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Clinicians’ Guide to Cannabidiol and Hemp Oils

Open AccessPublished:August 21, 2019DOI:https://doi.org/10.1016/j.mayocp.2019.01.003

      Abstract

      Cannabidiol (CBD) oils are low tetrahydrocannabinol products derived from Cannabis sativa that have become very popular over the past few years. Patients report relief for a variety of conditions, particularly pain, without the intoxicating adverse effects of medical marijuana. In June 2018, the first CBD-based drug, Epidiolex, was approved by the US Food and Drug Administration for treatment of rare, severe epilepsy, further putting the spotlight on CBD and hemp oils. There is a growing body of preclinical and clinical evidence to support use of CBD oils for many conditions, suggesting its potential role as another option for treating challenging chronic pain or opioid addiction. Care must be taken when directing patients toward CBD products because there is little regulation, and studies have found inaccurate labeling of CBD and tetrahydrocannabinol quantities. This article provides an overview of the scientific work on cannabinoids, CBD, and hemp oil and the distinction between marijuana, hemp, and the different components of CBD and hemp oil products. We summarize the current legal status of CBD and hemp oils in the United States and provide a guide to identifying higher-quality products so that clinicians can advise their patients on the safest and most evidence-based formulations. This review is based on a PubMed search using the terms CBD, cannabidiol, hemp oil, and medical marijuana. Articles were screened for relevance, and those with the most up-to-date information were selected for inclusion.

      Abbreviations and Acronyms:

      BCP (β-caryophyllene), CBD (cannabidiol), DEA (Drug Enforcement Administration), ECS (endocannabinoid system), FDA (Food and Drug Administration), THC (tetrahydrocannabinol)
      Article Highlights
      • Cannabidiol (CBD) is a nonintoxicating compound extracted from Cannabis sativa plants that has gained popularity for medical uses ranging from epilepsy to pain control and addiction treatment because of its differing mechanism of action from marijuana and its safety profile.
      • Although important preclinical and pilot human studies have suggested a potential role for CBD in numerous clinical situations, thorough clinical studies have only been performed on intractable epilepsy syndromes for which Epidiolex, a CBD drug, was approved by the US Food and Drug Administration for use.
      • The legal landscape of CBD remains complex because of differing state and federal laws giving access to medical hemp and marijuana products.
      • The CBD and hemp oil product market remains a concerning one because of noted variability in CBD and tetrahydrocannabinol levels in products, as well as lack of regulation in production and distribution.
      • Although CBD and hemp oils remain an unproven therapeutic option, physicians should remain open to the possible future role these products may play in the management of a variety of difficult to treat diseases, in particular pain and addiction treatment in the context of the opioid crisis.
      One of the biggest challenges facing health care today is combatting opioid abuse, with medical and nonmedical overuse of opioids exacting a huge toll on society in recent years.
      • Kolodny A.
      • Courtwright D.T.
      • Hwang C.S.
      • et al.
      The prescription opioid and heroin crisis: a public health approach to an epidemic of addiction.
      Although there has been a larger focus on reducing opioid prescriptions and preventing nonmedical use of opioids, there is an increasing interest in finding more treatment options for patients in pain,
      • Kroenke K.
      • Cheville A.
      Management of chronic pain in the aftermath of the opioid backlash.
      and the diverse field of integrative medicine has been finding an increasing role in this area.
      • Abbasi J.
      As opioid epidemic rages, complementary health approaches to pain gain traction.
      • Nahin R.L.
      • Boineau R.
      • Khalsa P.S.
      • Stussman B.J.
      • Weber W.J.
      Evidence-based evaluation of complementary health approaches for pain management in the United States.
      One promising area has been use of the plant Cannabis sativa, both in medical marijuana as well as hemp and cannabidiol (CBD) oils, with some evidence that access to medical marijuana is correlated with a decrease in opioid use, although there has been controversy about the risks and benefits of encouraging poorly regulated medical use of a known substance of abuse.
      • Hasin D.S.
      US epidemiology of cannabis use and associated problems.
      • Olfson M.
      • Wall M.M.
      • Liu S.M.
      • Blanco C.
      Cannabis use and risk of prescription opioid use disorder in the United States.
      Cannabidiol and hemp oils have become especially popular because of their low tetrahydrocannabinol (THC) levels, resulting in attributed medical benefits without the “high” of marijuana.
      • Aubrey A.
      Anxiety relief without the high? new studies on CBD, a cannabis extract.
      However, clinicians have concerns about whether these treatment options are legal, safe, and effective and are largely unfamiliar with these products.
      • Peachman R.R.
      Clinicians support medical marijuana use in children with cancer, but lack knowledge.
      • Rubin R.
      Medical marijuana is legal in most states, but physicians have little evidence to guide them.
      Therefore, we provide an overview of the scientific work on cannabinoids, CBD, and hemp oil and clarify the distinction between marijuana, hemp, and the different components of CBD and hemp oil products so that clinicians may be able to direct their patients to the safest and most evidence-based products.
      Cannabis sativa has long been utilized by human populations across the world for its therapeutic properties, from pain relief to treatment of epilepsy.
      • Friedman D.
      • Sirven J.I.
      Historical perspective on the medical use of cannabis for epilepsy: ancient times to the 1980s.
      Marijuana and hemp are 2 strains of the same plant, C sativa, with marijuana being cultivated over the years for its THC content and hemp for its myriad other uses including paper, clothing, and food.
      • Cherney J.H.
      • Small E.
      Industrial hemp in North America: production, politics, and potential.
      Despite considerable sociopolitical obstacles, scientific understanding of C sativa has progressed substantially in the past 30 years as the many active ingredients of the C sativa strains were isolated and major discoveries were made regarding the body’s own endogenous cannabinoids and the endocannabinoid system (ECS).
      • Pacher P.
      • Bátkai S.
      • Kunos G.
      The endocannabinoid system as an emerging target of pharmacotherapy.

      The Endocannabinoid System

      It is now known that the ECS is globally involved in maintaining homeostasis in the body, connecting all of the body’s organs and systems.
      • Woods S.C.
      The endocannabinoid system: mechanisms behind metabolic homeostasis and imbalance.
      The ECS has been implicated in a variety of disease states and important regulatory functions, from chronic inflammatory conditions and regulation of immune homeostasis in the gut to anxiety and migraines.
      • Witkamp R.
      • Meijerink J.
      The endocannabinoid system: an emerging key player in inflammation.
      • Acharya N.
      • Penukonda S.
      • Shcheglova T.
      • Hagymasi A.T.
      • Basu S.
      • Srivastava P.K.
      Endocannabinoid system acts as a regulator of immune homeostasis in the gut.
      • Bluett R.J.
      • Gamble-George J.C.
      • Hermanson D.J.
      • Hartley N.D.
      • Marnett L.J.
      • Patel S.
      Central anandamide deficiency predicts stress-induced anxiety: behavioral reversal through endocannabinoid augmentation.
      • Baron E.P.
      Comprehensive review of medicinal marijuana, cannabinoids, and therapeutic implications in medicine and headache: what a long strange trip it's been….
      Although the body has its own endogenous cannabinoids, most notably anandamide and 2-arachidonylglycerol, plant-derived cannabinoids (phytocannabinoids) have been researched as potential therapeutic options in a variety of areas because of their modulation of the ECS.
      • Benarroch E.E.
      Synaptic effects of cannabinoids: complexity, behavioral effects, and potential clinical implications.
      • Zou S.
      • Kumar U.
      Cannabinoid receptors and the endocannabinoid system: signaling and function in the central nervous system.
      • Pertwee R.G.
      • Howlett A.C.
      • Abood M.E.
      • et al.
      International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2.
      Figure 1 summarizes the basic molecular biology of the ECS, as well as some of the molecular effects of phytocannabinoids.
      Figure thumbnail gr1
      Figure 1Modulation of the endocannabinoid system by phytocannabinoids.
      • Zou S.
      • Kumar U.
      Cannabinoid receptors and the endocannabinoid system: signaling and function in the central nervous system.
      • Pertwee R.G.
      • Howlett A.C.
      • Abood M.E.
      • et al.
      International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2.
      • Pertwee R.G.
      The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin.
      Figure depicts the basic actions of the endogenous cannabinoids anandamide (AN) and 2-arachidonylglycerol (2-AG) on the G protein–coupled cannabinoid receptors 1 and 2 (CB1 and CB2) in presynaptic neurons in both the central and peripheral nervous system. The green-shaded compounds are common phytocannabinoids and other herbal inclusions in hemp oils that have been found to affect the normal endocannabinoid in some way, either through modulation of the CB receptors (eg, tetrahydrocannabinol [THC] agonism of CB1 receptors) or by other routes not depicted, such as inhibition of enzymatic breakdown of endocannabinoids or other receptor modulation. BCP = β-caryophyllene; GABA = γ-aminobutyric acid; TRPV = transient receptor potential vanilloid.

      Phytocannabinoids

      Although the body contains its extensive ECS that works through endogenous cannabinoids, many plant-derived cannabinoids have been discovered that act on the ECS as well. The first ones were discovered in the context of C sativa research, with more than 80 phytocannabinoid compounds being discovered in the marijuana plant alone.
      • Brenneisen R.
      Chemistry and analysis of phytocannabinoids and other Cannabis constituents.
      Phytocannabinoids and other important C sativa components such as terpenoids have now also been documented in a variety of other plants and foodstuffs, such as carrots, cloves, black pepper, ginseng, and Echinacea.
      • Russo E.B.
      Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects.
      • Gertsch J.
      • Pertwee R.G.
      • Di Marzo V.
      Phytocannabinoids beyond the Cannabis plant - do they exist?.
      The most notable and well-understood phytocannabinoids are THC and CBD, the most common phytocannabinoids in marijuana and hemp strains, respectively.
      • Brenneisen R.
      Chemistry and analysis of phytocannabinoids and other Cannabis constituents.
      Tetrahydrocannabinol has been noted to work mostly through the CB1 receptor as an agonist, leading to its well-known intoxicating effects.
      • Borgelt L.M.
      • Franson K.L.
      • Nussbaum A.M.
      • Wang G.S.
      The pharmacologic and clinical effects of medical cannabis.
      Cannabidiol, on the other hand, has been found to work through a variety of complex pharmacological actions, such as inhibition of endocannabinoid reuptake, transient receptor potential vanilloid 1 and G protein–coupled receptor 55 activation, and increasing the activity of serotonin 5-HT1A receptors.
      • Bisogno T.
      • Hanus L.
      • De Petrocellis L.
      • et al.
      Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide.
      • Russo E.B.
      Cannabidiol claims and misconceptions.
      • Di Marzo V.
      • Bifulco M.
      • De Petrocellis L.
      The endocannabinoid system and its therapeutic exploitation.
      • Campos A.C.
      • Moreira F.A.
      • Gomes F.V.
      • Del Bel E.A.
      • Guimarães F.S.
      Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders.
      Cannabidiol’s minimal agonism of the CB receptors likely accounts for its negligible psychoactivity when compared with THC.
      • Fasinu P.S.
      • Phillips S.
      • ElSohly M.A.
      • Walker L.A.
      Current status and prospects for cannabidiol preparations as new therapeutic agents.
      Figure 2 summarizes the different endocannabinoids, phytocannabinoids, and synthetic cannabinoids. The synthetic cannabinoids are laboratory-derived THC preparations that have been US Food and Drug Administration (FDA) approved for various usages, as well as nabiximols, which is a nonsynthetic 1:1 THC and CBD preparation that has been approved in the United Kingdom for pain and spasticity related to multiple sclerosis. Nabiximols is not approved by the FDA.
      • Whiting P.F.
      • Wolff R.F.
      • Deshpande S.
      • et al.
      Cannabinoids for medical use: a systematic review and meta-analysis.
      Notably, there are many other components in hemp extracts, and many products boast of being “full-spectrum” in retaining these other components, each with their own attributed effects that are theorized to synergize through what is termed the entourage effect—essentially that the whole plant is greater than the sum of its parts.
      • Russo E.B.
      Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects.

      Legal and Regulatory Considerations

      Since the 1970 Controlled Substances Act outlawed growing and selling of both hemp and marijuana, hemp continued to remain illegal to grow in the United States until passage of the 2014 Agricultural Act, which distinguished between hemp and marijuana legality for the first time. The law defined “industrial hemp” as “Cannabis sativa L. and any part of such plant, whether growing or not, with a delta-9-THC content of no more than 0.3% on dry weight basis,” and this allowed industrial hemp to be grown for “research purposes.”
      Agricultural Act of 2014, HR 2642, 113th Cong, 2nd Sess (2014).
      However, it is technically illegal to introduce any supplement or food containing CBD into interstate commerce (as would be the case when ordering online), so most products are imported from Europe and then processed and distributed in the United States.
      • Mead A.
      The legal status of cannabis (marijuana) and cannabidiol (CBD) under U.S. law.
      Additionally, 3 states—Idaho, South Dakota, and Nebraska—still do not have any C sativa access laws, and CBD and hemp oils are therefore illegal to sell or consume there. For all other states, CBD and hemp oils are legal as long as the THC content is below the 0.3% threshold. It is also important to note that patients using CBD products may test positive for marijuana on drug screening, as was noted in the Epidiolex drug trials.
      Epidiolex [package insert]. Carlsbad, CA: Greenwich Biosciences, Inc; 2018.
      Figure 3 lists the current laws regarding CBD oils and medical marijuana in the United States available from the National Conference of State Legislatures website, which has helpful information on medical marijuana and CBD laws on a state-by-state basis.
      State medical marijuana laws. National Conference of State Legislatures. NCSL website.
      Importantly, although many states have allowed use of medical marijuana, physicians may only “certify” or “recommend” that their patients may use medical marijuana for a certain condition and cannot issue a prescription for specific cannabis products because they are not approved by the FDA or Drug Enforcement Administration (DEA).
      • Mead A.
      The legal status of cannabis (marijuana) and cannabidiol (CBD) under U.S. law.
      Notably, because CBD and hemp oils do not contain intoxicating amounts of THC, they do not require a certification or recommendation from a physician to be purchased and consumed. However, there have been numerous warning letters sent by the FDA to companies about inconsistent ingredients in their products, with many products containing higher amounts of THC than legally allowed while also containing less CBD than labeled.
      • US Food and Drug Administration
      Warning letters and test results for cannabidiol-related products, 2015-2017.
      Additionally, now that CBD is the subject of an investigational new drug authorization for Epidiolex, it is no longer considered legal by the FDA to use it in dietary supplement products and foodstuffs.
      • US Food and Drug Administration
      FDA and marijuana: questions and answers.
      Figure thumbnail gr3
      Figure 3State cannabis programs.
      From the National Conference of State Legislatures,
      State medical marijuana laws. National Conference of State Legislatures. NCSL website.
      with permission.
      Finally, although nearly all states have passed some sort of C sativa access laws, the federal government and the DEA still consider CBD and hemp oils to be schedule I substances. Although the DEA did reduce Epidiolex, the pure CBD drug recently approved by the FDA for intractable epilepsy conditions, Dravet syndrome, and Lennox-Gastaut syndrome, to a schedule V classification, they still remain “concerned about the proliferation and illegal marketing of unapproved CBD-containing products with unproven medical claims.”
      • LaVito A.
      DEA reschedules Epidiolex, marijuana-derived drug, paving the way for it to hit the market. CNBC website.

      CBD and Hemp Oils

      Definitions

      Because of variation in the legislation regarding the C sativa plant as well as the tremendous increase of new products being marketed, there has been an accompanying lack of clarity about the different types of hemp and CBD oils. Depending on what part of the plant is being extracted, there will be different components present. The phytocannabinoids such as THC and CBD, as well as terpenoids like β-caryophyllene (BCP) and limonene, collect in the flowers and leaves.
      • Potter D.J.
      The Propagation, Characterisation, and Optimisation of Cannabis sativa as a Phytopharmaceutical [PhD thesis].
      Conversely, the seeds of the C sativa contain little to no phytocannabinoids, instead being rich in omega-6 and omega-3 essential fatty acids, substantial amounts of γ-linolenic acid, and other nutritious antioxidants.
      • Callaway J.C.
      Hempseed as a nutritional resource: an overview.
      Additionally, there are “cannabis oil” products as well, which are oils derived from the marijuana plant that have high levels of THC.
      • Grof C.P.L.
      Cannabis, from plant to pill.
      Table 1 summarizes these differences.
      Table 1Hemp Seed, CBD, and Cannabis Oils
      VariableHemp seed oils
      • Callaway J.C.
      Hempseed as a nutritional resource: an overview.
      Hemp/CBD oils
      • Russo E.B.
      Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects.
      Cannabis oils
      • Russo E.B.
      Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects.
      • Grof C.P.L.
      Cannabis, from plant to pill.
      Part of plant extractedSeedsFlowers and leaves of hemp plantFlowers and leaves of marijuana plant
      Main componentsOmega-6 and omega-3 fatty acids, γ-linolenic acid, nutritious antioxidantsMostly CBD and BCP with other smaller-quantity phytocannabinoids and terpenoidsMostly THC with some CBD and other phytocannabinoids and terpenoids
      THC levelsNone<0.3% Dry weight>0.3% Dry weight (often very high amounts such as 80%)
      CBD levelsLittle to noneMore than average cannabis plants (12%-18% CBD, often higher due to postextraction enrichment)Lower levels (10%-15%)
      UsesNutritional supplement, other uses of hemp such as clothing and fibersMedicinal uses of CBD and full-spectrum hemp oilsMedicinal uses of THC
      BCP = β-caryophyllene; CBD = cannabidiol; THC = tetrahydrocannabinol.
      Products may be marketed as “full-spectrum” formulas, dietary supplements, hemp oils, or CBD-enriched products, coming in the forms of oils, balms, sprays, capsules, soft gels, oral applicators, foodstuffs such as gummy bears, and even chew toys for pets. The most popular products contain a diverse array of phytocannabinoids from C sativa as well as other phytocannabinoids and terpenoids derived from other plants and foodstuffs such as clove, hops, ashwagandha, and turmeric. These products are being marketed for a variety of uses such as sleep aids, pain relief, or stress reduction. Because of this inconsistency in ingredient choices, as well as amounts and method of administration, it is difficult to know which ingredient accounts for a specific symptom relief. Cannabidiol is the most well-studied phytocannabinoid and will be the primary focus in this article because it is also the main ingredient in most products. Table 2 is provided for reference on the most common ingredients included in CBD and hemp oils when looking at potential products.
      Table 2Common Components and Added Ingredients in CBD and Hemp Oil Products
      IngredientChemical classificationApproximate concentration in hemp
      • Potter D.J.
      The Propagation, Characterisation, and Optimisation of Cannabis sativa as a Phytopharmaceutical [PhD thesis].
      Other sourcesMechanism of actionPotential therapeutic actions
      CannabidiolPhytocannabinoidUp to 40%None knownAnandamide uptake inhibitor, TRPV1 receptor activation, GPR55 receptor activation, 5-HT1A activation
      • Di Marzo V.
      • Bifulco M.
      • De Petrocellis L.
      The endocannabinoid system and its therapeutic exploitation.
      • Campos A.C.
      • Moreira F.A.
      • Gomes F.V.
      • Del Bel E.A.
      • Guimarães F.S.
      Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders.
      • Pertwee R.G.
      The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin.
      Antiepileptic, antinociceptive, anti-inflammatory, anxiolytic, antidepressive, addiction management/treatment, inflammatory dermatologic conditions, neuroprotective, others
      • Donvito G.
      • Nass S.R.
      • Wilkerson J.L.
      • et al.
      The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain.
      • Ren Y.
      • Whittard J.
      • Higuera-Matas A.
      • Morris C.V.
      • Hurd Y.L.
      Cannabidiol, a nonpsychotropic component of cannabis, inhibits cue-induced heroin seeking and normalizes discrete mesolimbic neuronal disturbances.
      • Hurd Y.L.
      • Yoon M.
      • Manini A.F.
      • et al.
      Early phase in the development of cannabidiol as a treatment for addiction: opioid relapse takes initial center stage.
      • Friedman D.
      • Devinsky O.
      Cannabinoids in the treatment of epilepsy.
      • Devinsky O.
      • Cross J.H.
      • Laux L.
      • et al.
      Cannabidiol in Dravet Syndrome Study Group. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome.
      • Devinsky O.
      • Marsh E.
      • Friedman D.
      • et al.
      Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial.
      • Devinsky O.
      • Patel A.D.
      • Cross J.H.
      • et al.
      GWPCARE3 Study Group
      Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome.
      • Devinsky O.
      • Patel A.D.
      • Thiele E.A.
      • et al.
      GWPCARE1 Part A Study Group. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome.
      • Burstein S.
      Cannabidiol (CBD) and its analogs: a review of their effects on inflammation.
      • Crippa J.A.
      • Derenusson G.N.
      • Ferrari T.B.
      • et al.
      Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report.
      • Fogaça M.V.
      • Campos A.C.
      • Coelho L.D.
      • Duman R.S.
      • Guimarães F.S.
      The anxiolytic effects of cannabidiol in chronically stressed mice are mediated by the endocannabinoid system: role of neurogenesis and dendritic remodeling.
      • Linge R.
      • Jiménez-Sánchez L.
      • Campa L.
      • et al.
      Cannabidiol induces rapid-acting antidepressant-like effects and enhances cortical 5-HT/glutamate neurotransmission: role of 5-HT1A receptors.
      • Hindocha C.
      • Freeman T.P.
      • Grabski M.
      • et al.
      Cannabidiol reverses attentional bias to cigarette cues in a human experimental model of tobacco withdrawal.
      • Gonzalez-Cuevas G.
      • Martin-Fardon R.
      • Kerr T.M.
      • et al.
      Unique treatment potential of cannabidiol for the prevention of relapse to drug use: preclinical proof of principle.
      • Oláh A.
      • Tóth B.I.
      • Borbíró I.
      • et al.
      Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes.
      • McGuire P.
      • Robson P.
      • Cubala W.J.
      • et al.
      Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: a multicenter randomized controlled trial.
      • Karl T.
      • Garner B.
      • Cheng D.
      The therapeutic potential of the phytocannabinoid cannabidiol for Alzheimer's disease.
      • Watt G.
      • Karl T.
      In vivo evidence for therapeutic properties of cannabidiol (CBD) for Alzheimer's disease.
      • Chagas M.H.
      • Zuardi A.W.
      • Tumas V.
      • et al.
      Effects of cannabidiol in the treatment of patients with Parkinson's disease: an exploratory double-blind trial.
      • Russo E.B.
      Clinical endocannabinoid deficiency reconsidered: current research supports the theory in migraine, fibromyalgia, irritable bowel, and other treatment-resistant syndromes.
      • Irving P.M.
      • Iqbal T.
      • Nwokolo C.
      • et al.
      A randomized, double-blind, placebo-controlled, parallel-group, pilot study of cannabidiol-rich botanical extract in the symptomatic treatment of ulcerative colitis.
      TetrahydrocannabinolPhytocannabinoid<0.3%None knownBinds to CB1 receptors
      • Pertwee R.G.
      The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin.
      Antiemetic, antinociceptive, others
      • Pertwee R.G.
      The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin.
      β-CaryophylleneSesquiterpenoidLess than 1%Black pepper, clove, rosemary, hopsBinds to CB2 receptors
      • Klauke A.L.
      • Racz I.
      • Pradier B.
      • et al.
      The cannabinoid CB2 receptor-selective phytocannabinoid beta-caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic pain.
      Anxiolytic, anti-nociceptive
      • Gertsch J.
      • Leonti M.
      • Raduner S.
      • et al.
      Beta-caryophyllene is a dietary cannabinoid.
      • Katsuyama S.
      • Mizoguchi H.
      • Kuwahata H.
      • et al.
      Involvement of peripheral cannabinoid and opioid receptors in β-caryophyllene-induced antinociception.
      • Bahi A.
      • Al Mansouri S.
      • Al Memari E.
      • Al Ameri M.
      • Nurulain S.M.
      • Ojha S.
      β-Caryophyllene, a CB2 receptor agonist produces multiple behavioral changes relevant to anxiety and depression in mice.
      • Gulluni N.
      • Re T.
      • Loiacono I.
      • et al.
      Cannabis essential oil: a preliminary study for the evaluation of the brain effects.
      LimoneneTerpenoidLess than 1%Citrus fruits, rosemaryInduction of glutathioneAntioxidant, antitumor activity
      • Bai J.
      • Zheng Y.
      • Wang G.
      • Liu P.
      Protective effect of D-limonene against oxidative stress-induced cell damage in human lens epithelial cells via the p38 pathway.
      CannabichromenePhytocannabinoidVaries considerably with strainNone knownAnandamide uptake inhibitor
      • De Petrocellis L.
      • Ligresti A.
      • Moriello A.S.
      • et al.
      Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes.
      Antinociceptive
      • Maione S.
      • Piscitelli F.
      • Gatta L.
      • et al.
      Non-psychoactive cannabinoids modulate the descending pathway of antinociception in anaesthetized rats through several mechanisms of action.
      CannabigerolPhytocannabinoidVaries considerably with strainNone knownAnandamide uptake inhibitor
      • Maione S.
      • Piscitelli F.
      • Gatta L.
      • et al.
      Non-psychoactive cannabinoids modulate the descending pathway of antinociception in anaesthetized rats through several mechanisms of action.
      Anti-inflammatory, neuroprotective
      • Borrelli F.
      • Fasolino I.
      • Romano B.
      • et al.
      Beneficial effect of the non-psychotropic plant cannabinoid cannabigerol on experimental inflammatory bowel disease.
      • Valdeolivas S.
      • Navarrete C.
      • Cantarero I.
      • Bellido M.L.
      • Muñoz E.
      • Sagredo O.
      Neuroprotective properties of cannabigerol in Huntington's disease: studies in R6/2 mice and 3-nitropropionate-lesioned mice.
      EchinaceaAlkylamidesNoneZanthoxylum (Sichuan pepper)Binds to CB2 receptors
      • Raduner S.
      • Majewska A.
      • Chen J.Z.
      • et al.
      Alkylamides from Echinacea are a new class of cannabinomimetics: Cannabinoid type 2 receptor-dependent and -independent immunomodulatory effects.
      • Chicca A.
      • Raduner S.
      • Pellati F.
      • et al.
      Synergistic immunomopharmacological effects of N-alkylamides in Echinacea purpurea herbal extracts.
      • Hohmann J.
      • Rédei D.
      • Forgo P.
      • et al.
      Alkamides and a neolignan from Echinacea purpurea roots and the interaction of alkamides with G-protein-coupled cannabinoid receptors.
      Anti-inflammatory, antioxidant, antimicrobial
      • Hohmann J.
      • Rédei D.
      • Forgo P.
      • et al.
      Alkamides and a neolignan from Echinacea purpurea roots and the interaction of alkamides with G-protein-coupled cannabinoid receptors.
      • Hou C.C.
      • Chen C.H.
      • Yang N.S.
      • et al.
      Comparative metabolomics approach coupled with cell- and gene-based assays for species classification and anti-inflammatory bioactivity validation of Echinacea plants.
      • Hu C.
      • Kitts D.D.
      Studies on the antioxidant activity of Echinacea root extract.
      • Hudson J.B.
      Applications of the phytomedicine Echinacea purpurea (purple coneflower) in infectious diseases.
      BoswelliaTriterpenesNoneAlso known as frankincenseInhibition of prostaglandin E2 synthase
      • Siemoneit U.
      • Koeberle A.
      • Rossi A.
      • et al.
      Inhibition of microsomal prostaglandin E2 synthase-1 as a molecular basis for the anti-inflammatory actions of boswellic acids from frankincense.
      Anti-inflammatory
      • Siemoneit U.
      • Koeberle A.
      • Rossi A.
      • et al.
      Inhibition of microsomal prostaglandin E2 synthase-1 as a molecular basis for the anti-inflammatory actions of boswellic acids from frankincense.
      TurmericCurcuminoids (eg, diferuloylmethane, demethoxycurcumin)NoneNone knownMay bind to CB1 receptors
      • Hassanzadeh P.
      • Hassanzadeh A.
      The CB1 receptor-mediated endocannabinoid signaling and NGF: the novel targets of curcumin.
      Unclear in preclinical, purported antinociceptive and anti-inflammatory properties
      • Nelson K.M.
      • Dahlin J.L.
      • Bisson J.
      • Graham J.
      • Pauli G.F.
      • Walters M.A.
      The essential medicinal chemistry of curcumin.
      AshwagandaSteroidal alkaloids and lactonesNoneAlso known as Withania somniferaPossible mimicry of GABA
      • Chandrasekhar K.
      • Kapoor J.
      • Anishetty S.
      A prospective, randomized double-blind, placebo-controlled study of safety and efficacy of a high-concentration full-spectrum extract of ashwagandha root in reducing stress and anxiety in adults.
      Stress reduction, anxiolytic, immuno-modulatory
      • Chandrasekhar K.
      • Kapoor J.
      • Anishetty S.
      A prospective, randomized double-blind, placebo-controlled study of safety and efficacy of a high-concentration full-spectrum extract of ashwagandha root in reducing stress and anxiety in adults.
      MagnoliaPolyphenolsNoneAlso known as magnolia barkBinds to CB2 receptors
      • Rempel V.
      • Fuchs A.
      • Hinz S.
      • et al.
      Magnolia extract, magnolol, and metabolites: activation of cannabinoid CB2 receptors and blockade of the related GPR55.
      Antioxidant, anti-inflammatory
      • Shen J.L.
      • Man K.M.
      • Huang P.H.
      • et al.
      Honokiol and magnolol as multifunctional antioxidative molecules for dermatologic disorders.
      GABA = γ-aminobutyric acid; GPR55 = G protein–coupled receptor 55; TRPV1 = transient receptor potential vanilloid 1.

      Potential Therapeutic Actions

      The chief ingredients of hemp oils are phytocannabinoids such as CBD and terpenoids such as BCP and limonene. However, there is a paucity of clinical research conducted on these important components because most research focuses on THC and CB1 receptors (the primary target of THC).
      • Borgelt L.M.
      • Franson K.L.
      • Nussbaum A.M.
      • Wang G.S.
      The pharmacologic and clinical effects of medical cannabis.
      Much less data are available on CBD, which works via a variety of complex mechanisms noted previously,
      • Pertwee R.G.
      The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin.
      and BCP, which works through the less-understood CB2 receptors.
      • Gertsch J.
      • Leonti M.
      • Raduner S.
      • et al.
      Beta-caryophyllene is a dietary cannabinoid.
      According to a recent systematic review on the medical uses of cannabinoids, there was moderate-quality evidence to support the use of cannabinoids for chronic pain and spasticity, and low-quality evidence to support use for nausea and vomiting due to chemotherapy, weight gain in HIV infection, sleep disorders, and Tourette syndrome.
      • Whiting P.F.
      • Wolff R.F.
      • Deshpande S.
      • et al.
      Cannabinoids for medical use: a systematic review and meta-analysis.
      However, it is important to realize that most of the randomized controlled trials examined in this systematic review for each condition were of the 3 prescriptible THC drugs dronabinol, nabilone, and nabiximols; only 4 trials were found for CBD, and none for any of the other phytocannabinoids or terpenoids present in C sativa oils,
      • Whiting P.F.
      • Wolff R.F.
      • Deshpande S.
      • et al.
      Cannabinoids for medical use: a systematic review and meta-analysis.
      again demonstrating the lack of solid scientific research conducted on them.
      In June 2018, the FDA approved Epidiolex, a purified CBD oral solution that was found to provide major reductions in total seizure frequency vs placebo for patients with Dravet and Lennox-Gastaut syndromes. The research on these conditions is the most thorough clinical research that has been performed on CBD and for now should be relied on for understanding CBD’s safety and adverse effects, which will be discussed subsequently in this article. Although the use of CBD has been theorized for a variety of other conditions from migraines and inflammatory conditions to depression and anxiety, only preclinical and pilot studies have been performed for any of these uses, and therefore there is little guidance for physicians if their patient is interested in trying CBD or hemp oils for these conditions.
      As for CBD and hemp oils’ potential for use in the treatment of chronic pain, in the most recent review on the topic in 2018, Donvito et al
      • Donvito G.
      • Nass S.R.
      • Wilkerson J.L.
      • et al.
      The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain.
      wrote that “an overwhelming body of convincing preclinical evidence indicates that cannabinoids produce antinociceptive effects in inflammatory and neuropathic rodent pain models.” Additionally, it has been reported that CBD may be able to treat addiction through reduced activation of the amygdala during negative emotional processing and has been found to reduce heroin-seeking behavior, likely through its modulation of dopamine and serotonin.
      • Ren Y.
      • Whittard J.
      • Higuera-Matas A.
      • Morris C.V.
      • Hurd Y.L.
      Cannabidiol, a nonpsychotropic component of cannabis, inhibits cue-induced heroin seeking and normalizes discrete mesolimbic neuronal disturbances.
      • Hurd Y.L.
      • Yoon M.
      • Manini A.F.
      • et al.
      Early phase in the development of cannabidiol as a treatment for addiction: opioid relapse takes initial center stage.
      • Katsidoni V.
      • Anagnostou I.
      • Panagis G.
      Cannabidiol inhibits the reward-facilitating effect of morphine: involvement of 5-HT1A receptors in the dorsal raphe nucleus.
      • Hurd Y.L.
      Cannabidiol: swinging the marijuana pendulum from ‘weed’ to medication to treat the opioid epidemic.
      Cannabidiol therefore represents an attractive option in chronic pain treatment, particularly in the context of opioid abuse, not only because of its potential efficacy but also because of its limited misuse and diversion potential as well as safety profile.
      • Hurd Y.L.
      Cannabidiol: swinging the marijuana pendulum from ‘weed’ to medication to treat the opioid epidemic.
      More research will be needed because these were pilot human studies with small sample sizes, but they represent potential future areas of cannabinoid use in the clinical treatment of pain relief and opioid abuse. Additionally, more reflection on the right political and industrial means to go about expanding access to CBD is needed in the context of controversial evidence supporting expanding access to medical marijuana as a pain control option.
      • Olfson M.
      • Wall M.M.
      • Liu S.M.
      • Blanco C.
      Cannabis use and risk of prescription opioid use disorder in the United States.
      • Hurd Y.L.
      Cannabidiol: swinging the marijuana pendulum from ‘weed’ to medication to treat the opioid epidemic.

      Safety and Adverse Effects

      No rigorous safety studies have been done on “full-spectrum” phytocannabinoid oils because these products are relatively new, but the separate ingredients have been examined somewhat, generally with no major adverse effects noted.
      • Bergamaschi M.M.
      • Queiroz R.H.
      • Zuardi A.W.
      • Crippa J.A.
      Safety and side effects of cannabidiol, a Cannabis sativa constituent.
      • Iffland K.
      • Grotenhermen F.
      An update on safety and side effects of cannabidiol: a review of clinical data and relevant animal studies.
      Cannabidiol doses up to 300 mg/d have been used safely for up to 6 months,
      • Cunha J.M.
      • Carlini E.A.
      • Pereira A.E.
      • et al.
      Chronic administration of cannabidiol to healthy volunteers and epileptic patients.
      • Trembly B.
      • Sherman M.
      Double-blind clinical study of cannabidiol as a secondary anticonvulsant.
      and doses of 1200 to 1500 mg/d were used in a study by Zuardi et al
      • Zuardi A.W.
      • Morais S.L.
      • Guimarães F.S.
      • Mechoulam R.
      Antipsychotic effect of cannabidiol.
      • Zuardi A.
      • Crippa J.
      • Dursun S.
      • et al.
      Cannabidiol was ineffective for manic episode of bipolar affective disorder.
      for up to 4 weeks. In the recent larger studies on CBD treatment for epileptic patients, CBD had associated adverse effects of somnolence, decreased appetite, and diarrhea noted in up to 36% of patients, although these adverse effects were less severe and less frequent when compared with the usual adverse effects of clobazam treatment.
      • Friedman D.
      • Devinsky O.
      Cannabinoids in the treatment of epilepsy.
      • Devinsky O.
      • Cross J.H.
      • Laux L.
      • et al.
      Cannabidiol in Dravet Syndrome Study Group. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome.
      • Devinsky O.
      • Marsh E.
      • Friedman D.
      • et al.
      Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial.
      • Devinsky O.
      • Patel A.D.
      • Cross J.H.
      • et al.
      GWPCARE3 Study Group
      Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome.
      • Devinsky O.
      • Patel A.D.
      • Thiele E.A.
      • et al.
      GWPCARE1 Part A Study Group. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome.
      In addition, it was noted that a considerable number of patients in these studies had elevated liver function test results, and the FDA recommends liver function tests before beginning Epidiolex treatment, as well as 1 month and 3 months after initiation of treatment; thus, physicians should be cautious in patients with known decreased hepatic function who choose to use CBD and hemp oils. We recommend consulting the FDA label for Epidiolex for more information on safety, adverse effects, and dosing that was gathered from the Epidiolex trials.
      Epidiolex [package insert]. Carlsbad, CA: Greenwich Biosciences, Inc; 2018.
      In the context of treating pain, one study reported the safety of oral CBD administration (400-800 mg) alongside fentanyl administration, attributed to their different mechanisms of action.
      • Manini A.F.
      • Yiannoulos G.
      • Bergamaschi M.M.
      • et al.
      Safety and pharmacokinetics of oral cannabidiol when administered concomitantly with intravenous fentanyl in humans.
      However, other drug-drug interactions have been noted, or at least hypothesized, based on the metabolism of CBD by the cytochrome P450 superfamily, which includes warfarin and various epilepsy drugs.
      • Stout S.M.
      • Cimino N.M.
      Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review.
      • Grayson L.
      • Vines B.
      • Nichol K.
      • Szaflarski J.P.
      UAB CBD Program
      An interaction between warfarin and cannabidiol, a case report.
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      • Geffrey A.L.
      • Pollack S.F.
      • Bruno P.L.
      • Thiele E.A.
      Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy.
      The other ingredients in CBD and hemp oils are usually at such small concentrations that they are unlikely to cause severe interactions, but care should still be taken with identifying ingredients present in a product and possible safety issues.
      In addition, it is important to be aware of the presence of synthetic cannabinoids available on the market, such as “spice.” These substances have severe adverse effects and have led to hospitalizations following ingestion.
      • Louh I.K.
      • Freeman W.D.
      A ‘spicy’ encephalopathy: synthetic cannabinoids as cause of encephalopathy and seizure.
      • Kuehn B.
      Synthetic cannabidiol poisoning.
      As to the labeling of concentrations in products, a 2017 survey reported that of 84 online CBD and hemp oil products examined, only 26 were accurately labeled for CBD and THC content, with CBD often being overlabeled and THC underlabeled, consistent with the statements made by the FDA.
      • US Food and Drug Administration
      Warning letters and test results for cannabidiol-related products, 2015-2017.
      • Bonn-Miller M.O.
      • Loflin M.J.E.
      • Thomas B.F.
      • Marcu J.P.
      • Hyke T.
      • Vandrey R.
      Labeling accuracy of cannabidiol extracts sold online.
      There have also been documented cases of pediatric THC intoxication related to CBD product ingestion, likely due to this noted variation in products, signaling the need for more regulation of the market.
      • Crippa J.A.
      • Crippa A.C.
      • Hallak J.E.
      • Martin-Santos R.
      • Zuardi A.W.
      Δ9-THC intoxication by cannabidiol-enriched cannabis extract in two children with refractory epilepsy: full remission after switching to purified cannabidiol.

      Finding a Quality Product

      If patients and/or physicians choose to experiment with CBD and hemp oils, it is worthwhile to direct them toward the highest-quality product. This issue becomes all the more important when considering some of the problems noted previously. Because of the unclear regulations in the United States as well as some of the noted problems with online product labeling, it is recommended that patients utilize products imported from Europe, which actually has even more stringent requirements for low THC levels at less than 0.2% dry weight compared with the US requirement of less than 0.3% dry weight as well as a more established regulatory system for hemp.
      • Cherney J.H.
      • Small E.
      Industrial hemp in North America: production, politics, and potential.
      As with other herbal supplements, ensure that the product has been extracted by carbon dioxide with no solvents, is certified by the US Department of Agriculture as organic, and has been tested for pesticides/herbicides, which have been found in some products.
      • Migoya D.
      State recalls 50 Tree of Wellness medical pot products because of pesticide. The Denver Post website.
      Additionally, ensure that the product is not merely hemp seed oil, which although containing nutritious omega-3 fatty acids does not contain any of the phytocannabinoids or terpenoids.
      • Callaway J.C.
      Hempseed as a nutritional resource: an overview.
      It is up to the discretion of the physician whether to suggest trying “full-spectrum” formulations because no research is available on their safety and efficacy outside of certain components in separate contexts, whereas pure CBD oils have been studied much more rigorously in the recent seizure studies. Table 3 provides a checklist for determining a higher-quality product and company, based on requirements used by Mayo Clinic for collaboration with dietary supplement manufacturers.
      Table 3Checklist for Finding a High-Quality Cannabidiol and Hemp Oil Product
      • 1. Does it meet the following quality standards?
        • a.
          Current Good Manufacturing Practices (CGMP) certification from the US Food and Drug Administration
        • b.
          European Union (EU), Australian (AUS), or Canadian (CFIA) organic certification
        • c.
          National Science Foundation (NSF) International certification
      2. Does the company have an independent adverse event reporting program?
      3. Is the product certified organic or ecofarmed?
      4. Have their products been laboratory tested by batch to confirm tetrahydrocannabinol levels <0.3% and no pesticides or heavy metals?

      Conclusions and Future Research

      Cannabidiol and hemp oils are nonintoxicating and potentially useful phytocannabinoid substances that continue to grow in popularity. With increasing patient interest in and use of CBD and hemp oils, more research is indicated to better understand their potential efficacy and purported safety profile. Careful selection of a product is crucial for both safety and potential efficacy, and although the products do not have FDA approval for therapeutic use, patients continue to use them and physicians should inform themselves on both potential safety issues and potential therapeutic benefit. Chronic pain management continues to challenge patients and physicians alike, and investigation into potential therapies such as CBD and hemp oils is a promising area for the future of clinical pain management for both pain relief as well as addiction management. We encourage physicians to not disregard patients’ interest in these therapies and instead to retain clinical curiosity as well as healthy skepticism when it comes to attempts to explore new options, especially in the context of curbing addiction and opioid overuse. Our hope is that this article will inspire physicians to continue to educate both patients and themselves about alternative therapies utilized by growing numbers of the public, with the example of CBD and hemp oils in particular as it continues to come to the forefront of public interest.

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      Linked Article

      • Commercial Cannabidiol Caution: A New Gold Rush
        Mayo Clinic ProceedingsVol. 95Issue 1
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          We recently read with interest the review by VanDolah et al1 in Mayo Clinic Proceedings, summarizing the emerging landscape of commercially available cannabidiol (CBD) preparations, which are now subject to consumption by the general public because of the purported health benefits of CBD. We agree with the authors in that an open discussion exploring patient use of such substances is necessary for a complete history as well as for establishing patient rapport. We would add a word of caution about the use of products and would also suggest readers of Mayo Clinic Proceedings consider additional factors when discussing commercial CBD use with patients.
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      • In reply—Commercial Cannabidiol Caution: A New Gold Rush
        Mayo Clinic ProceedingsVol. 95Issue 1
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          We thank Scharf et al1 for their thoughtful comments, which basically reinforce the cautionary notes we sounded in the original article.
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