Cannabidiol (CBD)

Entourage and Synergies

The pharmacologic effects of cannabis depend on the combined effects of all the pharmacologically active constituents present. The interplay of the different constituents that determine the therapeutic benefits is known as the “Entourage Effect,” or synergistic effect, in which it is the combined effects of all the constituents that determine the ultimate therapeutic effects.

 

Links to other Pertinent Educational Pages:

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Cannabidiol (CBD):

 

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Entourage Effects:

 

 

Entourage Effects – Introduction

The pharmacologic effects of cannabis depend on the combined effects of all the pharmacologically active constituents present. The interplay of the different constituents that determine the therapeutic benefits is known as the “Entourage Effect,” or synergistic effect, in which it is the combined effects of all the constituents that determine the ultimate therapeutic effects. There is a wide range of differences in both the number, amounts and ratios of different constituents in cannabis strains leading to a wide range of therapeutic benefits.

 

Different mechanisms of synergy have been proposed to explain the Entourage Effect: (i) multi-target effects; (ii) pharmacokinetic effects such as improved solubility or bioavailability; (iii) agent interactions; and (iv) modulation of adverse events.

 

  

 

Entourage Effect – THC and CBD

The strength and ratio of the two major cannabinoids, THC and CBD, play a dominate role in the clinical effects of cannabis. A synergy exists between these two components in which their combination produces effects that are uniquely determined by the amount and ratios of these two constituents. At low concentrations CBD antagonizes some effects of THC, regulating THC-related adverse effects like rapid heart rate, anxiety, sedation and hunger.

 

In one early study, CBD proved to be a critical factor in the ability of Sativex (nabiximols oromucosal extract consisting of a 1:1 ratio combination of THC and CBD) in successfully treating intractable cancer pain patients unresponsive to opioids (30% reduction in pain from baseline). In this study a high-THC extract devoid of CBD failed to distinguish from placebo. This may represent true synergy of the THC–CBD combination.

 

CBD products lack the potential benefit of the Entourage Effect contributed by the THC, and may be less effective than when combined with THC.

 

 

 

CBD and Terpenes

In addition to THC and CBD, other cannabinoids and terpenes are believed to impact the clinic effects of cannabis and contribute to the entourage effect. For this reason, the Broad Spectrum and Full Spectrum CBD products offer potentially greater clinical benefits compared with the CBD Isolates. While the theory is sound, there is little research evaluating specific constituent combinations or doses nor specific therapeutic benefits. Much of the research does not clearly identify the content of cannabinoids and terpenes present in the marijuana studied. As the industry grows and research begins to catch up, it may be possible to select specific Broad Spectrum and Full Spectrum products to match specific desired therapeutic benefits.

 

In the meantime, one can explore what is known about the therapeutic effects of specific cannabinoids and terpenes and look for CBD products which could likely target desired therapeutic benefits. Careful attention to Certificates of Analysis can guide one to better product choices.

See: Cannabinoids and Terpenes – An Overview

 

 

 

 

Entourage Effect – CBD & β-Caryophyllene (BCP)

There is evidence that combining  CBD and the terpene, β-Caryophyllene, may have a synergistic benefit with respect to pain and inflammation.

See: β-Caryophyllene

 

 

CBD & Limonene and Linalool

CBD is reported to have synergy with limonene and linalool. Both Limonene and linalool are able to increase the anti-anxiety benefits CBD.

 

 

 

Entourage Effect – CBD & Palmitoylethnolamide (PEA)

Palmitoylethnolamide (PEA) is a potent nutraceutical that is naturally produced in many plant and animal food sources, as well as in cells and tissues of mammals.  PEA has important neuroprotective, anti-inflammatory and analgesic actions both in the central and the peripheral nervous system. There are multiple mechanisms of action of PEA responsible for its therapeutic benefits, some that involve the endocannabinoid system (ECS) which is the basis of its proposed synergistic action with CBD, THC and other cannabinoids.

 

PEA produces indirect receptor-mediated effects within the ECS. PEA inhibits FAAH, the enzyme that breaks down endogenous (natural) cannabinoids (or endocannabinoids) such as anandamide (AEA), and plant cannabinoids (phytocannabinoids) like CBD and THC, that directly or indirectly activate CB2 and CB1 receptors. Likewise, PEA can indirectly activate the transient receptor potential vanilloid receptor type 1 (TRPV1) channels, which are also targets for the endocannabinoids. In addition, PEA is also able to increase AEA- or 2-AG-induced TRPV1 activation and desensitization . More recently, it has also been demonstrated that PEA can activate TRPV1 channels or increase the expression of CB2 receptors via PPAR-α receptors.

 

 

 

 

 

 

Resources:

National Academy of Sciences

The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research

 

These lay-person websites appear to be good resources for exploring medical marijuana:

  1. www.GreenCamp.com
  2. www.Healer.com
  3. www.MedicalJane.com
  4. www.ProjectCBD.org

 

 

References:

Epidiolex (cannabidiol)

  1. FDA approves CBD drug – Epidiolex – The Washington Post

Marinol (dronabinol)

  1. Marinol – dronabinol

  

Cannabidiol (CBD)- Overviews

  1. CANNABIDIOL (CBD) Pre-Review Report WHO 2017
  2. Cannabidiol – State of the art and new challenges for therapeutic applications. – 2017 PubMed – NCBI
  3. Molecular Targets of Cannabidiol in Neurological Disorders – 2015
  4. Clinicians’ Guide to Cannabidiol and Hemp Oils – 2019

 

CBD – Anxiety

  1. Overlapping Mechanisms of Stress-Induced Relapse to Opioid Use Disorder and Chronic Pain – Clinical Implications – 2016
  2. Cannabidiol Modulates Fear Memory Formation Through Interactions with Serotonergic Transmission in the Mesolimbic System – 2016
  3. Cannabidiol regulation of emotion and emotional memory processing: relevance for treating anxiety-related and substance abuse disorders. – PubMed – NCBI
  4. Review of the neurological benefits of phytocannabinoids – 2018
  5. Plastic and Neuroprotective Mechanisms Involved in the Therapeutic Effects of Cannabidiol in Psychiatric Disorders – 2017
  6. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. – PubMed – NCBI
  7. Evidences for the Anti-panic Actions of Cannabidiol – 2017
  8. Cannabidiol, a Cannabis sativa constituent, as an anxiolytic drug – 2012
  9. Cannabidiol Reduces the Anxiety Induced by Simulated Public Speaking in Treatment-Naïve Social Phobia Patients – 2011
  10. The non-psychoactive cannabis constituent cannabidiol is an orally effective therapeutic agent in rat chronic inflammatory and neuropathic pain. – PubMed – NCBI 2007

 

CBD – Interaction with THC

  1. Cannabidiol: a promising drug for neurodegenerative disorders? – PubMed – NCBI
  2. Oral Cannabidiol does not Alter the Subjective, Reinforcing or Cardiovascular Effects of Smoked Cannabis – 2015
  3. Taming THC – potential cannabis synergy and phytocannabinoid-terpenoid entourage effects – 2011
  4. A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. – PubMed – NCBI
  5. Clinical and Preclinical Evidence for Functional Interactions of Cannabidiol and Δ9-Tetrahydrocannabinol. 2018 – PubMed – NCBI
  6. Does Cannabis Composition Matter? Differential Effects of Delta-9-tetrahydrocannabinol and Cannabidiol on Human Cognition – 2017

 

 

CBD – Metabolites

  1. Human Metabolites of Cannabidiol – A Review on Their Formation, Biological Activity, and Relevance in Therapy – 2016

 

CBD – Drug-Metabolic Interactions

  1. Cannabidiol, a Major Phytocannabinoid, As a Potent Atypical Inhibitor for CYP2D6 – 2011
  2. The Effect of CYP2D6 Drug-Drug Interactions on Hydrocodone Effectiveness – 2014 
  3. Characterization of P-glycoprotein Inhibition by Major Cannabinoids from Marijuana – 2006

 

CBD – Formulations

  1. Self-nano-emulsifying drug delivery systems an update of the biopharmaceutical aspects – PubMed – 2016
  2. The effect of Pro NanoLipospheres (PNL) formulation containing natural absorption enhancers on the oral bioavailability of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) – PubMed – 2017

 

Medical Marijuana – Prescribing Guidelines

  1. Simplified guideline for prescribing medical cannabinoids in primary care – Canadian Family Physician – 2018
  2. Physician Recommendation of Medical Cannabis Guidelines Calif Medical Assoc – 2011
  3. Prescribing smoked cannabis for chronic noncancer pain. Preliminary recommendations – Canadian Family Physician – 2014

 

CBD – Pain

  1. The non-psychoactive cannabis constituent cannabidiol is an orally effective therapeutic agent in rat chronic inflammatory and neuropathic pain. – PubMed – NCBI 2007
  2. Molecular Targets of Cannabidiol in Neurological Disorders – 2015
  3. Cannabidiol Modulates Fear Memory Formation Through Interactions with Serotonergic Transmission in the Mesolimbic System – 2016
  4. Cannabidiol enhances morphine antinociception, diminishes NMDA-mediated seizures and reduces stroke damage via the sigma 1 receptor – 2018
  5. Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain. – PubMed – NCBI – 2018
  6. Cannabidiol for Pain Treatment – Focus on Pharmacology and Mechanism of Action – 2020
  7. The Effectiveness of Topical Cannabidiol Oil in Symptomatic Relief of Peripheral Neuropathy of the Lower Extremities – 2020

 

Medical Marijuana – Pain

  1. Use-of-Prescription-Pain-Medications-Among-Medical-Cannabis-Patients
  2. It is premature to expand access to medicinal cannabis in hopes of solving the US opioid crisis – 2018
  3. Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort – 2018
  4. Patterns and correlates of medical cannabis use for pain among patients prescribed long-term opioid therapy. – PubMed – NCBI
  5. Associations between medical cannabis and prescription opioid use in chronic pain patients – A preliminary cohort study – 2017
  6. Medical Marijuana for Treatment of Chronic Pain and Other Medical and Psychiatric Problems – A Clinical Review – 2015

 

Medical Marijuana – Opioids

  1. Use-of-Prescription-Pain-Medications-Among-Medical-Cannabis-Patients
  2. It is premature to expand access to medicinal cannabis in hopes of solving the US opioid crisis – 2018
  3. Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort – 2018
  4. Patterns and correlates of medical cannabis use for pain among patients prescribed long-term opioid therapy. – PubMed – NCBI
  5. Associations between medical cannabis and prescription opioid use in chronic pain patients – A preliminary cohort study – 2017
  6. The prevalence and significance of cannabis use in patients prescribed chronic opioid therapy: a review of the extant literature. – PubMed – NCBI
  7. The use of cannabis in response to the opioid crisis: A review of the literature. – PubMed – NCBI
  8. Medical Cannabis Laws and Opioid Analgesic Overdose Mortality in the United States, 1999–2010 – 2014
  9. Rationale for cannabis-based interventions in the opioid overdose crisis – 2017
  10. Cannabis and the Opioid Crisis – 2018
  11. Impact of co-administration of oxycodone and smoked cannabis on analgesia and abuse liability. – PubMed – NCBI
  12. Cannabinoid–Opioid Interaction in Chronic Pain
  13. Synergistic interactions between cannabinoid and opioid analgesics. – PubMed – NCBI
  14. FDA approves CBD drug – Epidiolex – The Washington Post
  15. Opioid transport by ATP-binding cassette transporters at the blood-brain barrier: implications for neuropsychopharmacology. – PubMed – NCBI – 2011
  16. Opioids and the Blood-Brain Barrier – A Dynamic Interaction with Consequences on Drug Disposition in Brain – 2017
  17. The pharmacokinetics and the pharmacodynamics of cannabinoids. – PubMed – NCBI – 2018
  18. Cannabinoids and Cytochrome P450 Interactions. – PubMed – NCBI – 2016
  19. Pharmacogenetics of Cannabinoids – 2017 Enhanced Brain Disposition and Effects of Δ9-Tetrahydrocannabinol in P-Glycoprotein and Breast Cancer Resistance Protein Knockout Mice. 2012
  20. Pharmacogenomics of methadone maintenance treatment. – PubMed – NCBI
  21. Relationship between ABCB1 polymorphisms and serum methadone concentration in patients undergoing methadone maintenance therapy (MMT). – PubMed – NCBI- 2016
  22. Impact of ABCB1 and CYP2B6 Genetic Polymorphisms on Methadone Metabolism, Dose and Treatment Response in Patients with Opioid Addiction – A Systematic Review and Meta-Analysis – 2014
  23. ABCB1 haplotype and OPRM1 118A > G genotype interaction in methadone maintenance treatment pharmacogenetics – 2012
  24. The opioid epidemic – a central role for the blood brain barrier in opioid analgesia and abuse – 2017
  25. Morphine and the blood-brain barrier – diffusion, uptake, or efflux? – 2017
  26. Cyclosporine-inhibitable Blood-Brain Barrier Drug Transport Influences Clinical Morphine Pharmacodynamics – 2013
  27. Methadone Treatment for Pain States – 2005
  28. Cyclosporine-inhibitable Cerebral Drug Transport Does not Influence Clinical Methadone Pharmacodynamics – 2014
  29. Targeting blood–brain barrier changes during inflammatory pain – an opportunity for optimizing CNS drug delivery – 2011
  30. Targeting Transporters – Promoting Blood-Brain Barrier Repair in Response to Oxidative Stress Injury – 2015
  31. The non-psychoactive cannabis constituent cannabidiol is an orally effective therapeutic agent in rat chronic inflammatory and neuropathic pain. – PubMed – NCBI 2007

 

Medical Marijuana –Misc

  1. A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. – PubMed – NCBI
  2. Cannabis and cannabis extracts – greater than the sum of their parts? – 2001
  3. Medical cannabis and mental health: A guided systematic review. 2016 – PubMed – NCBI
  4. Epidemiological characteristics, safety and efficacy of medical cannabis in the elderly. – PubMed – NCBI
  5. Cannabis-conclusions – 2017 National Academy of Sciences
  6. Cannabis-chapter-highlights – 2017 National Academy of Sciences
  7. Cannabis-report-highlights – 2017 National Academy of Sciences
  8. Clinical Endocannabinoid Deficiency (CECD): Can this Concept Explain Therapeutic Bene ts of Cannabis in Migraine, Fibromyalgia, Irritable Bowel Syndrome and other Treatment-Resistant Conditions?-2004
  9. Marijuana use and the risk of lung and upper aerodigestive tract cancers: results of a population-based case-control study. – PubMed – NCBI
  10. Cannabis use and cognitive function: 8-year trajectory in a young adult cohort. – PubMed – NCBI
  11. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. – PubMed – NCBI
  12. Cannabinoids and Cytochrome P450 Interactions. – PubMed – NCBI Pharmacogenetics of Cannabinoids – 2018
  13. Systematic review of systematic reviews for medical cannabinoids – 2018
  14. Adverse effects of medical cannabinoids – a systematic review – 2008
  15. Cannabimimetic effects modulated by cholinergic compounds. – PubMed – NCBI
  16. Antagonism of marihuana effects by indomethacin in humans. – PubMed – NCBI
  17. Pharmacokinetics and pharmacodynamics of cannabinoids. – PubMed – NCBI
  18. Clinical Pharmacodynamics of Cannabinoids – 2004
  19. Affinity and Efficacy Studies of Tetrahydrocannabinolic Acid A at Cannabinoid Receptor Types One and Two. – 2017
  20. Quality Control of Traditional Cannabis Tinctures – Pattern, Markers, and Stability – 2016
  21. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. – PubMed – NCBI
  22. Pharmacology of Cannabinoids
  23. Current-status-and-future-of-cannabis-research-Clin-Researcher-2015
  24. Medical Marijuana for Treatment of Chronic Pain and Other Medical and Psychiatric Problems – A Clinical Review – 2015

 

Medical Marijuana – Liposomal and Nanoformulations

  1. Phyto-liposomes as nanoshuttles for water-insoluble silybin–phospholipid complex
  2. Getting into the brain – liposome-based strategies for effective drug delivery across the blood–brain barrier – 2016

 

Medical Marijuana – Product Evaluation

  1. Labeling Accuracy of Cannabidiol Extracts Sold Online – 2017
  2. Public Health Focus > Warning Letters and Test Results for Cannabidiol-Related Products – 2017
  3. The Cannabinoid Content of Legal Cannabis in Washington State Varies Systematically Across Testing Facilities and Popular Consumer Products – 2018
  4. Quality Control of Traditional Cannabis Tinctures – Pattern, Markers, and Stability – 2016

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