Does CBD Oil Help With Stress

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More than 60 percent of CBD users were taking it for anxiety, according to a survey of 5,000 people. Does it help? Cannabidiol as a Potential Treatment for Anxiety Disorders Cannabidiol (CBD), a Cannabis sativa constituent, is a pharmacologically broad-spectrum drug that in recent years has drawn increasing

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More than 60 percent of CBD users were taking it for anxiety, according to a survey of 5,000 people. Does it help?

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By Dawn MacKeen

The CBD industry is flourishing, conservatively projected to hit $16 billion in the United States by 2025. Already, the plant extract is being added to cheeseburgers, toothpicks and breath sprays. More than 60 percent of CBD users have taken it for anxiety, according to a survey of 5,000 people, conducted by the Brightfield Group, a cannabis market research firm. Chronic pain, insomnia and depression follow behind. Kim Kardashian West, for example, turned to the product when “freaking out” over the birth of her fourth baby. The professional golfer Bubba Watson drifts off to sleep with it. And Martha Stewart’s French bulldog partakes, too.

What is CBD?

Cannabidiol, or CBD, is the lesser-known child of the cannabis sativa plant; its more famous sibling, tetrahydrocannabinol, or THC, is the active ingredient in pot that catapults users’ “high.” With roots in Central Asia, the plant is believed to have been first used medicinally — or for rituals — around 750 B.C., though there are other estimates too.

Cannabidiol and THC are just two of the plant’s more than 100 cannabinoids. THC is psychoactive, and CBD may or may not be, which is a matter of debate. THC can increase anxiety; it is not clear what effect CBD is having, if any, in reducing it. THC can lead to addiction and cravings; CBD is being studied to help those in recovery.

Cannabis containing 0.3 percent or less of THC is hemp. Although last year’s Farm Bill legalized hemp under federal law, it also preserved the Food and Drug Administration’s oversight of products derived from cannabis.

What are the claims?

CBD is advertised as providing relief for anxiety, depression and post-traumatic stress disorder. It is also marketed to promote sleep. Part of CBD’s popularity is that it purports to be “nonpsychoactive,” and that consumers can reap health benefits from the plant without the high (or the midnight pizza munchies).

Just as hemp seedlings are sprouting up across the United States, so is the marketing. From oils and nasal sprays to lollipops and suppositories, it seems no place is too sacred for CBD. “It’s the monster that has taken over the room,” Dr. Brad Ingram, an associate professor of pediatrics at the University of Mississippi Medical Center, said about all the wild uses for CBD now. He is leading a clinical trial into administering CBD to children and teenagers with drug-resistant epilepsy.

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Does CBD work?

“It’s promising in a lot of different therapeutic avenues because it’s relatively safe,” said James MacKillop, co-director of McMaster University’s Michael G. DeGroote Center for Medicinal Cannabis Research in Hamilton, Ontario.

Last year, the F.D.A. approved Epidiolex, a purified CBD extract, to treat rare seizure disorders in patients 2 years or older after three randomized, double-blind and placebo-controlled clinical trials with 516 patients that showed the drug, taken along with other medications, helped to reduce seizures. These types of studies are the gold standard in medicine, in which participants are divided by chance, and neither the subject nor the investigator knows which group is taking the placebo or the medication.

Understand Post-Traumatic Stress Disorder

The invasive symptoms of PTSD can affect combat veterans and civilians alike. Early intervention is critical for managing the condition.

  • Removing the Stigma: Misconceptions about how PTSD develops and its symptoms, can prevent people from seeking treatment.
  • Psychedelic Drugs: As studies continue to point to the therapeutic value of substances like MDMA, veterans are becoming unlikely advocates for their decriminalization.
  • Healing Power: Despite weight lifting being associated with violent bursts of brawn, many people find pumping iron to be a valuable tool in addressing PTSD.
  • Ripple Effect: Caring for someone with PTSD can be a taxing experience. A writer describes how her relationship changed when her partner developed the condition.

While there is hope for treating other conditions with the plant extract, Epidiolex remains the only CBD-derived drug approved by the F.D.A. Most of the research on cannabidiol has been in animals, and its current popularity has outpaced science. “We don’t have the 101 course on CBD quite figured out yet,” said Ryan Vandrey, an associate professor of psychiatry and behavioral sciences at Johns Hopkins University School of Medicine.

Does CBD help anxiety and PTSD?

For students with generalized social anxiety, a four-minute talk, with minimal time to prepare, can be debilitating. Yet a small experiment in the journal Neuropsychopharmacology found that CBD seemed to reduce nervousness and cognitive impairment in patients with social anxiety in a simulated public speaking task.

However, a double-blind study found healthy volunteers administered CBD had little to no change in their emotional reaction to unpleasant images or words, compared to the placebo group. “If it’s a calming drug, it should change their responses to the stimuli,” said Harriet de Wit, co-author of the study and a professor in the University of Chicago’s department of psychiatry and behavioral neuroscience. “But it didn’t.”

Many soldiers return home haunted by war and PTSD and often avoid certain activities, places or people associated with their traumatic events. The Department of Veterans Affairs is funding its first study on CBD, pairing it with psychotherapy.

“Our top therapies attempt to break the association between reminders of the trauma and the fear response,” said Mallory Loflin, an assistant adjunct professor at the University of California, San Diego and the study’s principal investigator. “We think that CBD, at least in animal models, can help that process happen a lot faster.” While large clinical trials are underway, psychologists say there isn’t compelling evidence yet as to whether this is a viable treatment.

Does CBD help sleep and depression?

Up in the wee hours of the night, stuck watching videos of puppies? CBD may be promising as a sleep aid; one of the side effects of the Epidiolex trials for epilepsy was drowsiness, according to Mr. MacKillop, a co-author of a review on cannabinoids and sleep. “If you are looking for new treatments for sleep, that may be a clue,” he said.

But he cautions that the side effects could have been because of an interaction with other medications the children were taking to control the seizures. So far, there hasn’t been a randomized, placebo-controlled, double-blind trial (the gold standard) on sleep disorders and CBD.

A recent chart review of 72 psychiatric patients treated with CBD found that anxiety improved, but not sleep. “Over all, we did not find that it panned out as a useful treatment for sleep,” said Dr. Scott Shannon, assistant clinical professor of psychiatry at the University of Colorado, Denver and the lead author of the review in The Permanente Journal.

Sleep can be disrupted for many reasons, including depression. Rodents seemed to adapt better to stressful conditions and exhibited less depressive-like behavior after taking CBD, according to a review in Journal of Chemical Neuroanatomy. “Surprisingly, CBD seems to act faster than conventional antidepressants,” wrote one of the authors of a new review, Sâmia Joca, a fellow at the Aarhus Institute of Advanced Studies in Denmark and an associate professor at the University of São Paulo in Brazil, in an email interview. Of course, it’s difficult to detect depression in animals, but the studies that Ms. Joca and her colleagues reviewed suggested that in models of chronic stress exposure, the mice and rats treated with CBD were more resilient.

But without clinical trials in humans, psychologists say CBD’s effect on depression is still a hypothesis, and not an evidence-based treatment.

Is CBD harmful?

“If you take pure CBD, it’s pretty safe,” said Marcel Bonn-Miller, an adjunct assistant professor at the University of Pennsylvania’s Perelman School of Medicine. Side effects in the Epidiolex trial included diarrhea, sleepiness, fatigue, weakness, rash, decreased appetite and elevated liver enzymes. Also, the safe amount to consume in a day, or at all during pregnancy, is still not known.

Recently, the F.D.A. sent a warning letter to Curaleaf Inc. about its “unsubstantiated claims” that the plant extract treats a variety of conditions from pet anxiety and depression to cancer and opioid withdrawal. (In a statement, the company said that some of the products in question had been discontinued and that it was working with the F.D.A.)

Dr. Smita Das, chair of the American Psychiatric Association’s Council on Addiction Psychiatry’s cannabis work group, does not recommend CBD for anxiety, PTSD, sleep or depression. With patients turning to these to unproven products, she is worried that they may delay seeking appropriate mental health care: “I’m dually concerned with how exposure to CBD products can lead somebody into continuing to cannabis products.”

Some CBD products may contain unwanted surprises. Forensic toxicologists at Virginia Commonwealth University examined nine e-liquids advertised as being 100 percent natural CBD extracts. They found one with dextromethorphan, or DXM, used in over-the counter cough medications and considered addictive when abused; and four with a synthetic cannabinoid, sometimes called Spice, that can cause anxiety, psychosis, tachycardia and death, according to a study last year in Forensic Science International.

Earlier research found fewer than a third of 84 products studied contained the amount of CBD on their labels. Some users of CBD have also failed drug tests when the product contained more THC than indicated.

This year, 1,090 people have contacted poison control centers about CBD, according to the American Association of Poison Control Centers. Over a third are estimated to have received medical attention, and 46 were admitted into a critical care unit, possibly because of exposure to other products, or drug interactions. In addition, concern over 318 animals poured into the American Society for the Prevention of Cruelty to Animals’ Animal Poison Control Center.

Is CBD a scam or not?

A few drops of CBD oil in a mocha or smoothie are not likely to do anything, researchers contend. Doctors say another force may also be at play in people feeling good: the placebo effect. That’s when someone believes a drug is working and symptoms seem to improve.

“CBD is not a scam,” said Yasmin Hurd, director of the Addiction Institute of Mount Sinai in New York City who led a double-blind study of 42 recovering heroin addicts and found that CBD reduced both cravings and cue-based anxiety, both of which can cycle people back into using. “It has a potential medicinal value, but when we are putting it into mascara and putting it into tampons, for God’s sake, to me, that’s a scam.”

Cannabidiol as a Potential Treatment for Anxiety Disorders

Cannabidiol (CBD), a Cannabis sativa constituent, is a pharmacologically broad-spectrum drug that in recent years has drawn increasing interest as a treatment for a range of neuropsychiatric disorders. The purpose of the current review is to determine CBD’s potential as a treatment for anxiety-related disorders, by assessing evidence from preclinical, human experimental, clinical, and epidemiological studies. We found that existing preclinical evidence strongly supports CBD as a treatment for generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive–compulsive disorder, and post-traumatic stress disorder when administered acutely; however, few studies have investigated chronic CBD dosing. Likewise, evidence from human studies supports an anxiolytic role of CBD, but is currently limited to acute dosing, also with few studies in clinical populations. Overall, current evidence indicates CBD has considerable potential as a treatment for multiple anxiety disorders, with need for further study of chronic and therapeutic effects in relevant clinical populations.

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Electronic supplementary material

The online version of this article (doi:10.1007/s13311-015-0387-1) contains supplementary material, which is available to authorized users.

Keywords: Cannabidiol, Endocannabinoids, Anxiety, Generalized anxiety disorder, Post-traumatic stress disorder

Introduction

Fear and anxiety are adaptive responses essential to coping with threats to survival. Yet excessive or persistent fear may be maladaptive, leading to disability. Symptoms arising from excessive fear and anxiety occur in a number of neuropsychiatric disorders, including generalized anxiety disorder (GAD), panic disorder (PD), post-traumatic stress disorder (PTSD), social anxiety disorder (SAD), and obsessive–compulsive disorder (OCD). Notably, PTSD and OCD are no longer classified as anxiety disorders in the recent revision of the Diagnostic and Statistical Manual of Mental Disorders-5; however, excessive anxiety is central to the symptomatology of both disorders. These anxiety-related disorders are associated with a diminished sense of well-being, elevated rates of unemployment and relationship breakdown, and elevated suicide risk [1–3]. Together, they have a lifetime prevalence in the USA of 29 % [4], the highest of any mental disorder, and constitute an immense social and economic burden [5, 6].

Currently available pharmacological treatments include serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, benzodiazepines, monoamine oxidase inhibitors, tricyclic antidepressant drugs, and partial 5-hydroxytryptamine (5-HT)1A receptor agonists. Anticonvulsants and atypical antipsychotics are also used to treat PTSD. These medications are associated with limited response rates and residual symptoms, particularly in PTSD, and adverse effects may also limit tolerability and adherence [7–10]. The substantial burden of anxiety-related disorders and the limitations of current treatments place a high priority on developing novel pharmaceutical treatments.

Cannabidiol (CBD) is a phytocannabinoid constituent of Cannabis sativa that lacks the psychoactive effects of ∆ 9- tetrahydrocannabinol (THC). CBD has broad therapeutic properties across a range of neuropsychiatric disorders, stemming from diverse central nervous system actions [11, 12]. In recent years, CBD has attracted increasing interest as a potential anxiolytic treatment [13–15]. The purpose of this review is to assess evidence from current preclinical, clinical, and epidemiological studies pertaining to the potential risks and benefits of CBD as a treatment for anxiety disorders.

Methods

A search of MEDLINE (PubMed), PsycINFO, Web of Science Scopus, and the Cochrane Library databases was conducted for English-language papers published up to 1 January 2015, using the search terms “cannabidiol” and “anxiety” or “fear” or “stress” or “anxiety disorder” or “generalized anxiety disorder” or “social anxiety disorder” or “social phobia” or “post-traumatic stress disorder” or “panic disorder” or “obsessive compulsive disorder”. In total, 49 primary preclinical, clinical, or epidemiological studies were included. Neuroimaging studies that documented results from anxiety-related tasks, or resting neural activity, were included. Epidemiological or clinical studies that assessed CBD’s effects on anxiety symptoms, or the potential protective effects of CBD on anxiety symptoms induced by cannabis use (where the CBD content of cannabis is inferred via a higher CBD:THC ratio), were included.

CBD Pharmacology Relevant to Anxiety

General Pharmacology and Therapeutic Profile

Cannabis sativa, a species of the Cannabis genus of flowering plants, is one of the most frequently used illicit recreational substances in Western culture. The 2 major phyto- cannabinoid constituents with central nervous system activity are THC, responsible for the euphoric and mind-altering effects, and CBD, which lacks these psychoactive effects. Preclinical and clinical studies show CBD possesses a wide range of therapeutic properties, including antipsychotic, analgesic, neuroprotective, anticonvulsant, antiemetic, antioxidant, anti-inflammatory, antiarthritic, and antineoplastic properties (see [11, 12, 16–19] for reviews). A review of potential side effects in humans found that CBD was well tolerated across a wide dose range, up to 1500 mg/day (orally), with no reported psychomotor slowing, negative mood effects, or vital sign abnormalities noted [20].

CBD has a broad pharmacological profile, including interactions with several receptors known to regulate fear and anxiety-related behaviors, specifically the cannabinoid type 1 receptor (CB1R), the serotonin 5-HT1A receptor, and the transient receptor potential (TRP) vanilloid type 1 (TRPV1) receptor [11, 12, 19, 21]. In addition, CBD may also regulate, directly or indirectly, the peroxisome proliferator-activated receptor-γ, the orphan G-protein-coupled receptor 55, the equilibrative nucleoside transporter, the adenosine transporter, additional TRP channels, and glycine receptors [11, 12, 19, 21]. In the current review of primary studies, the following receptor-specific actions were found to have been investigated as potential mediators of CBD’s anxiolytic action: CB1R, TRPV1 receptors, and 5-HT1A receptors. Pharmacology relevant to these actions is detailed below.

The Endocannabinoid System

Following cloning of the endogenous receptor for THC, namely the CB1R, endogenous CB1R ligands, or “endocannabinoids” (eCBs) were discovered, namely anandamide (AEA) and 2-arachidonoylglycerol (reviewed in [22]). The CB1R is an inhibitory Gi/o protein-coupled receptor that is mainly localized to nerve terminals, and is expressed on both γ-aminobutryic acid-ergic and glutamatergic neurons. eCBs are fatty acid derivatives that are synthesized on demand in response to neuronal depolarization and Ca 2+ influx, via cleavage of membrane phospholipids. The primary mechanism by which eCBs regulate synaptic function is retrograde signaling, wherein eCBs produced by depolarization of the postsynaptic neuron activate presynaptic CB1Rs, leading to inhibition of neurotransmitter release [23]. The “eCB system” includes AEA and 2-arachidonoylglycerol; their respective degradative enzymes fatty acid amide hydroxylase (FAAH) and monoacylglycerol lipase; the CB1R and related CB2 receptor (the latter expressed mainly in the periphery); as well as several other receptors activated by eCBs, including the TRPV1 receptor, peroxisome proliferator-activated receptor-γ, and G protein-coupled 55 receptor, which functionally interact with CB1R signaling (reviewed in [21, 24]). Interactions with the TRPV1 receptor, in particular, appear to be critical in regulating the extent to which eCB release leads to inhibition or facilitation of presynaptic neurotransmitter release [25]. The TRPV1 receptor is a postsynaptic cation channel that underlies sensation of noxious heat in the periphery, with capsacin (hot chili) as an exogenous ligand. TRPV1 receptors are also expressed in the brain, including the amygdala, periaqueductal grey, hippocampus, and other areas [26, 27].

The eCB system regulates diverse physiological functions, including caloric energy balance and immune function [28]. The eCB system is also integral to regulation of emotional behavior, being essential to forms of synaptic plasticity that determine learning and response to emotionally salient, particularly highly aversive events [29, 30]. Activation of CB1Rs produces anxiolytic effects in various models of unconditioned fear, relevant to multiple anxiety disorder symptom domains (reviewed in [30–33]). Regarding conditioned fear, the effect of CB1R activation is complex: CB1R activation may enhance or reduce fear expression, depending on brain locus and the eCB ligand [34]; however, CB1R activation potently enhances fear extinction [35], and can prevent fear reconsolidation. Genetic manipulations that impede CB1R activation are anxiogenic [35], and individuals with eCB system gene polymorphisms that reduce eCB tone—for example, FAAH gene polymorphisms—exhibit physiological, psychological, and neuroimaging features consistent with impaired fear regulation [36]. Reduction of AEA–CB1R signaling in the amygdala mediates the anxiogenic effects of corticotropin-releasing hormone [37], and CB1R activation is essential to negative feedback of the neuroendocrine stress response, and protects against the adverse effects of chronic stress [38, 39]. Finally, chronic stress impairs eCB signaling in the hippocampus and amygdala, leading to anxiety [40, 41], and people with PTSD show elevated CB1R availability and reduced peripheral AEA, suggestive of reduced eCB tone [42].

Accordingly, CB1R activation has been suggested as a target for anxiolytic drug development [15, 43, 44]. Proposed agents for enhancing CB1R activation include THC, which is a potent and direct agonist; synthetic CB1R agonists; FAAH inhibitors and other agents that increase eCB availability, as well as nonpsychoactive cannabis phytocannabinoids, including CBD. While CBD has low affinity for the CB1R, it functions as an indirect agonist, potentially via augmentation of CB1R constitutional activity, or via increasing AEA through FAAH inhibition (reviewed in [21]).

Several complexities of the eCB system may impact upon the potential of CBD and other CB1R-activating agents to serve as anxiolytic drugs. First, CB1R agonists, including THC and AEA, have a biphasic effect: low doses are anxiolytic, but higher doses are ineffective or anxiogenic, in both preclinical models in and humans (reviewed in [33, 45]). This biphasic profile may stem from the capacity of CB1R agonists to also activate TRPV1 receptors when administered at a high, but not low dose, as demonstrated for AEA [46]. Activation of TRPV1 receptors is predominantly anxiogenic, and thus a critical balance of eCB levels, determining CB1 versus TRPV1 activation, is proposed to govern emotional behavior [27, 47]. CBD acts as a TRPV1 agonist at high concentrations, potentially by interfering with AEA inactivation [48]. In addition to dose-dependent activation of TRPV1 channels, the anxiogenic versus anxiolytic balance of CB1R agonists also depends on dynamic factors, including environmental stressors [33, 49].

5-HT1A Receptors

The 5-HT1A receptor (5-HT1AR) is an established anxiolytic target. Buspirone and other 5-HT1AR agonists are approved for the treatment of GAD, with fair response rates [50]. In preclinical studies, 5-HT1AR agonists are anxiolytic in animal models of general anxiety [51], prevent the adverse effects of stress [52], and enhance fear extinction [53]. Both pre- and postsynaptic 5-HT1ARs are coupled to various members of the Gi/o protein family. They are expressed on serotonergic neurons in the raphe, where they exert autoinhibitory function, and various other brain areas involved in fear and anxiety [54, 55]. Mechanisms underlying the anxiolytic effects of 5-HT1AR activation are complex, varying between both brain region, and pre- versus postsynaptic locus, and are not fully established [56]. While in vitro studies suggest CBD acts as a direct 5-HT1AR agonist [57], in vivo studies are more consistent with CBD acting as an allosteric modulator, or facilitator of 5-HT1A signaling [58].

Preclinical Evaluations

Generalized Anxiety Models

Relevant studies in animal models are summarized in chronological order in Table ​ Table1. 1 . CBD has been studied in a wide range of animal models of general anxiety, including the elevated plus maze (EPM), the Vogel-conflict test (VCT), and the elevated T maze (ETM). See Table ​ Table1 1 for the anxiolytic effect specific to each paradigm. Initial studies of CBD in these models showed conflicting results: high (100 mg/kg) doses were ineffective, while low (10 mg/kg) doses were anxiolytic [59, 60]. When tested over a wide range of doses in further studies, the anxiolytic effects of CBD presented a bell-shaped dose–response curve, with anxiolytic effects observed at moderate but not higher doses [61, 90]. All further studies of acute systemic CBD without prior stress showed anxiolytic effects or no effect [62, 65], the latter study involving intracerebroventricular rather than the intraperitoneal route. No anxiogenic effects of acute systemic CBD dosing in models of general anxiety have yet been reported. As yet, few studies have examined chronic dosing effects of CBD in models of generalized anxiety. Campos et al. [66] showed that in rat, CBD treatment for 21 days attenuated inhibitory avoidance acquisition [83]. Long et al. [69] showed that, in mouse, CBD produced moderate anxiolytic effects in some paradigms, with no effects in others.

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Table 1

Study Animal Route Dose Model Effect Receptor Involvement
Silveira Filho et al. [59] WR i.p. 100 mg/kg,
acute
GSCT No effect NA
Zuardi et al. [60] WR i.p. 10 mg/kg,
acute
CER Anxiolytic NA
Onaivi et al. [61] ICR mice i.p. 0.01, 0.10, 0.50, 1.00, 2.50, 5.00, 10.00, 50.00, 100.00 mg/kg, acute EPM Anxiolytic Effects ↓ by IP flumazenil, unchanged by naloxone
Guimaraes et al. [61] WR i.p. 2.5, 5.0, 10.0 and 20.0 mg/kg, acute EPM Anxiolytic NA
Moreira et al. [62] WR i.p. 2.5, 5.0 and 10.0 mg/kg, acute VCT Anxiolytic Effect unchanged by IP flumazenil
Resstel et al. [63] WR i.p. 10 mg/kg, acute CFC Anxiolytic NA
Campos et al. [64] WR dlPAG 15.0, 30.0, 60.0 nmol/0.2 μl, acute EPM Anxiolytic Both effects ↓ by intra-dlPAG WAY100635 but not intra-dlPAG AM251
VCT Anxiolytic
Bitencourt et al. [65] WR i.c.v. 2.0 μg/μl
5 min before extinction, acute
CFC
extinction
Anxiolytic Extinction effect ↓ by SR141716A but not capsazepine
EPM before and 24 h after CFC No effect before CFC
Anxiolytic following CFC
Campos et al. [66] WR dlPAG 30, 60 mg/kg, acute EPM Anxiolytic Intra-dlPAG capsazepine renders 60 mg/kg anxiolytic
Resstel et al. [67] WR i.p. 1, 10 or 20 mg/kg, acute RS Anxiolytic,
↓ Pressor
↓ Tachycardia
All effects ↓ by systemic WAY100635
EPM 24 h
following RS
Anxiolytic
Soares et al. [68] WR dlPAG 15, 30 or 60 nmol, acute ETM Anxiolytic
Panicolytic
All effects ↓ by intra-dlPAG WAY100635 but not AM251
PAG E-stim Panicolytic
Long et al. [69] C57BL/6 J mice i.p. 1, 5, 10, 50 mg/kg, chronic, daily/21 d EPM No effect NA
L-DT 1 mg/kg
anxiolytic
SI No effect
OF 50 mg/kg anxiolytic
Lemos et al. [70] WR i.p.
PL
IL
10 mg/kg IP, 30 nmol intra-PL and intra-IL, acute CFC IP and PL anxiolytic IL anxiogenic NA
Casarotto et al. [71] C57BL/6 J mice i.p. 15, 30, and 60 mg/kg, acute, or subchronic, daily/7 d MBT Anticompulsive Effect ↓ by IP AM251 but not WAY100635
Gomes et al. [72] WR BNST 15, 30, and 60 nmol, acute EPM Anxiolytic Both effects ↓ by intra BNST WAY100635
VCT Anxiolytic
Granjeiro et a l. [73] WR Intracisternal 15, 30, and 60 nmol, acute RS Anxiolytic, ↓Pressor ↓Tachycardia NA
EPM 24 h after RS Anxiolytic
Deiana et al. [74] SM i.p.
Oral
120 mg/kg, acute MBT Anticompulsive NA
Uribe-Marino et al. [75] SM i.p. 0.3, 3.0, 30.0 mg/kg, acute PS Panicolytic NA
Stern et al. [76] WR i.p. 3, 10, 30 mg/kg
immediately after retrieval, acute
Reconsolidation blockade Anxiolytic
1 and 7 d old fear memories disrupted
Effect ↓ by AM251 but not WAY100635
Campos et al. [77] WR i.p. 5 mg/kg, subchronic, daily/7 d EPM following PS Anxiolytic Effects ↓ by IP WAY100635
Hsiao et al. [78] WR CeA 1 μg/μl REM sleep time ↓ REM sleep suppression NA
EPM Anxiolytic
OF Anxiolytic
Gomes et al. [79] WR BNST 15, 30, 60 nmol, acute CFC Anxiolytic Both effects ↓ by intra-BNST WAY100635
El Batsh et al. [80] LE-H R i.p. 10 mg/kg, chronic,
daily/14 d
CFC Anxiogenic NA
Campos et al. [81] C57BL/6 mice i.p. 30 mg/kg 2 h after CUS,
chronic daily/14 d
EPM Anxiolytic Both effects ↓ by AM251
NSF Anxiolytic
Do Monte et al. [82] L-E HR IL 1 μg or 0.4 μg/0.2 μl 5 min before extinction daily/4 d Extinction of CFC Anxiolytic Effect ↓ by IP rimonabant
Campos et al. [83] Rat i.p. 5 mg/kg, chronic, daily/21 d ETM Anxiolytic
Panicolytic
Panicolytic effect ↓ by intra-dlPAG WAY100635
Almeida et al. [84] Rat i.p. 1, 5, 15 mg/kg, acute SI Anxiolytic NA
Gomes et al. [85] WR BNST 30 and 60 nmol, acute RS Anxiogenic
↑ Tachydardia
Effect ↓ by WAY100635
Twardowschy et al. [86] SM i.p. 3 mg/kg, acute PS Panicolytic Effects ↓ by IP WAY100635
Focaga et al. [87] WR PL 15, 30, 60 nmol, acute EPM Anxiogenic All effects ↓ by intra PL WAY100635
Anxiolytic EPM effect post-RS ↓ by IP metyrapone
EPM after RS Anxiolytic
CFC Anxiolytic
Nardo et al. [88] SM i.p. 30 mg/kg, acute MBT Anticompulsive NA
da Silva et al. [89] WR SNpr 5 μg/0.2 μl GABAA blockade in dlSC Panicolytic Both effects ↓ by AM251

Effective doses are in bold

Receptor specific agents: AM251 = cannabinoid receptor type 1 (CB1R) inverse agonist; WAY100635 = 5-hydroxytryptamine 1A antagonist; SR141716A = CB1R antagonist; rimonabant = CB1R antagonist; capsazepine = transient receptor potential vanilloid type 1 antagonist; naloxone = opioid antagonist; flumazenil = GABAA receptor antagonist

Anxiolytic effects in models used: CER = reduced fear response; CFC = reduced conditioned freezing; CFC extinction = reduced freezing following extinction training; EPM = reduced % time in open arm; ETM = decreased inhibitory avoidance; L-DT = increased % time in light; VCT = increased licks indicating reduced conflict; NSF = reduced latency to feed; OF = increased % time in center; SI = increased social interaction

Anticomplusive effects: MBT = reduced burying

Panicolytic effects: ETM = decreased escape; GABAA blockade in dlSC = defensive immobility, and explosive escape; PAG-E-Stim = increased threshold for escape; PS = reduced explosive escape

WR = Wistar rats; SM = Swiss mice; L-E HR = Long–Evans hooded rats; i.p. = intraperitoneal; dlPAG = dorsolateral periaqueductal gray; i.c.v. = intracerebroventricular; PL = prelimbic; IL = infralimbic; BNST = bed nucleus of the stria terminalis; CeA = amygdala central nucleus; SNpr = substantia nigra pars reticularis; CUS = chronic unpredictable stress; GSCT = Geller–Seifter conflict test; CER = conditioned emotional response; EPM = elevated plus maze; VCT = Vogel conflict test; CFC = contextual fear conditioning; RS = restraint stress; ETM = elevated T maze; PAG E-stim = electrical stimulation of the dlPAG; L-DT = light–dark test; SI = social interaction; OF = open field; MBT = marble-burying test; PS = predator stress; NSF = novelty suppressed feeding test; GABAA = γ-aminobutyric acid receptor A; dlSC = deep layers superior colliculus; REM = rapid eye movement; NA = not applicable

Anxiolytic effects of CBD in models of generalized anxiety have been linked to specific receptor mechanisms and brain regions. The midbrain dorsal periaqueductal gray (DPAG) is integral to anxiety, orchestrating autonomic and behavioral responses to threat [91], and DPAG stimulation in humans produces feelings of intense distress and dread [92]. Microinjection of CBD into the DPAG produced anxiolytic effects in the EPM, VGC, and ETM that were partially mediated by activation of 5-HT1ARs but not by CB1Rs [65, 68]. The bed nucleus of the stria terminalis (BNST) serves as a principal output structure of the amygdaloid complex to coordinate sustained fear responses, relevant to anxiety [93]. Anxiolytic effects of CBD in the EPM and VCT occurred upon microinjection into the BNST, where they depended on 5-HT1AR activation [79], and also upon microinjection into the central nucleus of the amygdala [78]. In the prelimbic cortex, which drives expression of fear responses via connections with the amygdala [94], CBD had more complex effects: in unstressed rats, CBD was anxiogenic in the EPM, partially via 5-HT1AR receptor activation; however, following acute restraint stress, CBD was anxiolytic [87]. Finally, the anxiolytic effects of systemic CBD partially depended on GABAA receptor activation in the EPM model but not in the VCT model [61, 62].

As noted, CBD has been found to have a bell-shaped response curve, with higher doses being ineffective. This may reflect activation of TRPV1 receptors at higher dose, as blockade of TRPV1 receptors in the DPAG rendered a previously ineffective high dose of CBD as anxiolytic in the EPM [66]. Given TRPV1 receptors have anxiogenic effects, this may indicate that at higher doses, CBD’s interaction with TRPV1 receptors to some extent impedes anxiolytic actions, although was notably not sufficient to produce anxiogenic effects.

Stress-induced Anxiety Models

Stress is an important contributor to anxiety disorders, and traumatic stress exposure is essential to the development of PTSD. Systemically administered CBD reduced acute increases in heart rate and blood pressure induced by restraint stress, as well as the delayed (24 h) anxiogenic effects of stress in the EPM, partially by 5-HT1AR activation [67, 73]. However intra-BNST microinjection of CBD augmented stress-induced heart rate increase, also partially via 5-HT1AR activation [85]. In a subchronic study, CBD administered daily 1 h after predator stress (a proposed model of PTSD) reduced the long-lasting anxiogenic effects of chronic predator stress, partially via 5-HT1AR activation [77]. In a chronic study, systemic CBD prevented increased anxiety produced by chronic unpredictable stress, in addition to increasing hippocampal AEA; these anxiolytic effects depended upon CB1R activation and hippocampal neurogenesis, as demonstrated by genetic ablation techniques [81]. Prior stress also appears to modulate CBD’s anxiogenic effects: microinjection of CBD into the prelimbic cortex of unstressed animals was anxiogenic in the EPM but following restraint stress was found to be anxiolytic [87]. Likewise, systemic CBD was anxiolytic in the EPM following but not prior to stress [65].

PD and Compulsive Behavior Models

CBD inhibited escape responses in the ETM and increased DPAG escape electrical threshold [68], both proposed models of panic attacks [95]. These effects partially depended on 5-HT1AR activation but were not affected by CB1R blockade. CBD was also panicolytic in the predator–prey model, which assesses explosive escape and defensive immobility in response to a boa constrictor snake, also partially via 5-HT1AR activation; however, more consistent with an anxiogenic effect, CBD was also noted to decrease time spent outside the burrow and increase defensive attention (not shown in Table ​ Table1) 1 ) [75, 86] . Finally, CBD, partially via CB1Rs, decreased defensive immobility and explosive escape caused by bicuculline-induced neuronal activation in the superior colliculus [89]. Anticompulsive effects of CBD were investigated in marble-burying behavior, conceptualized to model OCD [96]. Acute systemic CBD reduced marble-burying behavior for up to 7 days, with no attenuation in effect up to high (120 mg/kg) doses, and effect shown to depend on CB1Rs but not 5-HT1ARs [71, 74, 88].

Contextual Fear Conditioning, Fear Extinction, and Reconsolidation Blockade

Several studies assessed CBD using contextual fear conditioning. Briefly, this paradigm involves pairing a neutral context, the conditioned stimulus (CS), with an aversive unconditioned stimulus (US), a mild foot shock. After repeated pairings, the subject learns that the CS predicts the US, and subsequent CS presentation elicits freezing and other physiological responses. Systemic administration of CBD prior to CS re-exposure reduced conditioned cardiovascular responses [63], an effect reproduced by microinjection of CBD into the BNST, and partially mediated by 5-HT1AR activation [79]. Similarly, CBD in the prelimbic cortex reduced conditioned freezing [70], an effect prevented by 5-HT1AR blockade [87]. By contrast, CBD microinjection in the infralimbic cortex enhanced conditioned freezing [70]. Finally, El Batsh et al. [80] reported that repeated CBD doses over 21 days, that is chronic as opposed to acute treatment, facilitated conditioned freezing. In this study, CBD was administered prior to conditioning rather than prior to re-exposure as in acute studies, thus further directly comparable studies are required.

CBD has also been shown to enhance extinction of contextually conditioned fear responses. Extinction training involves repeated CS exposure in the absence of the US, leading to the formation of a new memory that inhibits fear responses and a decline in freezing over subsequent training sessions. Systemic CBD administration immediately before training markedly enhanced extinction, and this effect depended on CB1R activation, without involvement of TRPV1 receptors [65]. Further studies showed CB1Rs in the infralimbic cortex may be involved in this effect [82].

CBD also blocked reconsolidation of aversive memories in rat [76]. Briefly, fear memories, when reactivated by re-exposure (retrieval), enter into a labile state in which the memory trace may either be reconsolidated or extinguished [97], and this process may be pharmacologically modulated to achieve reconsolidation blockade or extinction. When administered immediately following retrieval, CBD prevented freezing to the conditioned context upon further re-exposure, and no reinstatement or spontaneous recovery was observed over 3 weeks, consistent with reconsolidation blockade rather than extinction [76]. This effect depended on CB1R activation but not 5-HT1AR activation [76].

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Summary and Clinical Relevance

Overall, existing preclinical evidence strongly supports the potential of CBD as a treatment for anxiety disorders. CBD exhibits a broad range of actions, relevant to multiple symptom domains, including anxiolytic, panicolytic, and anticompulsive actions, as well as a decrease in autonomic arousal, a decrease in conditioned fear expression, enhancement of fear extinction, reconsolidation blockade, and prevention of the long-term anxiogenic effects of stress. Activation of 5-HT1ARs appears to mediate anxiolytic and panicolytic effects, in addition to reducing conditioned fear expression, although CB1R activation may play a limited role. By contrast, CB1R activation appears to mediate CBD’s anticompulsive effects, enhancement of fear extinction, reconsolidation blockade, and capacity to prevent the long-term anxiogenic consequences of stress, with involvement of hippocampal neurogenesis.

While CBD predominantly has acute anxiolytic effects, some species discrepancies are apparent. In addition, effects may be contingent on prior stress and vary according to brain region. A notable contrast between CBD and other agents that target the eCB system, including THC, direct CB1R agonists and FAAH inhibitors, is a lack of anxiogenic effects at a higher dose. Further receptor-specific studies may elucidate the receptor specific basis of this distinct dose response profile. Further studies are also required to establish the efficacy of CBD when administered in chronic dosing, as relatively few relevant studies exist, with mixed results, including both anxiolytic and anxiogenic outcomes.

Overall, preclinical evidence supports systemic CBD as an acute treatment of GAD, SAD, PD, OCD, and PTSD, and suggests that CBD has the advantage of not producing anxiogenic effects at higher dose, as distinct from other agents that enhance CB1R activation. In particular, results show potential for the treatment of multiple PTSD symptom domains, including reducing arousal and avoidance, preventing the long-term adverse effects of stress, as well as enhancing the extinction and blocking the reconsolidation of persistent fear memories.

Human Experimental and Clinical Studies

Evidence from Acute Psychological Studies

Relevant studies are summarized in Table ​ Table2. 2 . The anxiolytic effects of CBD in humans were first demonstrated in the context of reversing the anxiogenic effects of THC. CBD reduced THC-induced anxiety when administered simultaneously with this agent, but had no effect on baseline anxiety when administered alone [99, 100]. Further studies using higher doses supported a lack of anxiolytic effects at baseline [101, 107]. By contrast, CBD potently reduces experimentally induced anxiety or fear. CBD reduced anxiety associated with a simulated public speaking test in healthy subjects, and in subjects with SAD, showing a comparable efficacy to ipsapirone (a 5-HT1AR agonist) or diazepam [98, 105]. CBD also reduced the presumed anticipatory anxiety associated with undergoing a single-photon emission computed tomography (SPECT) imaging procedure, in both healthy and SAD subjects [102, 104]. Finally, CBD enhanced extinction of fear memories in healthy volunteers: specifically, inhaled CBD administered prior to or after extinction training in a contextual fear conditioning paradigm led to a trend-level enhancement in the reduction of skin conductance response during reinstatement, and a significant reduction in expectancy (of shock) ratings during reinstatement [106].

Table 2

Human psychological studies

Study Subjects,
design
CBD route,
dose
Measure Effect
Karniol et al. [99] HV,
DBP
Oral, 15, 30, 60 mg, alone or with THC,
acute, at 55, 95, 155, and 185 min
Anxiety and pulse rate after THC and at baseline ↓ THC-induced increases in subjective anxiety and pulse rate
No effect at baseline
Zuardi et al., [100] HV,
DBP
Oral 1 mg/kg alone or with THC, acute, 80 min STAI score after THC ↓ THC-induced increases in STAI scores
Zuardi et al. [98] HV,
DBP
Oral 300 mg,
acute, 80 min
VAMS, STAI and BP following SPST ↓ STAI scores
↓ VAMS scores
↓ BP
Martin-Santos et al. [101] HV,
DBP
Oral 600 mg,
acute, 1, 2, 3 h
Baseline anxiety and pulse rate No effect
Crippa et al. [102] 10 HV,
DBP
Oral 400 mg,
acute, 60 and 75 min
VAMS before SPECT
SPECT
↓ VAMS scores
Bhattacharyya et al. [103] 15 HV
DBP
Oral 600 mg,
acute, 1, 2, 3 h
STAI scores
VAMS scores
↓ STAI scores
↓ VAMS scores
Crippa et al. [104] SAD and HC
DBP
Oral 400 mg,
acute, 75 and 140 min
VAMS before SPECT
SPECT
↓ VAMS scores
Bergamaschi et al. [105] SAD and HC DBP Oral 600 mg, acute, 1, 2, 3 h VAMS, SSPS-N, cognitive impairment, SCR, HR after SPST ↓ VAMS, SSPS-N and cognitive impairment, no effect on SCR or HR
Das et al. [106] HV
DBP
Inhaled, 32 mg, acute, immediately following, before, after extinction SCR and shock expectancy following extinction CBD after extinction training produced trend level reduction in SCR and decreased shock expectancy
Hindocha et al. [107] Varying in schizotypy and cannabis use, DBP Inhaled, 16 mg, acute Baseline VAS anxiety No significant effect of CBD

HV = healthy volunteers; DBP = double-blind placebo; SAD = social anxiety disorder; HC = healthy controls; THC = Δ 9-tetrahydrocannabinol; STAI = Spielberger’s state trait anxiety inventory; VAMS = visual analog mood scale; BP = blood pressure; SPST = simulated public speaking test; SCR = skin conductance response; SPECT = single-photon emission computed tomography; SSPS-N = negative self-evaluation subscale; HR = heart rate; VAS = visual analog scale, CBD = cannabidiol

Evidence from Neuroimaging Studies

Relevant studies are summarized in Table ​ Table3. 3 . In a SPECT study of resting cerebral blood flow (rCBF) in normal subjects, CBD reduced rCBF in left medial temporal areas, including the amygdala and hippocampus, as well as the hypothalamus and left posterior cingulate gyrus, but increased rCBF in the left parahippocampal gyrus. These rCBF changes were not correlated with anxiolytic effects [102]. In a SPECT study, by the same authors, in patients with SAD, CBD reduced rCBF in overlapping, but distinct, limbic and paralimbic areas; again, with no correlations to anxiolytic effects [104].

Table 3

Study Subjects, design CBD route, dose, timing Measure Effect of CBD
Crippa et al. [102] 10 HV,
DBP
Oral 400 mg,
acute, 60 and 75 min
SPECT, resting (rCBF) ↓ rCBF in left medial temporal cluster, including amygdala and HPC, also ↓ rCBF in the HYP and posterior cingulate gyrus
↑ rCBF in left PHG
Borgwardt et al. [108] 15 HV,
DBP
Oral 600 mg,
acute, 1–2 h
fMRI during oddball and go/no-go task ↓ Activation in left insula, STG and MTG
Fusar-Poli et al. [109] 15 HV,
DBP
Oral 600 mg,
acute, 1–2 h
fMRI activation during fearful faces task ↓ Activation in left medial temporal region, including amygdala and anterior PHG, and in right ACC and PCC
Fusar-Poli et al. [110] 15 HV,
DBP
Oral 600 mg,
acute, 1–2 h
fMRI functional connectivity during fearful faces task ↓ Functional connectivity between L) AMY and ACC
Crippa et al. [104] SAD and HC
DBP
Oral 400 mg,
acute, 75 and 140 min
SPECT, resting (rCBF) ↓ rCBF in the left PHG, HPC and ITG.
↑ rCBF in the right posterior cingulate gyrus

CBD = cannabidiol; HV = healthy controls; DBP = double-blind placebo; SAD = social anxiety disorder; HC = healthy controls; SPECT = single-photo emission computed tomography; rCBF = regional cerebral blood flow; fMRI = functional magnetic resonance imaging; HPC = hippocampus; HYP = hypothalamus; PHG = parahippocampal gyrus; STG = superior temporal gyrus; MTG = medial temporal gyrus; ACC = anterior cingulate cortex; PCC = posterior cingulate cortex

In a series of placebo-controlled studies involving 15 healthy volunteers, Fusar-Poli et al. investigated the effects of CBD and THC on task-related blood-oxygen-level dependent functional magnetic resonance imaging activation, specifically the go/no-go and fearful faces tasks [109, 110]. The go/no-go task measures response inhibition, and is associated with activation of medial prefrontal, dorsolateral prefrontal, and parietal areas [111]. Response activation is diminished in PTSD and other anxiety disorders, and increased activation predicts response to treatment [112]. CBD produced no changes in predicted areas (relative to placebo) but reduced activation in the left insula, superior temporal gyrus, and transverse temporal gyrus. The fearful faces task activates the amygdala, and other medial temporal areas involved in emotion processing, and heightened amygdala response activation has been reported in anxiety disorders, including GAD and PTSD [113, 114]. CBD attenuated blood-oxygen-level dependent activation in the left amygdala, and the anterior and posterior cingulate cortex in response to intensely fearful faces, and also reduced amplitude in skin conductance fluctuation, which was highly correlated with amygdala activation [109]. Dynamic causal modeling analysis in this data set further showed CBD reduced forward functional connectivity between the amygdala and anterior cingulate cortex [110].

Evidence from Epidemiological and Chronic Studies

Epidemiological studies of various neuropsychiatric disorders indicate that a higher CBD content in chronically consumed cannabis may protect against adverse effects of THC, including psychotic symptoms, drug cravings, memory loss, and hippocampal gray matter loss [115–118] (reviewed in [119]). As THC acutely induces anxiety, this pattern may also be evident for chronic anxiety symptoms. Two studies were identified, including an uncontrolled retrospective study in civilian patients with PTSD patients [120], and a case study in a patient with severe sexual abuse-related PTSD [121], which showed that chronic cannabis use significantly reduces PTSD symptoms; however, these studies did not include data on the THC:CBD ratio. Thus, overall, no outcome data are currently available regarding the chronic effects of CBD in the treatment of anxiety symptoms, nor do any data exist regarding the potential protective effects of CBD on anxiety potentially induced by chronic THC use.

Summary and Clinical Relevance

Evidence from human studies strongly supports the potential for CBD as a treatment for anxiety disorders: at oral doses ranging from 300 to 600 mg, CBD reduces experimentally induced anxiety in healthy controls, without affecting baseline anxiety levels, and reduces anxiety in patients with SAD. Limited results in healthy subjects also support the efficacy of CBD in acutely enhancing fear extinction, suggesting potential for the treatment of PTSD, or for enhancing cognitive behavioral therapy. Neuroimaging findings provide evidence of neurobiological targets that may underlie CBD’s anxiolytic effects, including reduced amygdala activation and altered medial prefrontal amygdala connectivity, although current findings are limited by small sample sizes, and a lack of independent replication. Further studies are also required to establish whether chronic, in addition to acute CBD dosing is anxiolytic in human. Also, clinical findings are currently limited to SAD, whereas preclinical evidence suggests CBD’s potential to treat multiple symptom domains relevant to GAD, PD, and, particularly, PTSD.

Conclusions

Preclinical evidence conclusively demonstrates CBD’s efficacy in reducing anxiety behaviors relevant to multiple disorders, including PTSD, GAD, PD, OCD, and SAD, with a notable lack of anxiogenic effects. CBD’s anxiolytic actions appear to depend upon CB1Rs and 5-HT1ARs in several brain regions; however, investigation of additional receptor actions may reveal further mechanisms. Human experimental findings support preclinical findings, and also suggest a lack of anxiogenic effects, minimal sedative effects, and an excellent safety profile. Current preclinical and human findings mostly involve acute CBD dosing in healthy subjects, so further studies are required to establish whether chronic dosing of CBD has similar effects in relevant clinical populations. Overall, this review emphasizes the potential value and need for further study of CBD in the treatment of anxiety disorders.

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