Marijuana (Cannabis)

Cannabinoids

The therapeutic benefits from marijuana are derived from the more than 100 pharmacologically active constituents, including cannabinoids and terpenes. Cannabiniods are organic chemical compounds (alkaloids) found in cannabis plants and more than 600 have been identified.

 

The two best understood and most common of the cannabinoids are Δ-9 THC (tetrahydrocannabinol) and CBD (cannabidiol). While only the cannabinoids Δ-8 THC, Δ-9 THC, and their hydroxyl metabolites are psychoactive, many of the clinical benefits from marijuana also come from these cannabinoids as well as others. 

 

Links to other Pertinent Educational Pages:

Links to ALL Marijuana Educational Pages

 

See also:

 

The medical information on this site is provided as a resource for information only, and is not to be used or relied upon for any diagnostic or treatment purposes and is not intended to create any patient-physician relationship.  Readers are advised to seek professional guidance regarding the diagnosis and treatment of their medical concerns.

Key to Links:

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Definitions and Terms Related to Pain

 

This Page:

 

 

Cannabiniods

 

 

Botanical Cannabis and the Cannabinoid Acids

Phytocannabinoids (plant-base cannabinoids) are phenolic terpenes biosynthesized in nature nearly exclusively in the Cannabis plant. These cannabinoids are synthesized and stored predominantly in glandular trichomes, hair-like epidermal protrusions densely concentrated in the flowers of cannabis plants.

 

Botanical cannabis is highly variable in its chemical composition and content of the cannabinoids. In the cannabis plant, all cannabinoids are first biosynthesized into their acid form, mainly CBGA, Δ-9 THCA and CBDA.   CBGA is the first molecule formed in the biosynthetic pathway and different enzymes convert CBGA into Δ-9 THCA, CBDA and other cannabinoid acids.

 

Fresh cannabis plants actually contain little to no cannabinoids such as THC and CBD, but instead they contain only their acid cannabinoid forms, which are the precursors to THC and CBD respectively.  In the presence of heat such as from smoking or vaporizing, UV exposure, and/or drying from prolonged storage, these cannabinoid acids are enzymatically decarboxylated to form the active cannabinoids including CBG, THC and CBD.

 

Most of the pharmacologic effects of cannabis are derived from its many constituents, but are attributed mostly to the cannabinoids Δ-9-THC, CBD and CBG and numerous terpenes. Although the cannabinoid acids in fresh cannabis have no psychotropic qualities, they are known to possess pharmacological properties in their own right. While the acid cannabinoids have had much less research, they are gaining attention as more is learned about their therapeutic benefits, especially their analgesic and anti-inflammatory properties.

 

Δ-9 Tetrahydrocannabinolic Acid (Δ-9 THCA)

Δ-9 Tetrahydrocannabinolic acid (Δ-9 THCA or 2-COOH-THC) is a precursor of tetrahydrocannabinol (Δ-9 THC), the major active component of cannabis. Δ-9 THCA is found in variable quantities in fresh, undried cannabis, but is progressively decarboxylated and converted to Δ-9 THC with drying or with exposure to intense heat, although slow decarboxylation of ∆9-THC occurs at room temperature during aging.

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More than 90% of the THC in cannabis plants grown in Europe is present as Δ-9 THCA, while cannabis grown in hot climates of Africa and Asia contain considerable more Δ-9 THC. The ratio of ∆9-THCA to ∆9-THC in leaves and flowers of Cannabis sativa has been reported to range from 2:1 in Africa to > 20:1 in Switzerland. In samples of cannabis resin (hashish) the Δ-9 THCA/Δ-9 THC ratio is reported to range between 6.1:1 and 0.5:1.

 

 

For Δ-9 THCA to become activated and converted to Δ-9 THC for therapeutic use, it generally must be exposed to intense heat such as when cannabis is smoked or cooked into cannabis edibles. Δ-9 THCA is often the main constituent in cannabis resin concentrates, such as hashish and hash oil comprising 50% – 90% by weight.

 

It has been reported that five minutes of heating to 200-210°C is optimal for this conversion, a few seconds in a burning cannabis cigarette is sufficient. Cannabis products with a high content of Δ-9 THC (e.g., hashish) may be very potent without heating, but usually the potency and medicinal efficacy of cannabis products is significantly increased with smoking the dried plant matter, or by cooking and baking.

 

Δ-9 THCA ‘s potential benefits include reducing inflammation associated with arthritis and autoimmune diseases. It may also help reduce symptoms of neurological conditions such as Parkinson’s disease and amyotrophic lateral sclerosis (ALS).

 

Δ-9 THCA is not psychoactive like Δ-9 THC but it does have some immuno-modulating effects but they are not mediated by the cannabinoid CB1 and CB2 receptor pathways. Δ-9 THCA is a TRPA1 partial agonist, and a TRPM8 antagonist which may underlie a potential role in the analgesia, and anti-inflammatory and anti-nausea properties. 

 

 

 

Cannabadiolic Acid (CBDA)

Cannabidiolic acid (CBDA) is a phytocannabinoid found in raw cannabis, meaning fresh flowers and leaves that are unheated. CBDA is decarboxylated to CBD with heat and light exposure. CBDA is often ingested through consumption of raw cannabis juice. Like THCA, CBDA is a TRPA1 agonist, TRPV1 agonist, and TRPM8 antagonist which may underlie a potential role in the analgesia, and anti-inflammatory and anti-nausea properties. CBDA is a powerful anti-emetic and anti-anxiety agent (at least in rodents), and has anecdotal reports of benefit on skin and tumors.

Neurobiology of CBDA

In a 2020 study, CBDA was inactive at CB1 receptor (CB1R) and displayed only weak partial agonism at CB2 receptor (CB2R).  Apart from CB1R and CB2R activity, CBDA produces significant anxiolytic effects and is effective in reducing inflammatory pain, nausea and seizures in rodent models. Growing research suggests these effects of CBDa are mediated by 5HT1A.

 

The exact functions of CBDA and THCA physiologically suggest similar therapeutic benefits to CBD that may have the potential to work synergistically with CBD. These synergistic properties known as the “entourage effect” are currently thought to be the primary reason that lower CBD whole hemp extract dosing can be more therapeutic when compared to purified CBD.

 

 

THCA and CBDA concentrations depend on the species, strain, cultivation, and storage of the plant. The average concentrations in more than 30,000 cannabis preparations confiscated in the U.S. between 1980 and 1997 were 3.1% THCA and only 0.3% CBDA. Various strains and marijuana-based products are now available that contain substantially higher contents of these constituents, especially THC.

 

 

Δ-9 THC (Tetrahydrocannabinol)

THC has analgesic, anti-spasmodic, anti-tremor, anti-inflammatory, appetite stimulant and anti-emetic properties, whilst CBD is non-euphoric but has anti-anxiety, anti-depressant, anti-inflammatory, anti-convulsant, anti-psychotic, anti-oxidant, neuroprotective and immunomodulatory effects. CBD is a versatile anti-inflammatory analgesic through numerous distinct mechanisms.

 

The clinical benefits from marijuana are derived from the many constituents found in the plant, including more than 80 pharmacologically active cannabinoids. The two best understood and most common of these cannabinoids are THC (tetrahydrocannabinol) and CBD (cannabidiol). There is very limited scientific information on the pharmacology and toxicology of the other cannabinoids and pharmacologially active constituents found in cannabis. THC acts as a CB1 receptor partial agonist, while CBD is a negative allosteric modulator of the CB1 receptor.

 

With respect to the management of pain, studies suggest that THC alone may not be sufficient for a good analgesic effect. This means that THC may need to be combined with CBD in order to achieve good results. THC is responsible for many of the clinical effects of marijuana, including the analgesic, anti-spasmodic, anti-tremor, anti-inflammatory, appetite stimulant and anti-emetic properties. THC and its active metabolite, 11-Hydroxy-THC. are responsible for the “high” or euphoria associated with use of marijuana.

See:

Δ-9 THC

 

Delta 8 Tetrahydrocannabinol (Δ-8 THC)

See: Δ-8 THC

 

 

CBD (Cannabidiol)

CBD does not produce the mind-altering “high” effects like euphoria but it does reduce anxiety and enhance sleep. It has anti-inflammatory, anti-convulsant, anti-psychotic, anti-oxidant, neuroprotective and immunomodulatory effects. CBD is also thought to reduce nausea, particularly related to chemotherapy. CBD, in combination with THC, modulates some of the side effects of THC, including reducing THC-induced anxiety.

See: CBD (Cannabidiol)

 

 

CBG (Cannabigerol)

Cannabigerol (CBG) is notable among all other cannabinoids as being the precursor to each one of them, lending to its nickname: “The Mother All Cannabinoids.” In particular, it has a direct link to the three most significant and abundant cannabinoids: THC, CBD and CBC. Therefore, the more THC a cannabis plant contains, the less CBG and vice-versa. CBG is non-psychoactive and is found in the fresh cannabis plant. CBG is made by the decarboxylation of cannabigerolic acid (CBGA). CBG is a highly potent agonist for α2-adrenoceptor and a blocker of serotonin 5-HT1A receptor. This activity can decrease anxiety and muscle tension.

 

CBG is purported to reduce anxiety and symptoms of obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and depression.

 

CBG shows agonist and antagonist activity on TRP channels and antagonism at 5-HT1 and CB1 receptor. Additionally, CBG is an AEA reuptake inhibitor, and it showed colon anti-tumor activity by inhibiting transient receptor potential melastatin 8 (TRPM8) channels. When associated with CBD, it has anti-inflammatory activity by reducing tumor necrosis factor (TNF) expression and upregulating Interleukin–10 (IL-10) and Interleukin–37 (IL-37) levels.

 

CBN (Cannabinol)

The third most common constituent of marijuana is cannabinol (CBN). Cannabinol (CBN) is a non-psychoactive cannabinoid found in fresh cannabis plant, usually in low amounts.  Unlike other cannabinoids, CBN does not stem from cannabigerol (CBG) but is the nonenzymatic oxidative breakdown product of tetrahydrocannabinol (THC), seen in aged cannabis, and has about 25% of the potency of THC. In the evaluation of the freshness of a dried cannabis product levels of CBN, coupled with levels of THCA can potentially identify if the cannabis product has been stored properly. CBN is also formed by decarboxylation of CBNA.  but it is not yet (?) commercially available as an isolated compound.

 

Cannabinol (CBN) is helpful for treating neurological conditions including seizures and severe muscle stiffness. It may have antiinflammatory and neuropathic pain benefits.

 

CBN likely plays a small role in the pharmacologic effects of plant based cannabis products, but does show similar therapeutic properties to other phytocannabinoids, including pain relief as well as anticonvulsant, anti-inflammatory, and antibacterial activity. CBN is a relatively weak partial agonist of CB1 and CB2 but is a strong AEA uptake inhibitor. CBN behaves as a potent a-2 adrenoreceptor agonist, suggesting neuropathic pain benefits. It also is a moderate 5-HT1A antagonist suggesting antidepressant properties. CBN also inhibits transient receptor potential melastatin 8 (TRPM8) channels and it inhibits cyclooxygenase (COX, suggesting antiinflammatory and analgesic properties.

 

Average systemic bioavailability after smoking 19 mg CBN is about 26% (range: 8-65%), similar or somewhat higher than THC. Blood levels following oral ingestion and inhalation is similar to that of CBD.  The half lives for CBN are 17 hours and 29 hours after intravenous administration and smok- ing, respectively. Metabolism of CBN is similar to THC with excretion about 8% eliminated with urine and 35% excreted in feces within 72 h

 

 

 

CBDV (Cannabidivarin)

Cannabidivarin (CBDV) is a non-psychoactive cannabinoid known for its anticonvulsant effects.

Neurobiology of CBDV

CBDV (and CBD) activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro. In a 2020 study, CBDV displayed little to no activity at CB1 receptor (CB1R) but did display demonstrable affinity and activity at CB2 receptor (CB2R).

 

 

 

Cannabichromene (CBC)

Cannabichromene (CBC) is a CB2 receptor agonist and it interacts with TRP channels. It has potential for the treatment of pain and inflammation, having shown to have anti-inflammatory and analgesic activity and the ability to reduce THC intoxication in mice. CBC also appears to be a strong AEA uptake inhibitor.

 

Neurobiology of CBC

A 2020 study concluded that similar to CBG, CBC is a partial agonist at both the CB1 receptor (CB1R) and CB2 receptor (CB2R), with greater selectivity and potency at CB2R relative to CB1R. Previous studies have also observed weak partial agonism of CBC at both CB1R and CB2R8.

CBC has also been shown to be anti-inflammatory and to reduce hypermobility in a mouse model of gut inflammation, although these effects occur via TRPA1 and not cannabinoid receptors.

 

 

Tetrahydrocannabivarin (THCV)

∆9-THCV is about one fourth as pharmacologically active as ∆9-THC.

THCV appears to activate the 5-HT1A receptor which accounts for its apparent antipsychotic effects, reducing some of the symptoms of schizophrenia.

Neurobiology of THCV

THCV has been proposed to act at both the CB1 receptor (CB1R) and the CB2 receptor (CB2R), and possibly behave as a CB1R antagonist and CB2R agonist. A 2020 study found that THCV is only an agonist at both CB1R and CB2R and produced analgesic and anxiolytic effects. These effects are consistent with others’ observations in which THCV is able to reduce hyperalgesia in mice via both CB1R and CB2R. It is likely that the therapeutic effects of THCV are dependent on both cannabinoid receptors.

 

 

Resources:

National Academy of Sciences

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

 

www.Healer.com

This website appears to be good resource for exploring medical marijuana.

 

References:

   

Terpenes – Overviews:

  1. Taming THC – potential cannabis synergy and phytocannabinoid- 

Cannabinoids: Caryophyllene:

  1. (−)-β-Caryophyllene, a CB2 Receptor-Selective Phytocannabinoid, Suppresses Motor Paralysis and Neuroinflammation in a Murine Model of Multiple Sclerosis – 2017
  2. Antiallodynic effect of β-caryophyllene on paclitaxel-induced peripheral neuropathy in mice. – PubMed – NCBI

 

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

 

CBN

 

Cannabinoids – Pain

  1. Association of Cannabinoid Administration With Experimental Pain in Healthy Adults – 2018
  2. Effects of Cannabinoid Administration for Pain – A Meta-Analysis and Meta-Regression – 2019
  3. Cannabis-based medicines and the perioperative physician – 2019
  4. Cannabis‐based medicines for chronic neuropathic pain in adults – 2018
  5. Cannabinoids in the Descending Pain Modulatory Circuit- Role in Inflammation – 2020
  6. Current Evidence of Cannabinoid-Based Analgesia Obtained in Preclinical and Human Experimental Settings – PubMed – 2018
  7. Role of Cannabinoids and Terpenes in Cannabis-Mediated Analgesia in Rats – PubMed – 2019
  8. Medicinal Properties of Cannabinoids, Terpenes, and Flavonoids in Cannabis, and Benefits in Migraine, Headache, and Pain – An Update on Current Evidence and Cannabis Science – 2018
  9. The Molecular Mechanisms That Underpin the Biological Benefits of Full-Spectrum Cannabis Extract in the Treatment of Neuropathic Pain and Inflammation – PubMed – 2020
  10. Cannabis sativa L. an
    d Nonpsychoactive Cannabinoids – Their Chemistry and Role against Oxidative Stress, Inflammation, and Cancer – 2018
  11. Cannabinoid Delivery Systems for Pain and Inflammation Treatment – 2018
  12. Cannabinoid Formulations and Delivery Systems – Current and Future Options to Treat Pain – 2021

 

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

 

 

Cannabinoids: Tetrahydrocannabivarin (THCV):

  1. The phytocannabinoid, Δ9-tetrahydrocannabivarin, can act through 5-HT1A receptors to produce antipsychotic effects – 2015

 

Cannabinoids – 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
  25. Cannabis Use in Patients with Fibromyalgia – Effect on Symptoms Relief and Health-Related Quality of Life – 2011
  26. Weighing the Benefits and Risks of Medical Marijuana Use – A Brief Review – 2018
  27. A Marijuana-Drug Interaction Primer – Precipitants, Pharmacology, and Pharmacokinetics – 2019
  28. Myorelaxant Effect of Transdermal Cannabidiol Application in Patients with TMD – A Randomized, Double-Blind Trial – 2019
  29. Drug interactions with cannabinoids – 2020
  30. The effects of acute and sustained cannabidiol dosing for seven days on the haemodynamics in healthy men – A randomised controlled trial – 2019
  31. Novel approaches and current challenges with targeting the endocannabinoid system – 2020
  32. Herbal Preparations of Medical Cannabis – A Vademecum for Prescribing Doctors – 2020
  33. Cannabis is associated with clinical but not endoscopic remission in ulcerative colitis – A randomized controlled trial – 2020
  34. Practical Strategies Using Medical Cannabis to Reduce Harms Associated With Long Term Opioid Use in Chronic Pain – 2021
  35. Endocannabinoid Levels in Ulcerative Colitis Patients Correlate With Clinical Parameters and Are Affected by Cannabis Consumption – 2021
  36. The pharmacokinetics and the pharmacodynamics of cannabinoids – 2018
  37. In vitro and in vivo pharmacological activity of minor cannabinoids isolated from Cannabis sativa – 2020

 

Medical Marijuana – Product Evaluation

  1. Recommended methods for the identification and analysis of cannabis and cannabis products – 2009
  2. The Cannabinoid Content of Legal Cannabis in Washington State Varies Systematically Across Testing Facilities and Popular Consumer Products – 2018
  3. Quality Control of Traditional Cannabis Tinctures – Pattern, Markers, and Stability – 2016
  4. Cannabinoid, Terpene, and Heavy Metal Analysis of 29 Over-the-Counter Commercial Veterinary Hemp Supplements – 2020

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