formulations and dosing guidelines for clinicians do not formally exist at present, attention to tetrahydrocannabinol concentration and understanding of risks with inhalation can reduce risk. Conflicting information exists on the interaction between cannabis and immunotherapy as well as estrogen receptor interactions. Motivational interviewing can help engage in more productive, less stigmatized conversations.
Article
Rosmarinic acid (RA), an ester of caffeic acid and 3, 4‐dihydroxyphenyllactic acid, has anti‐inflammatory and neuroprotective activities. Herein, this study investigated in silico the drug‐likeness and the potential molecular targets to RA. Moreover, it tested the antidepressant‐like potential of RA in the lipopolysaccharide (LPS)‐induced depression model. RA (MW = 360.31 g/mol) meets the criteria of both Lipinski's rule of five and the Ghose filter. It also attends to relevant pharmacokinetic parameters. Target prediction analysis identified RA's potential targets and biological activities, including the peroxisome proliferator‐activated receptor (PPAR) and the cannabinoid receptors CB1 and CB2. In vivo, RA's acute, repetitive, and therapeutic administration showed antidepressant‐like effect since it significantly reduced the immobility time in the tail suspension test and increased grooming time in the splash test. Further, the pretreatment with antagonists of CB1, CB2, and PPAR‐γ receptors significantly blocked the antidepressant‐like effect of RA. Altogether, our findings suggest that cannabinoid receptors/PPAR‐γ signaling pathways are involved with the antidepressant‐like effect of RA. Moreover, this molecule meets important physicochemical and pharmacokinetic parameters that favor its bioavailability. RA constitutes a promising, innovative, and safe molecule for the pharmacotherapy of major depressive disorder.
Article
Full-text available
Although all current antipsychotics act by interfering with the action of dopamine at dopamine D2 receptors, two recent reports showed that 800 to 1000 mg of cannabidiol per day alleviated the signs and symptoms of schizophrenia, although cannabidiol is not known to act on dopamine receptors. Because these recent clinical findings may indicate an important exception to the general rule that all antipsychotics interfere with dopamine at dopamine D2 receptors, the present study examined whether cannabidiol acted directly on D2 receptors, using tritiated domperidone to label rat brain striatal D2 receptors. It was found that cannabidiol inhibited the binding of radio-domperidone with dissociation constants of 11 nm at dopamine D2High receptors and 2800 nm at dopamine D2Low receptors, in the same biphasic manner as a dopamine partial agonist antipsychotic drug such as aripiprazole. The clinical doses of cannabidiol are sufficient to occupy the functional D2High sites. it is concluded that the dopamine partial agonist action of cannabidiol may account for its clinical antipsychotic effects.
Article
Cannabidiol (CBD) represents a new promising drug due to a wide spectrum of pharmacological actions. In order to relate CBD clinical efficacy to its pharmacological mechanisms of action, we performed a bibliographic search on PUBMED about all clinical studies investigating the use of CBD as a treatment of psychiatric symptoms. Findings to date suggest that (a) CBD may exert antipsychotic effects in schizophrenia mainly through facilitation of endocannabinoid signalling and cannabinoid receptor type 1 antagonism; (b) CBD administration may exhibit acute anxiolytic effects in patients with generalised social anxiety disorder through modification of cerebral blood flow in specific brain sites and serotonin 1A receptor agonism; (c) CBD may reduce withdrawal symptoms and cannabis/tobacco dependence through modulation of endocannabinoid, serotoninergic and glutamatergic systems; (d) the preclinical pro-cognitive effects of CBD still lack significant results in psychiatric disorders. In conclusion, current evidences suggest that CBD has the ability to reduce psychotic, anxiety and withdrawal symptoms by means of several hypothesised pharmacological properties. However, further studies should include larger randomised controlled samples and investigate the impact of CBD on biological measures in order to correlate CBD's clinical effects to potential modifications of neurotransmitters signalling and structural and functional cerebral changes.
Article
Background: Although increasing rates of cannabis use and cannabis use disorder (CUD) are well-documented among veterans, little is known about their use of cannabis specifically for medicinal purposes. The present study characterizes such use and compares veterans reporting cannabis use for medicinal (n = 66) versus recreational (n = 77) purposes on (a) sociodemographic factors, (b) psychiatric disorders (posttraumatic stress disorder [PTSD], major depressive disorder [MDD], and CUD), (c) other substance use, (d) reasons for cannabis use and cannabis-related problems, and (e) physical and mental health. Methods: Participants were veterans deployed post 9/11/2001 recruited from a Veterans Health Administration (VHA) facility (N = 143; mean [SD] age = 30.0 [6.6]; mean [SD] deployments = 1.7 [1.1]) who reported past-year cannabis use. Results: The most frequently endorsed conditions for medicinal cannabis (MC) use were anxiety/stress, PTSD, pain, depression, and insomnia. In logistic regression analyses adjusted for frequency of cannabis use, MC users were significantly more likely (OR = 3.16) to meet criteria for PTSD than recreational cannabis (RC) users. Relative to RC users, MC users reported significantly greater motivation for using cannabis to cope with sleep disturbance as well as significantly poorer sleep quality and worse physical health. Conclusions: Veterans who use cannabis for medicinal purposes differ significantly in sleep, physical and mental health functioning than veterans who use cannabis for recreational purposes. PTSD and sleep problems may be especially relevant issues to address in screening and providing clinical care to returning veterans who are using cannabis for medicinal purposes.
Article
Objective: Research in both animals and humans indicates that cannabidiol (CBD) has antipsychotic properties. The authors assessed the safety and effectiveness of CBD in patients with schizophrenia. Method: In an exploratory double-blind parallel-group trial, patients with schizophrenia were randomized in a 1:1 ratio to receive CBD (1000 mg/day; N=43) or placebo (N=45) alongside their existing antipsychotic medication. Participants were assessed before and after treatment using the Positive and Negative Syndrome Scale (PANSS), the Brief Assessment of Cognition in Schizophrenia (BACS), the Global Assessment of Functioning scale (GAF), and the improvement and severity scales of the Clinical Global Impressions Scale (CGI-I and CGI-S). Results: After 6 weeks of treatment, compared with the placebo group, the CBD group had lower levels of positive psychotic symptoms (PANSS: treatment difference=-1.4, 95% CI=-2.5, -0.2) and were more likely to have been rated as improved (CGI-I: treatment difference=-0.5, 95% CI=-0.8, -0.1) and as not severely unwell (CGI-S: treatment difference=-0.3, 95% CI=-0.5, 0.0) by the treating clinician. Patients who received CBD also showed greater improvements that fell short of statistical significance in cognitive performance (BACS: treatment difference=1.31, 95% CI=-0.10, 2.72) and in overall functioning (GAF: treatment difference=3.0, 95% CI=-0.4, 6.4). CBD was well tolerated, and rates of adverse events were similar between the CBD and placebo groups. Conclusions: These findings suggest that CBD has beneficial effects in patients with schizophrenia. As CBD's effects do not appear to depend on dopamine receptor antagonism, this agent may represent a new class of treatment for the disorder.
Article
A major factor associated with poor prognostic outcome after a first psychotic break is cannabis misuse, which is prevalent in schizophrenia and particularly common in individuals with recent-onset psychosis. Behavioral interventions aimed at reducing cannabis use have been unsuccessful in this population. Cannabidiol (CBD) is a phytocannabinoid found in cannabis, although at low concentrations in modern-day strains. CBD has a broad pharmacological profile, but contrary to ∆9-tetrahydrocannabinol (THC), CBD does not activate CB1 or CB2 receptors and has at most subtle subjective effects. Growing evidence indicates that CBD acts as an antipsychotic and anxiolytic, and several reports suggest neuroprotective effects. Moreover, CBD attenuates THC's detrimental effects, both acutely and chronically, including psychotogenic, anxiogenic, and deleterious cognitive effects. This suggests that CBD may improve the disease trajectory of individuals with early psychosis and comorbid cannabis misuse in particular-a population with currently poor prognostic outcome and no specialized effective intervention.
Article
Anxiety and related disorders are the most common mental conditions affecting the North American population. Despite their established efficacy, first-line antidepressant treatments are associated with significant side effects, leading many afflicted individuals to seek alternative treatments. Cannabis is commonly viewed as a natural alternative for a variety of medical and mental health conditions. Currently, anxiety ranks among the top five medical symptoms for which North Americans report using medical marijuana. However, upon careful review of the extant treatment literature, the anxiolytic effects of cannabis in clinical populations are surprisingly not well-documented. The effects of cannabis on anxiety and mood symptoms have been examined in healthy populations and in several small studies of synthetic cannabinoid agents but there are currently no studies which have examined the effects of the cannabis plant on anxiety and related disorders. In light of the rapidly shifting landscape regarding the legalization of cannabis for medical and recreational purposes, it is important to highlight the significant disconnect between the scientific literature, public opinion, and related policies. The aim of this article is to provide a comprehensive review of the current cannabis treatment literature, and to identify the potential for cannabis to be used as a therapeutic intervention for anxiety, mood, and related disorders. Searches of five electronic databases were conducted (PubMed, MEDLINE, Web of Science, PsychINFO, and Google Scholar), with the most recent in February 2017. The effects of cannabis on healthy populations and clinical psychiatric samples will be discussed, focusing primarily on anxiety and mood disorders.
Article
Prospective epidemiological studies have consistently demonstrated that cannabis use is associated with an increased subsequent risk of both psychotic symptoms and schizophrenia-like psychoses. Early onset of use, daily use of high-potency cannabis, and synthetic cannabinoids carry the greatest risk. The risk-increasing effects are not explained by shared genetic predisposition between schizophrenia and cannabis use. Experimental studies in healthy humans show that cannabis and its active ingredient, delta-9-tetrahydrocannabinol (THC), can produce transient, dose-dependent, psychotic symptoms, as well as an array of psychosis-relevant behavioral, cognitive and psychophysiological effects; the psychotogenic effects can be ameliorated by cannabidiol (CBD). Findings from structural imaging studies in cannabis users have been inconsistent but functional MRI studies have linked the psychotomimetic and cognitive effects of THC to activation in brain regions implicated in psychosis. Human PET studies have shown that acute administration of THC weakly releases dopamine in the striatum but that chronic users are characterised by low striatal dopamine. We are beginning to understand how cannabis use impacts on the endocannabinoid system but there is much still to learn about the biological mechanisms underlying how cannabis increases risk of psychosis. This article is part of the Special Issue entitled “A New Dawn in Cannabinoid Neurobiology”.
Article
There is an urgent need for more effective medications to treat major depressive disorder, as fewer than half of depressed patients achieve full remission and many are not responsive with currently available antidepressant medications or psychotherapy. It is known that prolonged stressful events are an important risk factor for major depressive disorder. However, there are prominent individual variations in response to stress: a relatively small proportion of people (10–20%) experiencing prolonged stress develop stress-related psychiatric disorders, including depression (susceptibility to stress), whereas most stress-exposed individuals maintain normal psychological functioning (resilience to stress). There have been growing efforts to investigate the neural basis of susceptibility versus resilience to depression. An accumulating body of evidence is revealing the genetic, epigenetic, and neurophysiological mechanisms that underlie stress susceptibility, as well as the active mechanisms that underlie the resilience phenotype. In this review, we discuss, mainly based on our own work, key pathological mechanisms of susceptibility that are identified as potential therapeutic targets for depression treatment. We also review novel mechanisms that promote natural resilience as an alternative strategy to achieve treatment efficacy. These studies are opening new avenues to develop conceptually novel therapeutic strategies for depression treatment.
Article
This review considers the potential influences of the use of cannabis for therapeutic purposes (CTP) on areas of interest to mental health professionals, with foci on psychological intervention and assessment. We identified 31 articles relating to CTP use and mental health, and 29 review articles on cannabis use and mental health that did not focus on use for therapeutic purposes. Results reflect the prominence of mental health conditions among the reasons for CTP use, and the relative dearth of high-quality evidence related to CTP in this context, thereby highlighting the need for further research into the harms and benefits of medical cannabis relative to other therapeutic options. Preliminary evidence suggests that CTP may have potential for the treatment of PTSD, and as a substitute for problematic use of other substances. Extrapolation from reviews of non-therapeutic cannabis use suggests that the use of CTP may be problematic among individuals with psychotic disorders. The clinical implications of CTP use among individuals with mood disorders are unclear. With regard to assessment, evidence suggests that CTP use does not increase risk of harm to self or others. Acute cannabis intoxication and recent CTP use may result in reversible deficits with the potential to influence cognitive assessment, particularly on tests of short-term memory.
Article
Anxiety disorders (separation anxiety disorder, selective mutism, specific phobias, social anxiety disorder, panic disorder, agoraphobia, and generalised anxiety disorder) are common and disabling conditions that mostly begin during childhood, adolescence, and early adulthood. They differ from developmentally normative or stress-induced transient anxiety by being marked (ie, out of proportion to the actual threat present) and persistent, and by impairing daily functioning. Most anxiety disorders affect almost twice as many women as men. They often co-occur with major depression, alcohol and other substance-use disorders, and personality disorders. Differential diagnosis from physical conditions—including thyroid, cardiac, and respiratory disorders, and substance intoxication and withdrawal—is imperative. If untreated, anxiety disorders tend to recur chronically. Psychological treatments, particularly cognitive behavioural therapy, and pharmacological treatments, particularly selective serotonin-reuptake inhibitors and serotonin–noradrenaline-reuptake inhibitors, are effective, and their combination could be more effective than is treatment with either individually. More research is needed to increase access to and to develop personalised treatments.