Marijuana (Cannabis)

∆-9 THC

The therapeutic benefits from marijuana are derived from the more than 100 pharmacologically active constituents, including cannabinoids and terpenes. The most abundant of the cannabinoids is Δ-9 THC (Delta 9-Tetrahydrocannabinol) which is responsible for many of the clinical benefits associated with marijuana. 


Links to other Pertinent Educational Pages:

Links to ALL Marijuana Educational Pages


See also: ∆-8 THC



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.

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Definitions and Terms Related to Pain


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Botanical Cannabis and the Cannabinoid Acids

The most abundant of the cannabinoids are Δ-9 THC (tetrahydrocannabinol) and CBD (cannabidiol). Only Δ-8 THC, Δ-9 THC, and their hydroxyl metabolites are psychoactive. Most of the clinical benefits from marijuana come from Δ-9 THC and CBD although other cannabinoids are likely contributory.


Botanical cannabis is highly variable in its chemical composition and content of THC and CBD. Fresh cannabis plants in actuality contain little to no THC or CBD but instead contain tetrahydrocannabinolic acid (THCA) and cannabadiolic acid (CBDA), the precursors or pro-drugs to THC and CBD respectively. These acid cannabinoids have had much less research, but are known to possess pharmacological properties in their own right. 

See: THCA ( tetrahydrocannabinolic acid)



Δ-9 THC (Tetrahydrocannabinol) – Overview

THC has analgesic, anti-spasmodic, anti-tremor, anti-inflammatory, appetite stimulant and anti-emetic properties, while 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. 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: THC (tetrahydrocannabinol pharmacokinetics)  




Δ-9 THC: Inhaling vs Sublingual vs Oral

THC is vaporized when heated to 315 degrees Fahrenheit compared to CBD which must be heated to 356 degrees Fahrenheit before it is vaporized.



Δ-9 THC: Clinical Benefits



Δ-9 THC – Euphoria and the “High” of Marijuana

The elephant in the room when discussing the benefits of marijuana is the “feel good” or euphoria associated with its use. The medical community focuses on the “medical benefits” of marijuana by emphasizing its effects on pain, anxiety, nausea and other pathologic signs or symptoms of various medical conditions. However, historically the most common motivation for using marijuana is to achieve the benefit of a “feel good” state of mind or euphoric mood.

A euphoric mood is characterized by positive feelings of strong happiness, excitement, and well-being. It is an amplified sense of pleasure that can offer therapeutic benefit by off-setting any negative feelings or mood one may be experiencing. While euphoria is one of the most pleasant mental states, when extreme it can become problematic and drive someone to repeatedly continue efforts to experience the feelings of euphoria again and again. This is the pathway that leads to “abuse” and addiction. Where is the line between therapeutic benefit and the evolution into a substance use disorder?

When use of THC or other drugs that stimulate a sense of heightened well-being or euphoria becomes problematic it appears to be related to dysregulation of the reward system in the brain. This dysregulation may be founded in underlying genetic variations of the reward system based on dopamine and serotonin levels involved in various reward pathways in the central nervous system. Or the dysregulation may be based on environmental conditions of increased stress, emotional imbalance or other non-genetic variables.

The vulnerability to developing an abusive or addictive relationship to THC, the basis of a Reward Deficiency Syndrome, is explored elsewhere on this website: Reward Deficiency SyndromeWhat should be emphasized when recommending THC for therapeutic benefit is its potential for problematic use and how to recognize when the therapeutic use of THC may be leading to problematic use.


It is important to understand and appreciate the beneficial impact of the “feel good” of THC use, and it is naive to ignore this benefit whether it is used for chronic pain, anxiety or other conditions. The “feel good” effect of THC is likely the basis of of one of the primary effects of THC use: relaxation, defined as “the state of being free from tension and anxiety with a reduced sense of stress.”

Reducing stress has enormous health benefits both directly and indirectly, for example, by improving the experience of chronic pain through its impact on the emotional and cognitive factors associated with pain. As a result of this effect of THC, one is able to cope better with their pain which perhaps should be considered the ultimate goal in pain management. Stress is a fundamental contributor to neuroinflammation, one of the driving forces behind chronic pain, and to systemic inflammation, one of the driving forces behind the non-infectious diseases of aging including cardiovascular diseases and diabetes.



Δ-9 THC – Pain

There have been a multitude of studies confirming benefit in various chronic pain syndromes with an oral-mucosal spray called Nabiximols (Sativex), approved in 30 countries for various neurological symptoms. 

Sativex is a tincture of cannabis made from cannabis plants. Each spray delivers a standardized dose of 2.7 mg THC and 2.5 mg CBD, along with additional cannabinoids, flavonoids, and terpenes in non-specified small amounts. Despite the standardized THC:CBD ratio, the actual concentrations of terpenes and other compounds are unknown. This creates uncertainty as to what components are providing most of the benefit, although synergistic effects are suspected. 

A study was performed comparing three variations of Sativex; 1:1 THC:CBD vs. THC alone vs. CBD alone. The sprays that contained THC showed the most pain benefit, over CBD alone. Other cannabis extract studies evaluating THC and CBD in varying doses also showed pain benefit, although these did not evaluate each cannabinoid individually



Δ-9 THC – Nausea

The strong anti-emetic benefits of THC have also been well documented in adults and children, and migraine-associated nausea and vomiting. In fact, the FDA has approved two synthetic forms of THC in the treatment of chemotherapy related nausea and vomiting; Dronabinol and Nabilone.



Δ-9 THC – Inflammation

THC is 20 times more anti-inflammatory than aspirin, twice as anti-inflammatory as hydrocortisone, and has well documented analgesic and anti-inflammatory benefits including arthritic and inflammatory conditions.



Δ-9 THC – Appetite Stimulation





THC: Mechanisms of Action

THC: Activity at the CB1 and CB2 Receptors

THC is a partial agonist at both the CB1 and the CB2 receptors, leading to a plethora of effects.

THC Activity at the CB1 Receptor

Partial agonism of the CB1 receptor by ∆9-THC is known to bring about the ‘high’ associated with cannabis use, as well as other effects that are potentially therapeutic. CB1 receptor activation inhibits pain and activates reward pathways, regulates mood, memory and cognition, stimulates appetite and modulates anxiety by reducing anxiety at low doses but triggering anxiety at high doses.

THC activity at the CB2 receptor

CB2 receptor activation is associated with anti-inflammatory activity. Activation of the CB2 receptor inhibits the inflammatory response in lymphocytes and microglia.


THC: Other Mechanisms of Action

Beyond CB1R, ∆9-THC itself is known to modulate the signaling of several proteins, including the orphan GPCR GPR55, and the TRP vanilloid 1 Ca2+ channel (TRPV1).

Working Notes from:

“Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort”

Eric P. Baron, Philippe Lucas2, Joshua Eades and Olivia Hogue


THC is one of the most researched cannabinoids, and the cause of the psychoactive side effects of cannabis, likely based on the modulation of glutamate and GABA systems. It is a partial agonist at CB1 greater than CB2 receptors, which are its primary mechanisms of action. However, other mechanisms of action include: activity as an agonist at the PPAR-γ and TRPA1 receptors; a 5HT3A antagonist; a glycine receptor activation enhancer via allosteric modification; reduces elevated intracellular calcium levels from TRPM8 activity (cold and menthol receptor 1 (CMR1)); elevates calcium levels by TRPA1 or TRPV2; and stimulates G Protein Receptor 18 and other nuclear receptors. THC reduces NMDA responses by 30-40%, blocks capsaicin-induced hyperalgesia, inhibits CGRP activity, increases cerebral 5HT production, decreases 5HT reuptake, and inhibits 5HT release from platelets, all of which may influence trigeminovascular migraine cir- cuitry. THC enhances analgesia from kappa opioid receptor agonist medications, stimulates production of beta-endorphin and increases proenkephalin mRNA levels in brainstem regions involved in pain processing, and intraventricular and intrathecal administration of THC produces analgesia similar to opioids.

THC is 20 times more anti-inflammatory than aspirin, twice as anti-inflammatory as hydrocortisone, and has well documented analgesic and anti-inflammatory benefits including arthritic and inflammatory conditions.


Drug Interactions

Metabolic Effects of Medications on Cannabinoids

CYP3A4 Inhibitors Effect on THC

Treatment with CYP3A4 inhibitors such as ketoconazole can produce an increase in Cmax and AUC of THC (1.2- and 1.8- fold, respectively). The increase in Cmax and AUC of the primary active metabolite of THC, 11-OH-THC,  can be 3 and 3.6-fold, respectively, and of that of CBD (2- and 2-fold, respectively). Therefore, if concomitant drug treatment with CYP3A4 inhibitors (e.g. itraconazole, ritonavir, clarithromycin) is started or stopped during treatment with THC or CBD, a dose adjustment may be required.


CYP3A4 Inducers Effect on Cannabinoids

Treatment with CYP3A4 inducers such as rifampicin can reduce the Cmax and AUC of THC (by 40% and 20%, respectively), the primary active metabolite of THC, 11-OH-THC, (by 85% and 87%, respectively) and CBD (by 50% and 60%, respectively). Therefore, concomitant treatment with strong enzyme inducers (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital, St John’s Wort) should be avoided whenever possible. Again, if combined drug treatment with CYP3A4 inducers (e.g. itraconazole, ritonavir, clarithromycin) are started or stopped during treatment with cannabinoids, a dose adjustment may be required within two weeks of starting or stopping the inducer.


Metabolic Effects of Cannabinoids on Medications

THC Induces CYP1A2

Tizanidine (Zanaflex)

THC has been reported to induce, or increase, levels of CYP 1A2, the enzyme that metabolizes tizanidine (Zanaflex) a commonly prescribed muscle relaxer used for neck pain and spasm. Tizanidine is a medication with a narrow therapeutic margin, meaning there may be a small range of optimal levels in which a little too low is ineffective but a little more may be too strong and associated with side effects. Thus adding, or discontinuing THC may result in significant changes in the clinical effects of tizanidine and caution should be applied to avoid loss of benefit or possible side effects respectively.


THC: Drug-Metabolic Interactions

The major cannabanoids, THC and CBD are both metabolized in the liver by the CYP450 enzymes 2C9, 2C19 and 3A4. Drugs that inhibit these enzymes may enhance or prolong the effects of THC and CBD. Whether people with genetic variants of these enzymes may experience altered effects from cannabinoids is not known.


UDP-glucuronosyltransferase (UGT) family of enzymes

The UDP-glucuronosyltransferase (UGT) family of enzymes found in the liver and kidneys play an important role in the metabolism of medications. These enzymes attach glucoronide to medications to facilitate their elimination. The interaction between UGTs and cannabinoids have not yet been thoroughly examined but a recent 2021 study evaluated the potential of Δ9-THC, CBD, and cannabinol (CBN), and their major metabolites, to inhibit the activity of UGT enzymes.

The highest inhibition was seen by CBD against the glucuronidation activity of UGTs 1A9, 2B4, 1A6, and 2B7 but strong inhibition of UGT1A9 and UGT2B7 was also found with THC and CBN. Regarding the metabolites of these cannabinoids, there was weak or no inhibition was found.

This inhibition of UGT activity by CBD, THC and CBN may play an important role in drug-drug interactions. Major cannabinoids found in the plasma of cannabis users inhibit several UDP-glucuronosyltransferase (UGT) enzymes, including UGT1A6, UGT1A9, UGT2B4, and UGT2B7. This study identified the potential of cannabinoids to inhibit all the major kidney UGTs as well as the two most abundant UGTs present in liver. This study suggests that as all three major kidney UGTs are inhibited by cannabinoids, greater drug- drug interaction effects might be observed from co-use of cannabinods and therapeutics that are cleared renally.





National Academy of Sciences

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

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




Terpenes – Overviews:

  1. Taming THC – potential cannabis synergy and phytocannabinoid-terpenoid entourage effects – 2011
  2. A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. – PubMed – NCBI
  3. Human Pharmacokinetic Parameters of Orally Administered Δ 9-Tetrahydrocannabinol Capsules Are Altered by Fed Versus Fasted Conditions and Sex Differences – PubMed
  4. 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


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


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


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
  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


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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