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The Future of CBD Oil as a Possible Pharmacologic Treatment Option in Psychiatry: The Current State of the Literature

Authors:

Abstract

Cannabidiol (CBD) is a non-psychoactive component of the cannabis plant. Potential pharmaceutical use for CBD targets the stress receptors in the human cannabinoid system. In June 2018, the FDA approved CBD oral solution for Dravet syndrome, which marked the first approved indication for CBD. This review explores the current evidence for CBD use in the treatment of psychiatric disorders.
There are many patients with psychiatric disorders who may benefit
from CBD therapy
Safety
Deemed to be a relatively safe compound
Good candidate for future clinical use in humans as it lacks
psychomimetic and other psychotropic effects
Efficacy
Controlled clinical trials are needed to determine efficacy for
psychiatric conditions
Past studies have been limited to small patient populations,
which suggests that further studies still need to be executed on a
larger scale to prove therapeutic benefits
Pharmacokinetics (PK) and Pharmacodynamics (PD)
Animal studies show that CBD has a narrow therapeutic dose
range
Research on a larger scale with human subjects is needed to
more clearly define the PK and PD of CBD
Dosing
Its narrow therapeutic index (NTI) and insufficient PK data,
warrants further research to elucidate appropriate dosing
Further research is needed to examine wider dose ranges of CBD
Mechanisms of Action
Determined that multiple mechanisms are involved that differ
from each other
Further research is needed to discover the exact mechanisms
responsible for its unique properties
The Future of CBD Oil as a Possible Pharmacologic Treatment Option in
Psychiatry: The Current State of the Literature
Authors and Affiliates: Ileana Arce, PharmD candidate 2020 [1]; Nisha Bhavsar, PharmD candidate 2021 [1]; Emily Casey, PharmD candidate 2021 [1]; Justine
Gabion, PharmD candidate 2020 [1]; Young Kim, PharmD candidate 2020 [1]; Soorim Yoo, PharmD candidate 2020 [1]; Megan E. Maroney, PharmD, BCPP [1,2].
1. Ernest Mario School of Pharmacy at Rutgers, the State University of New Jersey, 2. Monmouth Medical Center-RWJ Barnabas Health, Long Branch, NJ.
Cannabidiol (CBD) is a natural constituent of Cannabis sativa which has been
used medically throughout history.
CBD does not elicit psychoactive effects unlike tetrahydrocannabinol (THC)
Mediated through G-protein coupled receptors, cannabinoid type 1 (CB1) (in
the hippocampus, CNS), CB2 (in the immune system)
CB1 stimulation inhibits synaptic transmission of voltage-gated calcium
and potassium channels which prevents excessive neuronal activity to
reduce pain, anxiety, and inflammation
CB2 stimulation is limited in the central nervous system; CBD does not
affect CB2
CBD is highly lipophilic and readily crosses to intracellular sites of action
exerting effects of calcium homeostasis. This potentially provides
neuroprotective properties
CBD has a multifold mechanism of action:
oDecreases GPCR activity
oIndirectly inhibits glutamate release
at CB1 receptors
oMildly mediates release of cytokines
by stimulation of CB2 to reduce
inflammation and pain
oTargets transient receptor potential (TRP) channels which
modulate intracellular calcium
oMay activate adenosine receptors for anti-inflammatory effects
Past studies have shown benefits in the administration of CBD oil in patients
who have experienced a wide variety of disorders including anxiety and post
traumatic stress disorder.
Epidiolex (cannabidiol) (CBD) was approved by the FDA on June 25, 2018 for
the treatment of seizures associated with Lennox-Gastaut Syndrome (LGS) or
Dravet Syndrome (DS) in patients >2 years of age.
Sativex (tetrahydrocannabinol and cannabidiol) has not yet been approved by
the FDA but has been approved internationally for the adjunctive treatment
of multiple sclerosis in adults that experience neuropathic pain or spasticity
and who are unresponsive to other therapies; for the adjunctive treatment of
moderate-to-severe pain in adults with advanced cancer at the highest
tolerated dose of strong opioid therapy
BACKGROUND
OBJECTIVES
1. Health Canada. Information for Healthcare Professionals: Cannabis (marihuana, marijuana) and the cannabinoids (October 2018)
2. Campos AC, Moreira F, Gomes F, et al. Multiple Mechanisms Involved in the Large-Spectrum Therapeutic Potential of Cannabidiol
in Psychiatric Disorders. Philos Trans R Soc Lond B Biol Sci. 2012;376(1607):3364-3378.
3. Karl T, Garner B, Cheng D. The therapeutic potential of the phytocannabinoid cannabidiol for Alzheimer’s disease. Behav
Pharmacol. 2017;28:142-160.
4. Lee JLC, Bertoglio LJ, Guimaraes FS, et al. Cannabidiol regulation of emotion and emotional memory processing: relevance for
treating anxiety-related and substance abuse disorders. BR J Pharmacol. 2017;174(19):3242-3256.
5. Bitencourt RM, Takahashi RN. Cannabidiol as a Therapeutic Alternative for Post-traumatic Stress Disorder: From Bench Research to
Confirmation in Human Trials. Front Neurosci. 2018;12(502):1-10.
6. Zuardi AW, Crippa J, Hallak JEC, et al. Cannabidiol for the Treatment of Psychosis in Parkinson’s Disease. J Psychopharmacol.
2019;23(8):979-983.
7. Álverez BG, Izquierdo AY et al. The adult motor phenotype of Dravet syndrome is associated with mutation of the STXBP1 gene
and responds well to cannabidiol treatment. Seizure - European Journal of Epilepsy. August 2018;60:68-70.
8. Boggs DL, Surti T, Gupta A, et al. The effects of cannabidiol (CBD) on cognition and symptoms in outpatients with chronic
schizophrenia a randomized placebo controlled trial. Psychopharmacol. 2018;235(7):1923-1932.
9. Shannon S and Opila-Lehman J. Effectiveness of Cannabidiol One il for Pediatric Anxiety and Insomnia as Part of Posttraumatic
Stress Disorder: A Case Report. Perm J. 2016;20(4):108-111.
10. Russo M, Dattola V, Logiudice AL, et al. The role of Sativex in robotic rehabilitation in individuals with multiple sclerosis: Rational,
study design, and methodology. Medicine. 2018;96(46):1-5.
11. Hazekamp A. The Trouble with CBD Oil. Med Cannabis Cannabinoids. 2018;1:65-72.
12. Beardsley PM, Brands B, Ekwere IT, et al. Cannabidiol (CBD). Critical Review Report presented at WHO ECDD Fortieth Meeting.
Geneva, Switzerland. 2018 June.
RESOURCES
CONCLUSIONS
A literature search was completed using OVID to compile articles related to
the current place in pharmacotherapy of CBD and its potential for treating
psychiatric disorders.
Search terms utilized: “Cannabinoids” “Cannabidiol” “Pharmacotherapy” and
“CBD”
The search was further limited to include articles that met the following
criteria:
English language
Published between January 1st, 2016 and July 31st, 2018
(Articles published earlier were added if deemed)
Reviewing at least one of the following: Anxiety, Schizophrenia, Post-
traumatic Stress Disorder (PTSD), Alzheimer’s Disease (AD), Parkinson’s
Disease, and/or Multiple Sclerosis (MS)
Relevant case reports, pre-clinical trials, as well as clinical trials were also
included in the search
A total of 8 articles were identified and included in the literature review
Anxiety/Substance Abuse: Human/preclinical trials supports anxiolytic effects
of CBD in disruption of fear memory reconsolidation and extinction of fear.
Possible mechanism has been shown to be via activation of one of the key
neurotransmitters, serotonin (5HT-1A). Author supports further investigation
of CBD as a common treatment for the disorder, especially its effects on
serotonin. Effects on processing of addictive memory as well as other possible
pharmacological mechanisms still need to be researched. A higher ratio of
CBD:THC may be more favorable.
Post-Traumatic Stress Disorder (PTSD): Both human/preclinical studies
on this subtype of anxiety disorder have shown significant
improvements in symptoms of the disease. Author suggests further
investigation of how the cannabinoid system and serotonergic
neurotransmission are involved in aversive memory processing.
Case report of a 10 year old female patient with PTSD secondary to
sexual abuse has shown that CBD oil can be effective in reducing
symptoms of anxiety and insomnia secondary to PTSD.
Chronic Schizophrenia: Parallel-group, 6-week randomized placebo controlled
trial looking at a fixed tablet dosage form of CBD oil in stable patients treated
with antipsychotics; found that although well-tolerated, CBD was not
associated with improvements in cognitive and symptom evaluation scales.
Alzheimers Disease (AD): Only done in-vitro; multiple methods of
administration used; author suggests looking specifically more into how the
CB2 receptors are related to an immunologic response that ultimately leads to
inflammatory neurodegeneration in AD; higher (10 fold or greater) ratio of
CBD:THC may be needed for efficacy.
Psychosis in Parkinson’s Disease: Pilot study with 6 patients with psychosis
symptoms were evaluated; powder form of CBD was used for evaluation,
which was found to be effective and well-tolerated. Author suggests a
randomized double-blind clinical trial to further confirm such observations,
possibly investigating the effects of CBD on dopamine, one of the key
neurotransmitters involved in psychosis and Parkinson's disease.
METHODS
RESULTS
Explore the use of CBD oil in behavioral psychiatric disorders and illnesses
Review past human trials or articles related to place in therapy of CBD oil, and
legal issues which have arisen in the past regarding the use of CBD oil
Find out how the efficacy/safety of CBD may be affected by different routes given
AKNOWLEDGEMENTS & AFFILIATIONS
Dr. Megan E. Maroney is a member of the Otsuka EXCEL Speakers Bureau and consultant for Novus Medical Education. She has
received educational honoraria from PlatformQ and Pharmacy Times.
We would like to sincerely recognize the contributions of Dr. Megan E. Maroney. Thank you for your help and guidance throughout
the development of this project.
A special thank you to Rutgers University for providing us with library resources as well as the Ernest Mario School of Pharmacy for
their encouragement of our participation in this project.
This research received no outside donations. The authors of this literature review have no conflicts of interest or affiliations with any
of the manufacturers or distributors of the pharmaceutical agents discussed.
Epidiolex Sativex
Class
Anticonvulsant
Analgesic, nonopioid; Cannabinoid; Skeletal muscle relaxant
Mechanism of
Action
Unknown antiepileptic action
Does not involve its effect on
cannabinoid receptors
Stimulates cannabinoid receptors CB1 and CB2 in CNS and dorsal root
ganglion;
Mediates cannabinoid
-
induced analgesia; Stimulation of CB2 receptors
modulates immune function through cytokine release
Administration
Oral liquid; Increased absorption with
high
-fat or high-calorie meals
Buccal spray only; Do not inhale, spray into nose or towards throat; Do
not spray to sore or inflamed mucosa
Contraindications
Hypersensitivity to cannabidiol or any
component of the formulation
Hypersensitivity to cannabinoids, propylene glycol, ethanol,
peppermint oil, or any other component of the formulation; Serious
cardiovascular disease, history of schizophrenia or any other psychotic
disorder; Women of child
-bearing potential who are not using a
reliable form of contraception; Males intending to start a family;
Pregnancy; Breast
-feeding; Children <18 years old
Adverse Effects
CNS depression, increased AST/ALT,
hypersensitivity reactions, suicidal
ideation, withdrawal from abrupt
discontinuation
Buccal mucosa irritation, cardiovascular effects, CNS effects,
genitourinary effects, substance abuse
ResearchGate has not been able to resolve any citations for this publication.
Article
Full-text available
Post-traumatic stress disorder (PTSD) is characterized by poor adaptation to a traumatic experience. This disorder affects approximately 10% of people at some point in life. Current pharmacological therapies for PTSD have been shown to be inefficient and produce considerable side effects. Since the discovery of the involvement of the endocannabinoid (eCB) system in emotional memory processing, pharmacological manipulation of eCB signaling has become a therapeutic possibility for the treatment of PTSD. Cannabidiol (CBD), a phytocannabinoid constituent of Cannabis sativa without the psychoactive effects of Δ9-tetrahydrocannabinol, has gained particular attention. Preclinical studies in different rodent behavioral models have shown that CBD can both facilitate the extinction of aversive memories and block their reconsolidation, possibly through potentialization of the eCB system. These results, combined with the currently available pharmacological treatments for PTSD being limited, necessitated testing CBD use with the same therapeutic purpose in humans as well. Indeed, as observed in rodents, recent studies have confirmed the ability of CBD to alter important aspects of aversive memories in humans and promote significant improvements in the symptomatology of PTSD. The goal of this review was to highlight the potential of CBD as a treatment for disorders related to inappropriate retention of aversive memories, by assessing evidence from preclinical to human experimental studies.
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In just a few years, cannabidiol (CBD) has become immensely popular around the world. After initially being discovered as an effective self-medication for Dravet syndrome in children, CBD is now sold and used to treat a wide range of medical conditions and lifestyle diseases. The cannabinoid CBD, a non-psychoactive isomer of the more infamous tetrahydrocannabinol (THC), is available in a growing number of administration modes, but the most commonly known is CBD oil. There are currently dozens, if not hundreds, of producers and sellers of CBD oils active in the market, and their number is increasing rapidly. Those involved vary from individuals who prepare oils on a small scale for family and (Facebook) friends to compounding pharmacies, pharmaceutical companies, and licensed cannabis producers. Despite the growing availability of CBD, many uncertainties remain about the legality, quality, and safety of this new “miracle cure.” As a result, CBD is under scrutiny on many levels, ranging from national health organizations and agricultural lobbyists to the WHO and FDA. The central question is whether CBD is simply a food supplement, an investigational new medicine, or even a narcotic. This overview paper looks into the known risks and issues related to the composition of CBD products, and makes recommendations for better regulatory control based on accurate labeling and more scientifically supported health claims. The intention of this paper is to create a better understanding of the benefits versus the risks of the current way CBD products are produced, used, and advertised.
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Rationale: Preliminary evidence suggests that cannabidiol (CBD) may be effective in the treatment of neurodegenerative disorders; however, CBD has never been evaluated for the treatment of cognitive impairments associated with schizophrenia (CIAS). Objective: This study compared the cognitive, symptomatic, and side effects of CBD versus placebo in a clinical trial. Methods: This study was a 6-week, randomized, placebo-controlled, parallel group, fixed-dose study of oral CBD (600 mg/day) or placebo augmentation in 36 stable antipsychotic-treated patients diagnosed with chronic schizophrenia. All subjects completed the MATRICS Consensus Cognitive Battery (MCCB) at baseline and at end of 6 weeks of treatment. Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) at baseline and biweekly. Results: There was no main effect of time or drug on MCCB Composite score, but a significant drug × time effect was observed (p = 0.02). Post hoc analyses revealed that only placebo-treated subjects improved over time (p = 0.03). There was a significant decrease in PANSS Total scores over time (p < 0. 0001) but there was no significant drug × time interaction (p = 0.18). Side effects were similar between CBD and placebo, with the one exception being sedation, which was more prevalent in the CBD group. Conclusions: At the dose studied, CBD augmentation was not associated with an improvement in MCCB or PANSS scores in stable antipsychotic-treated outpatients with schizophrenia. Overall, CBD was well tolerated with no worsening of mood, suicidality, or movement side effects. Trial registration: https://clinicaltrials.gov/ct2/show/NCT00588731.
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Introduction: Currently, none of the available multiple sclerosis (MS) disease-modifying medications has been shown to stop or reverse gait disability. Recently, the nabiximols has been tested for the treatment of spasticity and walking impairment in MS. Nabiximols (trade name Sativex) is an oromucosal spray formulation containing 1:1 fixed ratio of delta-9-tetrahydrocannabinol and cannabidiol derived from cloned Cannabis sativa L. plant. Method and analysis: A single-center, prospective, parallel design, single-blind trial will be conducted at the IRCCS Neurolesi "Bonino-Pulejo" (Italy) involving MS patients affected by spasticity and undergoing a Robotic Rehabilitation training. The aim of the study is to clarify the role of Sativex coupled to a robotic neurehabilitation training in MS patients in improving motor outcomes, by means of clinical, kinematic, and neurophysiological measures. Patients will be randomly divided in 2 groups: one taking only an oral antispastic drug and the other with Sativex in add-on. After 1 month, we will evaluate the response to Sativex (responder patients' amelioration >20% at MRS score) enrolling into the study the first 20 patients with a good response to Sativex, whereas other 20 no-responder individuals will continue their antispastic drug. All the 40 subjects, were divided into 2 groups (A: Sativex + Lokomat Training, and B: other antispastic+Lokomat Training), will perform a neurorobotic-assisted gait training (each session will last at least 45 minutes, 3 times per week, for a total of 20 sessions). All the patients will undergo a complete physical and neurological examination at baseline, at the end of the robotic training (T1), and 30 days after the end of the neurorehabilitation training (T2).
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Cannabidiol (CBD) is a major phytocannabinoid present in the Cannabis sativa plant. It lacks the psychotomimetic and other psychotropic effects that the main plant compound Δ(9)-tetrahydrocannabinol (THC) being able, on the contrary, to antagonize these effects. This property, together with its safety profile, was an initial stimulus for the investigation of CBD pharmacological properties. It is now clear that CBD has therapeutic potential over a wide range of non-psychiatric and psychiatric disorders such as anxiety, depression and psychosis. Although the pharmacological effects of CBD in different biological systems have been extensively investigated by in vitro studies, the mechanisms responsible for its therapeutic potential are still not clear. Here, we review recent in vivo studies indicating that these mechanisms are not unitary but rather depend on the behavioural response being measured. Acute anxiolytic and antidepressant-like effects seem to rely mainly on facilitation of 5-HT1A-mediated neurotransmission in key brain areas related to defensive responses, including the dorsal periaqueductal grey, bed nucleus of the stria terminalis and medial prefrontal cortex. Other effects, such as anti-compulsive, increased extinction and impaired reconsolidation of aversive memories, and facilitation of adult hippocampal neurogenesis could depend on potentiation of anandamide-mediated neurotransmission. Finally, activation of TRPV1 channels may help us to explain the antipsychotic effect and the bell-shaped dose-response curves commonly observed with CBD. Considering its safety profile and wide range of therapeutic potential, however, further studies are needed to investigate the involvement of other possible mechanisms (e.g. inhibition of adenosine uptake, inverse agonism at CB2 receptor, CB1 receptor antagonism, GPR55 antagonism, PPARγ receptors agonism, intracellular (Ca(2+)) increase, etc.), on CBD behavioural effects.
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Introduction: Anxiety and sleep disorders are often the result of posttraumatic stress disorder and can contribute to an impaired ability to focus and to demonstration of oppositional behaviors. Case presentation: These symptoms were present in our patient, a ten-year-old girl who was sexually abused and had minimal parental supervision as a young child under the age of five. Pharmaceutical medications provided partial relief, but results were not long-lasting, and there were major side effects. A trial of cannabidiol oil resulted in a maintained decrease in anxiety and a steady improvement in the quality and quantity of the patient's sleep. Discussion: Cannabidiol oil, an increasingly popular treatment of anxiety and sleep issues, has been documented as being an effective alternative to pharmaceutical medications. This case study provides clinical data that support the use of cannabidiol oil as a safe treatment for reducing anxiety and improving sleep in a young girl with posttraumatic stress disorder.
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Alzheimer's disease (AD) is the most common neurodegenerative disorder, characterized by progressive loss of cognition. Over 35 million individuals currently have AD worldwide. Unfortunately, current therapies are limited to very modest symptomatic relief. The brains of AD patients are characterized by the deposition of amyloid-β and hyperphosphorylated forms of tau protein. AD brains also show neurodegeneration and high levels of oxidative stress and inflammation. The phytocannabinoid cannabidiol (CBD) possesses neuroprotective, antioxidant and anti-inflammatory properties and reduces amyloid-β production and tau hyperphosphorylation in vitro. CBD has also been shown to be effective in vivo making the phytocannabinoid an interesting candidate for novel therapeutic interventions in AD, especially as it lacks psychoactive or cognition-impairing properties. CBD treatment would be in line with preventative, multimodal drug strategies targeting a combination of pathological symptoms, which might be ideal for AD therapy. Thus, this review will present a brief introduction to AD biology and current treatment options before outlining comprehensively CBD biology and pharmacology, followed by in-vitro and in-vivo evidence for the therapeutic potential of CBD. We will also discuss the role of the endocannabinioid system in AD before commenting on the potential future of CBD for AD therapy (including safety aspects).
The adult motor phenotype of Dravet syndrome is associated with mutation of the STXBP1 gene and responds well to cannabidiol treatment
  • B G Álverez
  • A Y Izquierdo
Álverez BG, Izquierdo AY et al. The adult motor phenotype of Dravet syndrome is associated with mutation of the STXBP1 gene and responds well to cannabidiol treatment. Seizure -European Journal of Epilepsy. August 2018;60:68-70.