benefits of cbd oil for mental health

5 Mental Health Uses for CBD

Kendra Cherry, MS, is an author and educational consultant focused on helping students learn about psychology.

Steven Gans, MD is board-certified in psychiatry and is an active supervisor, teacher, and mentor at Massachusetts General Hospital.

The cannabis plant has been utilized for medicinal purposes for thousands of years. The plant contains more than 80 different compounds, which are known as cannabinoids. While tetrahydrocannabinol (THC) is the most abundant and is well-known for its psychoactive properties, the second-most found compound, cannabidiol (CBD) does not have psychoactive effects.  

There has been a growing interest in the potential mental health benefits of CBD in recent years. A 2019 research letter published by JAMA Network Open reported a significant increase in Internet searches for CBD in the United States. While search rates remained steady between 2004 and 2014, there was a 125.9% increase between 2016 and 2017. In April 2019 alone, there were 6.4 million Google searches for CBD information.  

While there have been a number of studies suggesting that CBD might mental health benefits, a recent comprehensive review found that support for this use was scant and that further investigation is needed to substantiate the purported benefits.  

There are a number of conditions that CBD is purported to help, although more research is needed to determine the potential effects and benefits of CBD. Some of the existing studies suggest that CBD holds promise in the treatment of a number of conditions including depression, anxiety, epilepsy, and sleep issues, among other things.

Epilepsy

CBD appears to have a range of benefits for neurologic disorders, including decreasing the frequency and severity of seizures. Some of these conditions, such as Dravet syndrome and Lennox-Gastaut syndrome (LGS), may not respond well to anti-seizure medications. Viral clips of CBD treatments effectively alleviating seizures were shared widely in social media in recent years, and research has supported the effectiveness of these treatments.

A large-scale study on the use of CBD in the treatment of pediatric epilepsy found that CBD reduced the frequency of seizures by more than 50% in 43% of the patients with Dravet syndrome. The Food and Drug Administration (FDA) recently approved a cannabis-derived medication containing CBD, Epidiolex, to treat certain childhood seizure disorders.

Anxiety

Anxiety is a common problem for many people. Anxiety disorders affect an estimated 19.1% of U.S. adults each year. Some studies suggest that CBD may help alleviate symptoms of anxiety. One study look at the possible neural basis for CBD reducing symptoms of social anxiety disorder.

A 2015 study published in the journal Neurotherapeutics analyzed the existing preclinical studies on the use of CBD for anxiety and found that CBD was effective for a number of anxiety conditions including:

However, the authors of the study note that while the substance has considerable potential, further research is needed to better determine the therapeutic benefits and long-term effects.

Depression

According to the National Institute of Mental Health, depression is one of the most common mental disorders in the U.S., affecting an estimated 17.3 million adults each year. Effective treatments are available, which include psychotherapy and medication, although interest in complementary and alternative treatments has also grown in recent years.

CBD has been investigated for having potential antidepressant effects. Some antidepressants work by acting on serotonin receptors in the brain. Low serotonin levels may play a role in the development of depression, and animal studies suggest that CBD might have an impact on these receptors which may produce antidepressant effects.

A 2018 study found that the antidepressant-like effects that CBD produces depend upon the serotonin levels in the brain. Cannabidiol does not appear to increase serotonin levels but instead affects how the brain responds to serotonin that is already present in your body.

Sleep Difficulties

Because CBD may have a calming effect, it may also hold promise in treating sleeping difficulties. Sleep is a critical component of mental health and well-being, yet the Centers for Disease Control and Prevention (CDC) reports that a third of U.S. adults do not get the recommended amount of sleep each night. This is problematic since not getting enough sleep is linked to health conditions such as depression, type 2 diabetes, obesity, and heart disease.

One study conducted with adults who had symptoms of anxiety and poor sleep found that 65% experienced improvements in sleep quality scores after a month of taking an average of 25mg of CBD daily, although those scores fluctuated over time. Further research is needed to determine the possible effects of CBD on sleep.

Post-Traumatic Stress Disorder (PTSD)

PTSD affects approximately 6.1% of U.S. adults. It is characterized by symptoms including re-experiencing traumatic events, intrusive thoughts, nightmares, and avoidance of things that may trigger memories of the trauma.

Some research suggests that CBD may be helpful in reducing the symptoms of this condition. In one study published in the Journal of Alternative and Complementary Medicine, researchers found that an oral dose of CBD in addition to routine psychiatric treatment for PTSD was associated with a reduction in symptoms.  

Should You Try CBD?

While CBD holds promise, a recent comprehensive review of the research suggests that support for the mental health uses of CBD remains insufficient. This 2019 study was published in The Lancet Psychiatry and looked at 83 studies on the use of CBD to treat mental illness.  

The researchers looked specifically at six different disorders: depressive disorders, anxiety disorders, attention-deficit hyperactivity disorder, Tourette syndrome, post-traumatic stress disorder, and psychosis. The review examined previous studies dating from 1980 through 2018.

The review concluded that there is not enough evidence to support the use of CBD in the treatment of mental health conditions.

The study did find that pharmaceutical TCH (either with or without CBD) was linked to small improvements in symptoms of anxiety among people with other medical conditions such as chronic pain and MS, although this evidence was considered low-quality.

This does not mean that CBD isn't necessarily effective; of the studies reviewed, most only included a small number of participants, followed participants for a short period of time, and less than half were randomized controlled trials.

Instead, this study suggests that there simply isn't yet enough high-quality evidence to support the use of CBD to treat mental conditions. This may change in the future as more research is carried out.

Many experts remain optimistic that CBD may prove useful for a range of mental health conditions. "CBD has shown therapeutic efficacy in a range of animal models of anxiety and stress, reducing both behavioral and physiological (e.g., heart rate) measures of stress and anxiety," suggested Nora D. Volkow, the Director of the National Institute of Drug Abuse in testimony presented to the Senate Caucus on International Narcotics Control.

Types

CBD is available in a number of different forms and products. Cannabidiol can be extracted from both hemp and marijuana plants, which differ in terms of how much CBD and THC can be extracted.

CBD from hemp plants contains only small amounts of THC that are not sufficient to produce subjective psychoactive effects. CBD produced from marijuana plants, however, may contain varying amounts of THC which can produce unwanted effects.

There are also three main types of CBD available.

  • Isolate contains only CBD
  • Full-spectrum contains other compounds found in the cannabis plant, including THC
  • Broad-spectrum contains other compounds from the cannabis plant but not THC

People may choose to take a full-spectrum product because research has shown that when cannabinoids including THC and CBD are taken together, it magnifies the therapeutic impact, a phenomenon known as the entourage effect.   Research also suggests that CBD can actually counteract the negative effects caused by THC.  

Like full-spectrum CBD, products labeled as broad-spectrum contain multiple cannabinoids, which are purported to provide the therapeutic benefits of the entourage effect without the psychoactive effects of THC.

Some of the ways that CBD can be used include:

  • Oral: This includes oils (which are made by infusing cannabidiol with a carrier oil), oil tinctures (which are produced by combining CBD with alcohol or water), sprays, and capsules.
  • Topical: This includes salves or lotions that are applied to the skin
  • Edibles: This can include candies, gummies, and beverages.
  • Inhaled: Some CBD oils are specially formulated to be used as vaping oil, although there has been an increase in concern about the health dangers posed by vaping.

Topical solutions may produce localized effects, but only those taken by mouth are likely to produce any mental health effects. It is important to note that while there is a wide variety of these products available on the market, the FDA has not approved any over-the-counter (OTC) CBD product. Many of these products may vary in terms of what they contain, their potency, and their effectiveness.

It is also important to note that while hemp-derived CBD that contains less than 0.3% THC is legal by federal law, it is still illegal in some states. You should always check your state laws before purchasing a CBD product.

Possible Side Effects

While CBD may have some benefits, it is also important to consider some of the possible risks. Research suggests that CBD appears to be well-tolerated at doses up to 600mg.  

While CBD appears to be well-tolerated, that does not mean that it is without side effects. While these may vary depending on the individual, some reported side effects include:

  • Anxiety
  • Mood changes
  • Appetite changes
  • Nausea
  • Dizziness
  • Drowsiness

However, understanding the potential side effects is difficult because of the absence of regulation and manufacturing guidelines, which means that there is a lack of consistency in terms of purity and labeling. In other words, it is difficult to determine if the side effects are the same across different products, formulations, and dosages because it is often difficult to determine exactly what is in the products that are currently on the market.

Potential Pitfalls

It is important to talk to your doctor if you are thinking about taking CBD products. This is particularly true if you have an existing medical or psychiatric condition, or if you are currently taking any medications or supplements.

CBD may potentially have an effect on your condition or may interact with a medication that you are taking. For example, CBD can sometimes worsen symptoms of anxiety. CBD can also interfere with the metabolism of certain medications, which may change how your medications affect your body.

Some other concerns to consider before taking CBD:

  • Drug testing: There have been reports of people failing drug tests after using CBD products that are labeled as containing no THC. While most CBD products contain only trace amounts of THC, there is still the possibility that these products may produce a positive result on a drug test. It is also important to remember that full-spectrum CBD products do contain varying amounts of THC.  
  • Mislabeling: Labeling accuracy also appears to be a common problem. One study found that almost 70% of CBD products sold online were mislabeled and contained significant amounts of THC.   This can be problematic if you are taking CBD to address a mental health condition such as anxiety, since THC may have unwanted psychoactive effects. Mislabeling may also lead to positive drug test results, especially if the product contains more THC than it claims.
  • Other possible risks: Finally, it is important to remember that researchers still do not know all the possible risks or benefits of taking CBD. More research is needed to learn about the mental and physical long-term effects of CBD, so you should always use caution and consult your doctor before using it.

A Word From Verywell

If you are experiencing the symptoms of a mental health condition, you should talk to a doctor or mental health professional. Self-medicating with CBD or other supplements can lead to delays in treatment, which may cause your symptoms to worsen. CBD also has the potential to aggravate some symptoms such as anxiety, sleep problems, and psychosis.

If you are still interested in trying CBD as an addition to your regular treatment, work with a healthcare provider who can help monitor your symptoms. Your doctor may recommend a product and dosage that is appropriate based on your symptoms and any medications you are taking. Always be sure to watch out for any potential negative side effects and be sure to talk to your doctor before you stop taking CBD.

CBD Oil for Mental Health—Should You Take It Too?

Is this supplement simply snake oil, or is it actually good for mental health?

THE BASICS

  • What Is CBD?
  • Find a therapist near me

About 20 percent of the population suffers from some form of anxiety. If you have anxiety, you may be looking for a new way to relax your body and mind. Many of my patients and followers on Twitter and Facebook have reached out to ask me whether CBD oil is the newest snake oil, or whether can it really help ameliorate symptoms of anxiety without causing side effects.

What is CBD oil?

Cannabidiol (CBD) oil is a natural plant-based oil that contains phyto (plant) chemicals called cannabinoids. Cannabinoids are “feel good” molecules naturally made by the body when we are feeling relaxed and secure or involved in something that makes us happy, like hugging someone we care about or sitting down to a meal we are looking forward to. Cannabinoids are also released when we sleep well and exercise. Cannabinoids bind to little docking stations in our bodies called cannabinoid receptors that help stimulate those feel-good responses. Discovered in 1992, the main cannabinoid molecule is called anandamide, which is translated from the Sanskrit as “bliss molecule.”

The cannabinoid system is key to helping the body keep itself in balance. This system ensures our stomach and intestines run well, keeps inflammation down, and modulates pain while helping to maintain our mood in a good place. Research suggests the cannabinoids from CBD can stop the breakdown of anandamide. When we retain more anandamide in our body, there’s more bliss.

Will CBD oil make me high, like marijuana?

No, it will not. I tell my patients if you are looking to feel high, then you will be disappointed. Supplemental CBD oil comes from the hemp plant. Hemp is a cannabis plant and a close cousin of marijuana. However, CBD from hemp has practically no tetra-hydro-cannabinoids (THC). THC is the substance in marijuana that has psychoactive effects and can give you a high. In fact, a number of studies on CBD showed that CBD itself can counter the negative effects of THC—including appetite issues, weight gain, and paranoia.

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Is CBD oil legal?

CBD that comes from hemp is legal in all 50 states. As I mentioned in the last paragraph, CBD has no effective amount of THC. There is a tiny bit, but it is not enough to cause any psychoactive effects. As a result, there are none of the legal concerns associated with marijuana.

Is CBD effective for mental health challenges?

For decades, the World Health Organization’s expert committee on drug dependence has offered a long list of conditions that CBD may benefit. Research studies on both animals and humans have shown that CBD may help lower feelings of isolation, relieve autism symptoms, and reduce the effects of post-traumatic stress disorder (PTSD). It seems CBD can calm the brain and support the hippocampus, which is a brain area important for healthy emotion and memory.

One study showed CBD could reduce social anxiety in a way comparable to ipsapirone and diazepam (valium). A 2012 double-blind, randomized clinical trial looked at the benefits of CBD for psychosis. In this study, 40 volunteer patients were given CBD or an antipsychotic. Both treatments helped patient symptoms equally, while the group taking CBD enjoyed many fewer side effects and no problems with movement, weight gain, or hormonal dysregulation—all common side effects of antipsychotic medications. A version of CBD oil was just studied for its benefits in childhood epilepsy—and will now be released as simply a CBD oil.

THE BASICS

  • What Is CBD?
  • Find a therapist near me

Is CBD safe?

CBD seems to be exceedingly safe. In fact, the FDA-approved use of CBD in epilepsy was studied in children, which suggests both kids and adults can use it safely. While it has effects on relaxing the body and helping with pain, CBD does not suppress the breathing centers of the brain the way opioid drugs do, which is why there is not the concern, even in overdose, that you would have for pain-killing drugs.

Since the 1960s, medical research has collected research supporting the safety of CBD. Typical doses of 10mg to 100mg a day show no negative effects. Even one study where patients took 1,280 mg a day did not see a problem. The director of the National Institute of Drug Abuse has stated that CBD oil is safe, and recently the FDA approved CBD oil for use in children with epilepsy.

CBD Essential Reads

Could CBD Oil Help Treat Schizophrenia?

Despite What You May Think, CBD Is Not Weed

I have been working with CBD in my practice for about two years and have not seen a problem. Sometimes, when patients get more relaxed, it can give them a strange sensation. Understandably, that can be concerning to patients who are not used to feeling calm.

Please note that, because of the way the liver works, CBD may affect the clearance of other drugs you are taking. As always, it’s a good idea to check with your doctor before starting any new herbal supports, especially if you are taking prescription medications.

Can CBD oil cause a positive result in a drug test?

Since CBD has practically no THC, there is, in theory, little to no chance it will create a positive drug urine test. And, the follow-up confirmatory test for marijuana is too specific to come up positive from CBD. Having said this, it is important to purchase CBD from nutraceutical companies who manufacture it from varieties of hemp containing the lowest THC.

If you are not sure, and this issue could be a problem for you, you may not want to risk it—or talk to your employers about CBD oil first, before using it.

How much CBD oil should I take?

I usually recommend that patients start with 15mg of CBD once or twice a day. This oil is best taken with food. Instead of self-prescribing, I strongly recommend you work with a practitioner knowledgeable in natural medicine who is experienced with CBD, especially if you are taking other medications and/or if you have mental health symptoms that could be severe.

How about the CBD beverages and foods that are so popular?

Right now, many companies are trying to fill their shelves with CBD-infused products. My guess is that the vast majority of these are not of good quality and may contain little to no CBD. If you are going to use CBD oil as a supplement for mental health, ask your practitioner for a high-quality version that you can take in a prescribed dosage. Don’t try to get it through other products where the amount and quality are not well understood.

Remember: General anxiety support

In my books, I always recommend not simply taking supplements for anxiety, but making dietary and lifestyle changes and adopting stress-relieving rituals and therapies to bring full healing to your body. Also, visit with your doctor regularly or when issues pop up. While CBD is a very good supplement, I find its power is enhanced when combined with natural modifications.

For a more thorough look at the research and references, please see my academic review on CBD here.

Beale C. et al. Prolonged Cannabidiol Treatment Effects on Hippocampal Subfield Volumes in Current Cannabis Users. Cannabis and Cannabinoid ResearchVol. 3, No. 1. Published Online:1 Apr 2018

Bongiorno PB. CBD for Mental Health. Naturopathic News and Reviews. in press.

Crippa JA, et al. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. J Psychopharmacol. 2011 Jan;25(1):121-30

Croxford JL, Yamamura T. Cannabinoids and the immune system: potential for the treatment of inflammatory diseases? J Neuroimmunol. 2005 Sep; 166(1-2):3-18.

Dasgupta A. Chapter 10. Laboratory methods for measuring drugs of abuse in urine. in Alcohol, Drugs, Genes and the Clinical Laboratory An Overview for Healthcare and Safety Professionals. Academic Press. 2017, Pages 167-191

FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm611046.htm accessed on August 13, 2018.

Hahn B. The Potential of Cannabidiol Treatment for Cannabis Users With Recent-Onset Psychosis. Schizophr Bull. 2018 Jan 13;44(1):46-53.

Leweke FM et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2012 Mar 20;2:e94. doi: 10.1038/tp.2012.15.

Lewis M. CBD for Head Trauma. Integrative Medicine for Mental Health. Presentation. September 2018. Dallas, Texas.

McGuire P1, et al. Cannabidiol (CBD) as an Adjunctive Therapy in Schizophrenia: A Multicenter Randomized Controlled Trial. Am J Psychiatry. 2018;175(3):225-231.

Martin-Santos R, et al. Acute effects of a single, oral dose of d9-tetrahydrocannabinol (THC) and cannabidiol (CBD) administration in healthy volunteers. Curr Pharm Des. 2012; 18(32):4966-79.

Perucca, E. Cannabinoids in the Treatment of Epilepsy: Hard Evidence at Last? J Epilepsy Res. 2017 Dec; 7(2): 61–76.

Zuardi AW, et al. Cannabidiol monotherapy for treatment-resistant schizophrenia. J Psychopharmacol. 2006 Sep; 20(5):683-6.

The therapeutic role of Cannabidiol in mental health: a systematic review

The therapeutic application of cannabidiol (CBD) is gaining interest due to expanding evidence for its use.

Objective

To summarize the clinical outcomes, study designs and limitations for the use of CBD and nabiximols (whole plant extract from Cannabis sativa L. that has been purified into 1:1 ratio of CBD and delta-9-tetrahydrocannabinol) in the treatment of psychiatric disorders.

Materials and method

A systematic review was conducted including case reports, case series, open-label trials, non-randomized and randomized controlled trials (RCTs). The search resulted in 23 relevant studies on CBD and nabiximols in the treatment of a wide range of psychiatric disorders. The quality of evidence was judged by using the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence that ranges from Level 1 to Level 5 based on the quality and study design. These levels of evidence help in grading the recommendations, including Grade A (strong), Grade B (moderate), Grade C (weak), and Grade D (weakest).

Results

CBD and CBD-containing compounds such as nabiximols were helpful in alleviating psychotic symptoms and cognitive impairment in patients with a variety of conditions, and several studies provided evidence of effectiveness in the treatment of cannabis withdrawal and moderate to severe cannabis use disorder with Grade B recommendation. There is Grade B recommendation supporting the use of CBD for the treatment of schizophrenia, social anxiety disorder and autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD). Grade C recommendation exists for insomnia, anxiety, bipolar disorder, posttraumatic stress disorder, and Tourette syndrome. These recommendations should be considered in the context of limited number of available studies.

Conclusion

CBD and CBD-containing compounds such as nabiximols were helpful in alleviating symptoms of cannabis-related disorders, schizophrenia, social anxiety disorder, and comorbidities of ASD, and ADHD with moderate recommendation. However, there is weaker evidence for insomnia, anxiety, bipolar disorder, posttraumatic stress disorder, and Tourette syndrome. The evidence for the use of CBD and CBD-containing compounds for psychiatric disorders needs to be explored in future studies, especially large-scale and well-designed RCTs.

Introduction

Cannabis sativa, a species of cannabis plant, is well known to humankind, with its earliest use in ancient Chinese culture dating as far back as 2700 B.C. (Zuardi, 2006). The use of medical cannabis in China was reported in the world’s oldest pharmacopoeia (Martin et al., 1999). However, interest in the role of cannabis flourished in the late twentieth century after the recognition of an endogenous cannabinoid system in the brain (Zuardi, 2006; Martin et al., 1999). More recently, research has centered on the description and cloning of specific receptors and the therapeutic effects of medical cannabis, and different cannabinoids in the cannabis plant have gained interest (Martin et al., 1999). Recent studies have focused on the therapeutic role of medical cannabis in different disorders. As a result, there is a growing need to summarize and review the evidence for its therapeutic and adverse effects as an aid to public health policy development, and to provide direction and impetus to pharmaceutical research in this field.

The cannabis plant has more than 140 cannabinoid compounds, with Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) attracting significant interest (Citti et al., 2018). Δ9-THC is the primary psychoactive ingredient, and CBD is a non-intoxicating ingredient (Zuardi, 2006; Citti et al., 2018). Evidence from preclinical studies suggested that CBD had potential therapeutic benefits ranging from antiinflammatory to neuroprotective, antipsychotic, analgesic, anticonvulsant, antiemetic, antioxidant, antiarthritic, and antineoplastic properties; for a review, see (Pertwee, 2006). CBD has several receptors and molecular targets. This compound antagonizes the action of CB1 and CB2 receptor agonist (Blessing et al., 2015; Peres et al., 2018). The CB1 and CB2 receptors are coupled negatively through G-proteins to adenylate cyclase and positively to mitogen-activated protein kinase (Pertwee, 2006). In addition to CB1 and CB2 receptor activity, CBD is an agonist of vanilloid receptor TRPV1. It also acts as an agonist of serotonin receptor 5-hydroxytryptamine (5-HT1A), an antagonist of G-protein-coupled receptor GPR55, and an inverse agonist of GPR3, GPR6, and GPR12 (Peres et al., 2018). Data from single-photon emission computed tomography showed CBD to exert anxiolytic effects by acting on paralimbic and limbic pathways (Crippa et al., 2011). The agonist effect of CBD on 5-HT1A also supports its anxiolytic and antidepressant properties (Russo et al., 2005). CBD inhibits enzymatic hydrolysis and anandamide uptake through its agonist action on CB1, CB2, and TRPV1 receptors (Peres et al., 2018). In addition, CBD indirectly enhances endogenous anandamide signaling by inhibiting the intercellular degradation of anandamide (Leweke et al., 2012). This endogenous neurotransmitter exerts antipsychotic effects in patients with schizophrenia (Leweke et al., 2012).

The pharmacokinetic profile of CBD has been extensively explored in the existing literature. A recently published systematic review of the pharmacokinetics of CBD found that the area under curve (AUC0 − t) and maximum serum concentration (Cmax) occurs between 1 and 4 h (Millar et al., 2018). The AUC0 − t and Cmax reach maximum values faster after smoking or inhalation compared to oral or oromucosal routes. Bioavailability was 31% after smoking, but no other studies reported the absolute bioavailability of CBD after other routes in humans. The half-life of CBD ranges between 1.4 and 10.9 h after oromucosal spray and 2–5 days after chronic oral administration (Millar et al., 2018). Fed states and lipid formulations increase Cmax (Millar et al., 2018). The bioavailability of oral CBD ranges between 11 and 13%, compared to 11 to 45% (mean 31%) via inhalation (Scuderi et al., 2009). CBD is well-tolerated, yet despite a relatively lower risk of drug–drug interactions, it should be used cautiously in combination with drugs metabolized by the CYP3A4 and CYP2C19 pathways, and the substrates of UDP-glucuronosyltransferases UGT1A9 and UGT2B7 (Millar et al., 2018). The clinical relevance of these interactions needs to be explored in future studies (Brown & Winterstein, 2019).

Dronabinol and nabilone are synthetic in origin, whereas nabiximols is plant-based (Papaseit et al., 2018). The percentage of THC and its ratio to CBD (THC/CBD ratio) defines the potency and psychoactive effects of a given formulation (Papaseit et al., 2018). Those with higher CBD/Δ9-THC ratios have euphoric, anxiolytic, and relaxing effects, whereas lower CBD/Δ9-THC ratios have sedative properties (Papaseit et al., 2018). Nabiximols, a CBD-containing compound, contains Δ9-THC and CBD at a 1:1 ratio (Papaseit et al., 2018). The Food and Drug Administration has approved Epidiolex® (an oral formulation of CBD) for two forms of childhood seizures (Lennox–Gastaut syndrome and Dravet syndrome) in children 2 years of age and older (Papaseit et al., 2018).

Previous efforts to synthesize the evidence for medical cannabis use in patients with psychiatric disorders have been published (Hoch et al., 2019; Lowe et al., 2019). For example, Hoch et al. conducted an excellent systematic review that summarized four systematic reviews and 14 randomized controlled trials (RCTs), but did not consider non-clinical trial evidence (case reports and case series) (Hoch et al., 2019). A review by Mandolini et al. recently summarized the clinical findings from 14 studies of psychiatric disorders, but these authors did not provide information about nabiximols (Mandolini et al., 2018). In contrast to the review articles noted above, the present article aims to provide a more comprehensive review of the use of CBD and CBD-containing compounds such as nabiximols to treat psychiatric disorders. The present review included studies focused on schizophrenia, cannabis-related disorders, attention deficit hyperactivity disorder (ADHD), comorbidities in autism spectrum disorder (ASD), social anxiety disorder (SAD), other anxiety disorders, insomnia, bipolar disorder, post-traumatic stress disorder (PTSD), psychosis in Parkinson’s disease, and Tourette syndrome. This article broadly reviews the efficacy, safety, and psychiatric benefits of CBD and CBD-containing compounds (nabiximols). We distinguish clearly here between the clinical findings for CBD and nabiximols, as the latter also contains THC.

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Methods

Eligibility criteria

The main inclusion criterion was studies of the psychiatric use of CBD and CBD-containing compounds such as nabiximols. Only case reports, case series, retrospective chart reviews, open-label trials, and RCTs were considered. All books, conference papers, theses, editorials, review articles, metaanalyses, in-vitro studies, laboratory studies, animal studies, studies of participants without psychiatric disorders, and abstract-only articles were excluded. No restrictions on language, country, publication year, or patients’ age, gender, or ethnicity were applied.

Search strategy

Eight electronic databases were searched on October 28th, 2018: PubMed, Scopus, Web of Science, POPLINE, New York Academy of Medicine Grey Literature Report, PsycINFO, Psycarticles, and CINAHL. The following search strategy was used in all cases: (CBD OR Cannabi* OR nabiximols) AND (psychiat* OR Depress* OR Anxiety OR Psycho* OR schizo* OR Bipolar OR Substance OR ADHD OR Attention OR Autism) AND (treatment). The manual search of references of included studies was performed by four independent reviewers.

Study selection

The search results from the eight databases were imported to Endnote v. 7 (Thompson Reuters, CA, USA) to remove any duplicates. Four independent reviewers (RK, NM, AF, MAF) screened the titles and abstracts (when available), followed by full-text screening of each included article with the predetermined eligibility criteria. All articles included after full-text screening were then searched manually. Discrepancies were resolved by consensus through discussion among reviewers, or with guidance from a third reviewer (SN).

Data extraction and grading

The data were extracted independently by the authors, and were cross-checked by discussion among the four reviewers (RK, NM, AF, MAF), with guidance from the senior author (SN) in case of discrepancy. The data were categorized as pertaining to target diagnosis, study design, sample size, duration of the trial, age range, dose ranges, measurement scales, clinical outcomes, study limitations, and common side effects.

The Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence was used to grade the quality of evidence (OCEBM, 2019). Level 1 evidence is for systematic review of RCTs or individual RCT of narrow confidence interval, Level 2 for cohort studies or systematic review of cohort studies, Level 3 for case-control studies or systematic review of case-control studies, and Level 4 for case-series for studies focused on therapy, prevention, etiology and harm (OCEBM, 2019). These levels of evidence are used to generate Grades of Recommendation. Grade A is for consistent level 1 studies, Grade B for consistent level 2 or 3 studies or extrapolations from level 1 studies, and Grade C for level 4 studies or extrapolations from level 2 or 3 studies. Grade D is ranked for level 5 evidence or inconsistent or inclusive studies of any level (OCEBM, 2019).

Results & discussion

The search of eight electronic databases and our manual screening method generated 511 results. After the removal of duplicates, titles and abstracts were screened, resulting in the exclusion of 459 articles. Full-text screening of 52 articles was performed, and 23 articles meeting the inclusion criteria were analyzed. Figure 1 summarizes the screening process.

PRISMA Flow Diagram

Of the 23 articles, there were eight RCTs, one clinical trial, four open-label trials, one retrospective chart review, seven case reports, and two case series, comprising a total patient population of 526. The studies focused on CBD and nabiximols use in the treatment of schizophrenia, cannabis-related disorders, ADHD, ASD and comorbidities, anxiety, insomnia, SAD, bipolar disorder, PTSD, psychosis in Parkinson’s disease, and Tourette syndrome. No studies of substance use disorders other than cannabis use were identified. In this review article, the authors have used DSM-5 terminologies for most of the disorders except for DSM-IV-Text Revised terminology of substance dependence. A comparable DSM-5 terminology of moderate-severe substance use disorder was used in this case.

Qualitative synthesis of eligible studies

Schizophrenia and psychosis in Parkinson’s disease

There were three RCTs (164 patients), one clinical trial (27 patients), one case series (three patients), one case report for schizophrenia, and one open-label trial (six patients) for psychosis in Parkinson’s disease (Table 1) (Leweke et al., 2012; Hallak et al., 2010; Boggs et al., 2018; McGuire et al., 2018; Zuardi et al., 2006; Zuardi et al., 1995; Zuardi et al., 2009). Of the seven studies, level 2 evidence was found in three RCTs, level 3 evidence in two clinical trial, and level 4 evidence in one case report and one case series (OCEBM, 2019). Since most of the studies were from level 2 and level 3 evidence, there is Grade B recommendation for schizophrenia. The dose of CBD in these studies ranged from 200 to 1500 mg daily. The highest dose was titrated to 1500 mg daily as reported by Zuardi and colleagues (Zuardi et al., 1995). Irrespective of the study design, three studies reported that CBD alleviated psychotic symptoms and cognitive impairment in patients with chronic cannabis use and Parkinson’s disease (Leweke et al., 2012; Zuardi et al., 1995; Zuardi et al., 2009), while only two RCTs and one clinical trial provided evidence for the effectiveness of CBD among patients with schizophrenia, albeit with mixed results (Leweke et al., 2012; McGuire et al., 2018; Zuardi et al., 2009).

In a clinical trial, Hallak and colleagues suggested an improvement in schizophrenia-associated cognitive impairment with a CBD dose of 300 mg/day, while no significant improvement was seen at a CBD dose of 600 mg/day (Hallak et al., 2010). In another RCT, McGuire and colleagues found that CBD (1000 mg/day) improved positive psychotic symptoms, but failed to improve negative symptoms and general psychopathology associated with this illness (McGuire et al., 2018). In another RCT, Boggs and colleagues found that CBD (600 mg/day) failed to improve outcomes pertaining to reasoning and problem-solving domains (Boggs et al., 2018).

In a comparison of CBD with amisulpride, Leweke and colleagues reported similar improvements in patients taking CBD 800 mg/day and those taking amisulpride (Leweke et al., 2012). This study also indicated an increase in intrinsic anandamide signaling, an effect that explained the antipsychotic properties of CBD (Leweke et al., 2012). Moreover, CBD treatment was associated with a lower risk of extrapyramidal symptoms, less weight gain, and a lower increase in prolactin, which is a predictor of galactorrhea and sexual dysfunction (Leweke et al., 2012). An open-label study of CBD to treat psychosis in Parkinson’s disease also suggested promising results at a dose of 400 mg daily; however, there was a strong risk of bias because of inadequate blinding of participants, personnel and outcome assessors (Zuardi et al., 2009).

The remaining evidence comprised two minimal quality case reports and case series. Zuardi and colleagues were the first to report favorable findings for CBD in patients with schizophrenia (Zuardi et al., 1995). The dose of CBD ranged from 600 to 1500 mg daily in schizophrenia studies. A case series of three patients with treatment-resistant schizophrenia found improvement in only one patient (Zuardi et al., 2006). In the first case, there was an improvement in psychotic symptoms with CBD at 1280 mg/day; however, the symptoms worsened after CBD was discontinued. In second case, CBD was ineffective for the symptoms. Patient had an improvement in symptoms with clozapine. In the third case, no improvement with CBD and partial improvement with olanzapine were observed, although clozapine was subsequently required. In case 3, mild improvement was reported with CBD in a patient who had previously failed to respond to olanzapine, clozapine, or haloperidol decanoate. These results suggest a limited role of CBD in treatment-resistant schizophrenia (Zuardi et al., 2006). The dose were not individually mentioned for case 1 and 2.

Four of the included studies did not report any adverse effects of CBD among patients with psychosis. CBD was well-tolerated in these patients except for mild transient sedation, hyperlipidemia, and gastrointestinal distress. Patients with schizophrenia had fewer instances of extrapyramidal symptoms, less weight gain, and a lower increase in prolactin levels.

CBD is postulated to improve cognitive performance in psychosis through the mediation of CB1 and CB2 receptor agonism at lower concentrations (Hallak et al., 2010; Solowij et al., 2018; Manseau & Goff, 2015). This cognitive improvement has been hypothesized due to the higher concentration of cannabinoid receptors in the hypothalamus, suggesting a role in superior cognitive functioning (Hallak et al., 2010). Naturalistic studies of CBD report better cognitive performance including memory, increased grey matter in the hippocampus, and fewer psychotic symptoms in patients given higher doses of CBD (Solowij et al., 2018).

The therapeutic benefits for psychosis is hypothesized due to the inhibition of anandamide re-uptake and degradation, resulting in increased anandamide levels in the brain (Manseau & Goff, 2015). Increased anandamide levels and improvements in the symptoms of psychosis were reported in another 4-week-long RCT comparing the efficacy of CBD to amisulpride for the treatment of schizophrenia (Leweke et al., 2012). Interestingly, anandamide levels were elevated in patients with acute schizophrenia compared to chronic schizophrenia, indicating a compensatory increase in an acute state (Giuffrida et al., 2004).

Cannabis-related disorders

The present review included three RCTs (107 patients), two open-label trials (28 patients), one case series of four patients, and two case reports for cannabis-related disorders as summarized in Table 2 (Solowij et al., 2018; Crippa et al., 2013; Trigo et al., 2016a; Trigo et al., 2018; Trigo et al., 2016b; Allsop et al., 2014; Pokorski et al., 2017; Shannon & Opila-Lehman, 2015). Of the eight studies, level 2 evidence was found in three RCTs, level 3 evidence in two clinical trial, and level 4 evidence in two case reports and one case series (OCEBM, 2019). For cannabis-related disorders, there is Grade B recommendation based on majority of studies ranked at the level 2 and level 3 of evidence.

Four of these studies evaluated the efficacy of nabiximols, and four others reported the use of CBD. The doses tested ranged from 20 mg CBD to a maximum of 1200 mg/day. Nabiximols was used in spray form at doses ranging from an average of 28.9 sprays/day (equivalent to 77.5 mg THC or 71.7 mg CBD) to 40 sprays/day (equivalent to 108 mg THC or 100 mg CBD). In CBD-only studies the dose of CBD ranged from 200 to 600 mg/day in divided doses. All three RCTs in this section provided evidence for the use of nabiximols for moderate to severe cannabis use disorder. These trials tested different doses of nabiximols ranging from 21.6 mg THC and 20 mg CBD (twice a day) to 113.4 mg THC or 105 mg CBD per day. All trials reported lower withdrawal rates, better tolerance, and retention rates in the experimental group. Moreover, no serious adverse effects were reported in any of these studies. In one RCT, nabiximols (total dose of 21.6 mg THC and 20 mg CBD at 4 and 10 in evening and night, respectively) was associated with marked improvement in cannabis withdrawal symptoms, leading to shorter withdrawal times and higher retention rates (Allsop et al., 2014). In a second RCT, a fixed dose of nabiximols produced more positive results compared to self-titrated administration (Trigo et al., 2016a). Patients in the fixed-dose group had four sprays of medications every hour compared to four sprays as needed every hour in self-titrated dose group. The maximum dose was 40 sprays/day in the self-titrated dose group. Medication intake was higher with fixed doses, which were associated with fewer withdrawal symptoms compared to the self-titrated regimen (Trigo et al., 2016a). In another RCT, the efficacy and safety of nabiximols were compared to a placebo while all participants also received weekly motivational enhancement therapy (MET) and cognitive–behavioral therapy (CBT) (Trigo et al., 2018). The dose range of 4.1 to 12.8 sprays/day was reported among nabiximols group. The withdrawal scores in this study were similar in both groups (Trigo et al., 2018). Only one of the studies reported decreased appetite, while the number and severity of adverse effects were not reported or observed in the other two RCTs.

Two open-label studies testing the effectiveness of two different concentrations of CBD (200 mg/day and 600–1200 mg/day) obtained positive outcomes with doses as low as 600 mg/day (Hallak et al., 2010; Pokorski et al., 2017). These studies had a small sample size of eight (Solowij et al., 2018) and 20 (Pokorski et al., 2017) participants, respectively. In the former open-label trial with eight participants, a dose of 600 mg/day was tested, and two out of five participants completed the 7-day inpatient treatment. These two participants reported abstinence at follow-up (day 28), and the remaining three participants reported decreased use of cannabis, confirmed by blood and urine analysis. In the second group, participants took 600 mg twice a day. Two out of three participants reported abstinence and in the remaining one, cannabis use had decreased, as confirmed by blood and urine analysis. All participants showed a decrease in Cannabis Withdrawal Scale scores. The second open-label trial tested the effectiveness of 200 mg CBD in divided doses in improving cognition and depressive symptomatology among patients with chronic cannabis use, and found improvement in severity of depression, verbal learning, and memory performance, and decreased frequency of positive psychotic-like symptoms and level of distress from baseline to endpoint (Solowij et al., 2018). State anxiety increased with no change in trait anxiety, functional impairment, or accuracy on cognitive tests (Solowij et al., 2018).

The remaining studies were either case series or case reports; all found positive outcomes in withdrawal and cannabis-dependence symptoms (Crippa et al., 2013; Trigo et al., 2016b; Shannon & Opila-Lehman, 2015). Mean age in the case series was 35 years, although the first participant was 19 years old and the second was 27 years old. The case series used self-titrated nabiximols at a dose of 77.5–113.4 mg THC and 71.5–105.0 mg CBD (Trigo et al., 2016b). Moreover, all participants reported a significant reduction in craving (Crippa et al., 2013; Trigo et al., 2016b; Shannon & Opila-Lehman, 2015), quicker relief (Crippa et al., 2013), lower anxiety, and an improved sleep schedule (Shannon & Opila-Lehman, 2015). However, the case series reported increased craving scores during the first 2 weeks with a subsequent reduction in craving at week 9. CBD was well-tolerated in this patient population, except for decreased appetite reported in one study (Trigo et al., 2016b). For patients receiving nabiximols or CBD, treatment should be augmented with psychotherapeutic modalities considering the positive evidence for an effect on cravings.

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The effectiveness and tolerability of CBD and nabiximols for moderate to severe cannabis use disorder was reported in several studies. The efficacy may also be due to the synergetic or additive benefits of Δ9-THC and CBD rather than CBD alone. The Δ9-THC component of nabiximols decreases the severity of withdrawal symptoms, lowering the risk of relapse (Trigo et al., 2016a). However, there is mixed evidence for the role of nabiximols in cannabis-related craving (Trigo et al., 2016a; Trigo et al., 2018; Trigo et al., 2016b). Studies that included combined motivation enhancement and behavioral response prevention strategies suggested a reduction in craving (Trigo et al., 2016a; Trigo et al., 2018). CBD is thought to modulate the euphoric, anxiogenic, psychological, and physiological effects of Δ9-THC (Crippa et al., 2013). However, these benefits of CBD alone and in combination with THC need to be explored in head-to-head studies.

Other disorders

The present review included two RCTs (54 patients), one open-label trial (53 patients), one retrospective chart review (72 patients), and four case reports for CBD and nabiximols use in the treatment of other psychiatric disorders. Specifically, this review looked at ADHD (one RCT), comorbidities in ASD (one open-label trial), anxiety and sleep problems (one retrospective chart review), SAD (one clinical trial), bipolar disorder (one case report), PTSD (one case report), and Tourette syndrome (two case reports), as summarized in Table 3 (Cooper et al., 2017; Barchel et al., 2018; Bergamaschi et al., 2011; Shannon et al., 2019; Zuardi et al., 2010; Shannon & Opila-Lehman, 2016; Trainor et al., 2016; Pichler et al., 2019). Of the nine studies, level 2 evidence was found in two RCTs, level 3 evidence in one clinical trial, and level 4 evidence in one retrospective chart review, four case reports (OCEBM, 2019). There is Grade B recommendation for comorbidities in patients with ASD, anxiety disorders including SAD and sleep problems, and ADHD where as bipolar disorder, PTSD and Tourette Syndrome has Grade C recommendation. However, this should be considered in the context of fewer studies of each these diagnoses.

The oromucosal nabiximols spray was tested to evaluate its effects on cognitive performance, hyperactivity, inattention, and emotional lability in 15 participants in a placebo-controlled RCT (Cooper et al., 2017). The mean dose of nabiximols was 4.7 sprays per day (2.7 mg Δ9-THC and 2.5 mg CBD). Although an improvement in these symptoms was observed in the intervention group, it failed to reach statistical significance (Cooper et al., 2017). However, this result may not be valid or reliable due to the low power of the study.

One case report on the use of CBD by two patients with bipolar disorder showed limited to no improvement with doses of 600–1200 mg for bipolar mania in one of the patients (Shannon et al., 2019). The second patient was prescribed CBD 600 mg (5–9 days) and olanzapine (10–15 mg), followed by CBD 900–1200 mg (20–33 days), and showed improvement on the Brief Psychiatric Rating Scale (37% reduction) and Young Mania Rating Scale (33% reduction) with CBD and olanzapine, but no additional improvement with CBD monotherapy (Shannon et al., 2019). This effect was consistent with results from animal studies that modeled acute mania with dextroamphetamine (Shannon et al., 2019). The lack of effectiveness can be attributed to the shorter duration of treatment in both cases. This evidence from studies of bipolar mania should be considered in the context of different pharmacological agents responding differently to certain episodes of bipolar disorder. In animal studies, CBD induced a rapid, persistent antidepressant response by increasing brain-derived neurotrophic factor in the prefrontal cortex (Shannon et al., 2019). Given its possible antidepressant benefits, the role of CBD should be explored in unipolar and bipolar depression.

In an open-label trial involving children with ASD, Barchel and colleagues reported that a solution of CBD and Δ9-THC (1,20 ratio) was effective for hyperactivity, insomnia, self-injurious behaviors, and anxiety (Barchel et al., 2018). The median dose was 90 mg with an interquartile range (IQR) of 45–143 mg for CBD whereas The medical dose was 7 mg with IQR of 4–11 mg. In this cohort of 53 patients, 74.5% showed improvement in their comorbid symptoms, 68.4% in hyperactivity, 67.6% in self-injurious behaviors, 71.4% in sleep problems, and 47.1% in anxiety symptoms. This treatment regimen lasted for a median of 66 days. However, Salgado and Castellanos suggested guiding principles for the use of CBD in this population, including a better clinical understanding of CBD, open discussion with parents and patients, addressing their perceptions, promoting informed consent, and exercising caution in the use of CBD (Salgado & Castellanos, 2018). Patients with ASD make up a heterogeneous group of individuals with different comorbidities that should be considered.

The efficacy of CBD for SAD and PTSD was explored in three studies including one RCT, one case report, and one chart review. The RCT reported the results of a simulated public speaking test among 12 healthy control participants and 24 patients with SAD who received a single dose of CBD 600 mg or a placebo before the test. This study reported that pretreatment with CBD resulted in less anxiety, cognitive impairment, and discomfort during their speaking performance. It also resulted in a significant reduction in alertness in their anticipatory speech compared to the placebo group (Bergamaschi et al., 2011).

In a 10-year-old patient, 5 months of treatment with CBD oil (25 mg) and liquid CBD (6–12 mg) in a sublingual spray as needed was associated with less anxiety and better sleep quality, with no adverse effects (Shannon & Opila-Lehman, 2016). These results were replicated for anxiety in a recently published chart review of 72 adult patients with insomnia and anxiety (Shannon et al., 2019). Most patients in this group were given 25 mg CBD/day, while a few patients were given 50 or 75 mg/day, and one patient with schizoaffective disorder and trauma was given up to 175 mg/day. All patients showed less anxiety and improved sleep, with reductions of 65–80% in the Hamilton Anxiety Rating Scale and Pittsburgh Sleep Quality Index scores.

Nabiximols produced improvements in patients with Tourette syndrome at a much lower dose than what was used for cannabis-related disorders (Trainor et al., 2016; Pichler et al., 2019). These case reports tested two oromucosal nabiximols sprays used twice a day (total dose 10.8 mg Δ9-THC and 10 mg CBD per day) (Trainor et al., 2016), and the second also tested cannabis tincture (34 drops three times a day (Pichler et al., 2019). Both case reports found improvements in tic frequency (Trainor et al., 2016; Pichler et al., 2019), severity (Trainor et al., 2016; Pichler et al., 2019), quality of life, and social activity (Trainor et al., 2016). These treatments regimens were used for 4 weeks with the oromucosal spray form (Trainor et al., 2016) and 8 weeks for cannabis tincture (Pichler et al., 2019). The therapeutic benefits can be attributed to the anxiolytic and sleep-inducing properties of CBD (Trainor et al., 2016). It is difficult to ascertain whether these improvements were due to due to CBD, Δ9-THC, additive, or synergetic effects. The anxiolytic properties of CBD explain the attenuation of anxiety associated with the onset of tics, and the improvement in tics with a combination of Δ9-THC and CBD (Trainor et al., 2016; Pichler et al., 2019).

Adverse effects were reported in four of the studies, and included muscular seizures and spasms (Cooper et al., 2017), somnolence and changes in appetite (Barchel et al., 2018), fatigue, and sexually inappropriate behavior in a patient with developmental disorder (Shannon et al., 2019), mild sedation (Zuardi et al., 2010), and mild xerostomia (Pichler et al., 2019).

Summary of evidence

The present article provides a comprehensive review of the evidence supporting the use of CBD and CBD-containing compounds such as nabiximols to treat psychiatric disorders. CBD and nabiximols were effective in cannabis use-related disorders, and preliminary evidence was found in support of their use for other psychiatric disorders. Of the 23 studies reviewed here, level 2 evidence was found in eight RCTs, level 3 evidence in four open-label trials and one clinical trial, and level 4 evidence in one retrospective chart review, seven case reports, and two case series, according to the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence (OCEBM, 2019). This review covers the evidence for different routes of administration, e.g. oral, inhalation spray, and sublingual. The bioavailability of these routes (11–13% for oral vs. 11–43% for inhalation) varies significantly – a factor that can impact the efficacy of different formulations.

Their antipsychotic, neuroprotective, anxiolytic, and sedating properties suggest a potential therapeutic role of CBD and nabiximols to treat various psychiatric disorders. The use of CBD at higher doses (above 1200 mg per day) showed promising results in case studies of schizophrenia and psychosis in patients with Parkinson’s disease, except in treatment-resistant cases. Regarding the use of CBD to treat anxiety disorders, its anxiolytic effect can help patients with PTSD-related and social performance-related anxiety, and nabiximols can reduce the anxiety associated with the onset of tics. There is also favorable evidence in patients with ASD for reducing hyperactivity, self-injurious behaviors, anxiety, and insomnia. Nabiximols showed no credible effect in the treatment of ADHD, while CBD was also found to be ineffective for bipolar disorder. Of all the cases examined, the strongest evidence was found for the treatment of cannabis-related disorders. The use of nabiximols yielded positive results in multiple studies of moderate to severe cannabis use disorder; however, the use of CBD alone has not been adequately documented outside a few cases and case series. Notably, CBD compounds were helpful in alleviating psychotic symptoms and improving cognitive impairment in patients across a variety of conditions.

Recommendations for future research

This review found low-level evidence for the use of cannabis and nabiximols in a variety of disorders. Despite our comprehensive literature search, only a few RCTs related to the disorders of interest were found. These RCTs were marred by a number of limitations, most importantly failure to blind the outcome assessor, participants, and research personnel (in the open-label trials). In addition, most RCTs had a small sample size, critically reducing the power of the study to draw robust conclusions. The findings of the RCTs reviewed here need to be validated via a series of larger, well planned, randomized, double-blinded, and placebo-controlled studies. The present report can be used to design and plan further studies; however, at present the use of CBD and nabiximols in clinical practice cannot be recommended with confidence due to the drawbacks noted above.

The evidence from studies included in this review can guide future trials by providing information pertaining to the dosages, formulations and routes of administration of CBD and nabiximols. Moreover, future studies should investigate different routes of administration in light of the differences in bioavailability. In view of the (albeit limited) evidence for treatment-resistant schizophrenia, the role of CBD should be explored in the early stages of psychosis or as an adjunct medication. Although CBD was ineffective for bipolar mania, its possible efficacy as an antidepressant should be assessed in studies focused on bipolar depression. Nabiximols has been helpful in cannabis-related disorder and Tourette syndrome, owing to the synergetic benefits of CBD and THC. Future studies designed to explore the comparative benefits of these treatments can shed further light on their clinical potential. Future RCTs should also consider adding first-line treatment agents as comparison arms, to ascertain the comparative efficacy of CBD in different mental disorders. Although fewer side effects were reported overall by patients in the studies reviewed here, the vulnerability to addiction to cannabinoids should not be ignored.

Limitations of the review

This review article has several limitations that should be considered. This review article provides evidence for CBD and CBD-containing nabiximols are two different pharmacological agents. Nabiximols has two active compounds and included studies do not consider the separate effects of THC VS CBD. There is need for future analyses to carefully consider their benefits individually. Only one-third of studies (8/23) in this review article are RCTs and most of these RCTs had a small sample size decreasing the power of the study to draw robust conclusions.

Conclusion

The evidence reviewed here favors CBD use for patients with schizophrenia and psychosis in Parkinson’s disease in four out of seven studies, except in treatment-resistant cases. There is a Grade B recommendation this diagnosis based on the levels of evidence. Nabiximols and CBD were beneficial in cannabis-related disorders in almost all studies with Grade B recommendation, resulting in a decreased risk of withdrawal symptoms and dependence among participants. The effect on cannabis-related craving was pronounced, with an additive benefit from the use of psychotherapeutic options such as MET or CBT. One open-label trial suggested favorable evidence for the use of cannabinoids CBD and Δ9-THC for hyperactivity, self-injurious behaviors, and anxiety symptoms in patients with ASD with Grade B recommendation. CBD was helpful in patients with anxiety and insomnia related to SAD and PTSD in one chart review. Nabiximols was found to be effective in reducing the frequency and severity of tics and improving the quality of life in patients with Tourette syndrome according to case reports. There was no firm evidence to support CBD to treat bipolar mania (one case report) or nabiximols (one RCT) to treat ADHD. There is Grade B (moderate) recommendation for attention deficit hyperactivity disorder. Grade C recommendation (weaker) exists for insomnia, anxiety, bipolar disorder, posttraumatic stress disorder, and Tourette syndrome. These recommendations should be considered in the context of limited number of available studies. The authors recommend well-planned randomized controlled trials to further study the benefits of CBD and CBD-containing options such as nabiximols in patients with psychiatric disorders. It is also important to assess the individual pharmacodynamic and pharmacokinetic effects of CBD and Δ9-THC in different treatments.