Cannabinoids - April 2024

What Are Cannabinoids?

Scientists define the term “cannabinoids” in various ways.

The World Health Organization (WHO) states that cannabinoids are chemical components structurally related to delta-9-tetrahydrocannabinol (Δ9–THC)⁽²⁾. 

On the other hand, the Alcohol and Drug Foundation (ADF), an Australian-based charity organization, defines cannabinoids as a group of chemical entities, irrespective of structure or origin, that binds to the cannabinoid receptors of the body and brain with similar effects to Cannabis sativa plant derivatives⁽³⁾.

Cannabis sativa is the hemp plant that produces marijuana and cannabinoids⁽⁴⁾.

 The ADF also suggests three broad categories of cannabinoids: phytocannabinoids, endocannabinoids, and synthetic cannabinoids⁽⁵⁾. 

One study suggested that definitions vary depending on what aspect of the compound experts emphasize⁽⁶⁾. For example, scientists have defined cannabinoids in botany, chemistry, or pharmacology terms.

Based on the previous definitions, cannabinoids may mean:

• Group of naturally occurring compounds in Cannabis sativa plants. These types of cannabinoids are known distinctively as phytocannabinoids.
• Analogs and transformation products of Cannabis sativa
• Chemical components that bind to the cannabinoid receptors of the body and brain

According to Roger G. Pertwee, a co-founder of the International Cannabinoid Research Society (ICRS), the essential milestones in the pharmacohistory of cannabinoids are⁽⁷⁾:

• Discovery of the cannabinoids by the end of the 19th century
• The beginning of pharmacological characterization of cannabinoids in the 1940s
• The structural understanding and synthesis of CBD and THC
• The discovery of cannabinoid receptors and endogenous ligands of these receptors

Currently, more than 60 of the over 400 active ingredients of cannabis are cannabinoids⁽⁸⁾. 

Cannabinoids can provide various healthcare benefits. For example, cannabis and cannabinoids may potentially help some severe forms of epilepsy, chronic pain, and multiple sclerosis⁽⁹⁾. 

Cannabinoid research also has broader implications in the field of neuroscience, psychiatry, toxicology, and gastrointestinal research.

What Do Cannabinoids Do?

All cannabinoids attach to cannabinoid receptors in the brain as receptor agonists⁽¹⁰⁾. Agonists are compounds that bind to receptors to generate a functional or biological response.

Like opioids, cannabinoids can also act as analgesics to help alleviate chronic pain⁽¹¹⁾.  

Cannabinoid Receptors

Cannabinoids exert their effects through the two types of well-defined receptors, CB1 (cannabinoid-1) and CB2 (cannabinoid-2).

CB1 and CB2 receptors are present in the central nervous system (CNS) and peripheral tissues. CB1 receptors are predominant in the CNS, while CB2 receptors are primarily peripheral⁽¹²⁾.

CB1 receptors are the primary pharmacological targets of THC. The discovery of these receptors in 1988 prompted many studies to look for endogenous ligands related to cannabinoid receptors⁽¹³⁾.

Endogenous ligands refer to molecules within the body that bind to and activate a particular receptor. For example, anandamide is a cannabinoid neurotransmitter that acts as an endogenous ligand of CB1 receptors⁽¹⁴⁾.

Cannabinoid receptors may correlate with various physiological and pathophysiological functions in the body. These bodily functions include mood, appetite, pain sensation, vascular and nonvascular smooth muscle tone, and immune system.

Types of Cannabinoids

The two major cannabinoids that the cannabis plant produces are⁽¹⁵⁾:

• Tetrahydrocannabinol (THC)
• Cannabidiol (CBD)

On the other hand, the minor cannabinoids are⁽¹⁶⁾:

• Tetrahydrocannabinolic acid (THCA)
• Cannabigerol (CBG)
• Cannabichromene (CBC)
• Cannabidiolic acid (CBDA)
• Cannabidivarin (CBDV)

Major Cannabinoids

There are two major types of cannabinoids:

• Tetrahydrocannabinol (THC): This compound is the psychoactive (mind-altering) cannabinoid responsible for the “high” that many individuals associate with marijuana. THC’s adverse effects may include damage and impairment of the CNS and peripheral system⁽¹⁷⁾. 

For example, one study noted that THC may increase symptoms of cognitive impairment and psychosis (a condition in which the individual loses contact with reality)⁽¹⁸⁾. 

However, pharmaceutical companies have also used a synthetic version of THC to manufacture dronabinol, which is an oral form of cannabis that can help treat neuropathic pain.

• Cannabinol (CBN) forms are byproducts of THC. CBN production usually occurs by degradation during drying, storing, and consumption (heating) of cannabis products⁽¹⁹⁾.
• Cannabidiol (CBD): This type of cannabinoid is a derivative product of the cannabis plant (hemp and marijuana). However, unlike THC, CBD does not cause intoxication. 

There are many claims about the potential therapeutic benefits of CBD. For example, one research showed that CBD may have anti-inflammatory, analgesic, and neuroprotective properties⁽²⁰⁾. 

However, one of CBD’s most reliable uses may be the compound’s impact on treating severe forms of epilepsy⁽²¹⁾. As a result of this therapeutic effect, the United States (US) Food and Drug Administration (FDA) approved Epidiolex, which contains CBD, as an oral solution for treating specific seizures⁽²²⁾.

Despite an increasing number of studies showing the potential health and therapeutic benefits of CBD, the FDA advises consumers to be wary of the compound’s possible side effects.

Minor Cannabinoids

Below are examples of minor cannabinoids:

• Tetrahydrocannabinolic acid (THCA): This chemical substance is one of the naturally nonpsychoactive precursors to THC⁽²³⁾. The THCA synthase gene encodes the enzyme responsible for the final step in THC synthesis. 
• Cannabigerol (CBG): These are non-carboxylated cannabinoids that possess antibacterial properties. 

Cannabigerol compounds are “inactive” relative to THC. CBG has a slight affinity to CB1 receptors, roughly equal to CBD.

• Cannabichromene (CBC): Cannabichromene (CBC) is one of cannabis‘ most abundant phytocannabinoids. Moreover, CBC is an agonist at CB2 receptors. 
• Cannabidiolic acid (CBDA): Cannabidiolic acid is a version of CBD.

One study showed that CBDA may be a highly potent nonpsychoactive treatment for anticipatory nausea⁽²⁴⁾.

• Cannabidivarin (CBDV): This compound is a nonpsychoactive propyl analog of CBD. 

Cannabidivarin has undergone pre-clinical trials for autism spectrum disorders (ASD) and childhood epilepsy⁽²⁵⁾.

The Endocannabinoid System (ECS)

The endocannabinoid system (ECS) is a modulation system that links with CNS growth, synaptic plasticity, and the reactions to endogenous and environmental stimuli⁽²⁶⁾.

The ECS consists of cannabinoid receptors and endogenous cannabinoids (endocannabinoids). The enzymes responsible for endocannabinoid synthesis and degradation are also parts of the ECS.

Phytocannabinoids

The derivative of cannabinoid products of the cannabis plant is known as phytocannabinoids. 

The phytocannabinoids condense in the glandular trichomes (hairy outgrowths) of the female plant’s flowering heads⁽²⁷⁾.

Today, well-known phytocannabinoids include:

• Δ9– tetrahydrocannabinol (Δ9–THC)
• Cannabinol (CBN)
• Cannabidiol (CBD), 
• Cannabidivarin (CBDV) 
• Cannabigerol (CBG)
• Cannabichromene (CBC)

Synthetic Cannabinoids

Synthetic cannabinoids, also known as “spice” and “synthetic marijuana”, are a class of artificial chemicals that some people use as a possible alternative to marijuana. 

However, synthetic cannabinoids may have serious side effects that are very different from marijuana⁽²⁸⁾.

How Are Cannabinoids Used?

Users commonly smoke, vaporize, or eat synthetic cannabinoids.

Pharmaceutical cannabinoids are available in various forms, such as raw or botanical cannabis, oils, liquids, and oral sprays⁽²⁹⁾. 

The Effects of Cannabinoids on the Body

If a user smokes or vaporizes cannabis, the effects of cannabis and the cannabinoids it contains may be immediate. Overall effects may include⁽³⁰⁾:

• Euphoria
• Enhancement of sensory perception
• Difficulties in concentration
• Impairment of memory 
• Antinociception (body’s response to potentially harmful chemicals)

Can Cannabinoids Offer Any Benefits?

Cannabinoids may possess potential medical uses and help with several conditions and symptoms such as⁽³¹⁾: 

• Oral cannabinoids such as nabilone are effective antiemetics in adults experiencing chemotherapy-induced nausea and vomiting.
• Patients using cannabis or cannabinoids in adults to treat chronic pain are more likely to experience a clinically significant reduction in pain symptoms.
• Short-term use of oral cannabinoids may help improve patient-reported spasticity symptoms in adults with multiple sclerosis (MS).

However, cannabinoids‘ effects on the conditions above are modest. For all other issues, there remains insufficient data to assess their impacts.

Are Cannabis or Cannabinoids Helpful in Treating Health Conditions?

The Food and Drug Administration (FDA) in the United States has not approved cannabis or marijuana use to treat any medical condition⁽³²⁾. 

On the other hand, the FDA has authorized the use of the cannabis-derived drug Epidiolex and dronabinol (Marinol, Syndros).

Medical marijuana refers to Cannabis sativa plant derivatives that may help alleviate symptoms of certain medical conditions. Medical marijuana is another term for medical cannabis.

Studies on the various health benefits of cannabinoid compounds suggest a need for further understanding. 

For example, more research on the properties of CBD metabolites both in vitro and in vivo may help elucidate the therapeutic effects of CBD-containing preparations⁽³³⁾. 

Cannabinoids and Other Drugs

The effects of combining cannabis with other drugs, such as alcohol, prescription drugs, and over-the-counter medications are frequently uncertain.

Using cannabis and alcohol simultaneously may amplify some adverse effects, such as vomiting, nausea, and feelings of panic, anxiety, and paranoia⁽³⁴⁾.

One study showed that cannabinoid metabolites may act as inhibitors for several P450 enzymes (drug metabolism enzymes). The possible enzyme inhibition may help in facilitating cannabinoids’ drug-drug interactions⁽³⁵⁾. 

Cannabinoids and the FDA

The FDA recognizes growing interest in the potential value of cannabis for various medical conditions and research into the possible adverse side effects of cannabis use.

The FDA has yet to approve a cannabis marketing application to treat any disease or condition⁽³⁶⁾.

However, the agency has approved one cannabis-derived or cannabinoid drug product:

• Epidiolex (cannabidiol)

And three synthetic cannabis-related drug products:

• Cesamet (nabilone)
• Syndros (dronabinol)
• Marinol (dronabinol)

There are publicly existing extensive drug test studies on THC and CBD. 

For example, GW Pharmaceuticals‘ investigations into Sativex are publicly available online⁽³⁷⁾. Sativex is a nabiximol, a derivative product of cannabinoids with potential analgesic impact.

Are Cannabis and Cannabinoids Safe?

Cannabis and cannabinoids are relatively safe to use. The use of cannabis and cannabinoids is likely to be riskier when an individual is:

• Driving or operating heavy machinery
• Has a history of drug abuse
• Required to use judgment or motor coordination.
• Using alcohol or other drugs, especially stimulants like crystal methamphetamine (‘ice’) or ecstasy

The safety and tolerability of cannabinoid-based medicines remain unclear. However, one study showed that THC and CBD combination may be less acceptable for adults over 65 or 75⁽³⁸⁾.

Dosage and Preparation

Various cannabis dosage formulations and medical claims continue to grow today. However, there is no set dosage formulation of cannabis and insufficient information on the impact of specific chemical composition on pharmacological or adverse effect end-points⁽³⁹⁾.

Are Cannabinoids Legal?

The legality of cannabinoid products depends on the product type and the state.  Although purchasing cannabis in the United States is illegal under federal law, certain states have legalized marijuana products for medical and recreational purposes.

Cannabinoids are a reasonably broad topic to discuss. Individuals may want to research more on cannabinoids and CBD through ebooks identified by their DOIs (digital object identifier) number and citations for further information.

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1. FDA and Cannabis: Research and Drug Approval Process https://www.fda.gov/news-events/public-health-focus/fda-and-cannabis-research-and-drug-approval-process
2. Cannabis https://www.who.int/teams/mental-health-and-substance-use/alcohol-drugs-and-addictive-behaviours/drugs-psychoactive/cannabis
3. Cannabinoids https://adf.org.au/drug-facts/cannabinoids/
4. Cannabinoids https://www.sciencedirect.com/science/article/pii/B9780123864543002670
5. Ibid.
6. On the definition of cannabinoids: botanical? chemical? pharmacological? https://pubmed.ncbi.nlm.nih.gov/7298866/
7. Cannabinoid pharmacology: the first 66 years https://bpspubs.onlinelibrary.wiley.com/doi/10.1038/sj.bjp.0706406
8. Cannabis, a complex plant: different compounds and different effects on individuals https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736954/
9. Cannabis (Marijuana) and Cannabinoids: What You Need To Know  https://www.nccih.nih.gov/health/cannabis-marijuana-and-cannabinoids-what-you-need-to-know
10. Cannabinoids https://www.sciencedirect.com/topics/neuroscience/cannabinoids
11. Cannabinoids and Pain: New Insights From Old Molecules https://pubmed.ncbi.nlm.nih.gov/30542280/
12. Pharmacologic Management of Lower Urinary Tract Storage and Emptying Failure https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/cannabinoids
13. Brain activity of anandamide: a rewarding bliss?https://www.nature.com/articles/s41401-018-0075-x
14. Ibid.
15. 6: Cannabinoids and Terpenes https://connect.springerpub.com/content/book/978-0-8261-4312-9/part/part03/chapter/ch06
16. Ibid.
17. Harmful Effects of Smoking Cannabis: A Cerebrovascular and Neurological Perspective https://www.frontiersin.org/articles/10.3389/fphar.2019.01481/full
18. Cannabis use and cognition in schizophrenia https://www.frontiersin.org/articles/10.3389/neuro.09.053.2009/full
19. Development & Modification of Bioactivity https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/cannabinol
20. Effects of Cannabidiol on Exercise Physiology and Bioenergetics: A Randomised Controlled Pilot Trial https://sportsmedicine-open.springeropen.com/articles/10.1186/s40798-022-00417-y
21. Cannabidiol (CBD)-what we know and what we don’t https://www.health.harvard.edu/blog/cannabidiol-cbd-what-we-know-and-what-we-dont-2018082414476
22. FDA Approves First Drug Comprised of an Active Ingredient Derived from Marijuana to Treat Rare, Severe Forms of Epilepsy https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-comprised-active-ingredient-derived-marijuana-treat-rare-severe-forms
23. Cannabis sativa: an overview https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/tetrahydrocannabinolic-acid
24. A comparison of cannabidiolic acid with other treatments for anticipatory nausea using a rat model of contextually elicited conditioned gaping https://link.springer.com/article/10.1007/s00213-014-3498-1
25. Cannabis sativa: Much more beyond Δ9-tetrahydrocannabinol https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/cannabidivarin
26. An introduction to the endogenous cannabinoid system https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789136/
27. Phytocannabinoids https://www.sydney.edu.au/lambert/medicinal-cannabis/phytocannabinoids.html
28. Synthetic cannabinoids: What are they? What are their effects? https://www.cdc.gov/nceh/hsb/chemicals/sc/default.html
29. Medicinal cannabis products https://www.tga.gov.au/sites/default/files/medicinal-cannabis-consumers-factsheet.pdf
30. The effects of cannabinoids on the brain https://pubmed.ncbi.nlm.nih.gov/10368032/
31. Therapeutic Effects of Cannabis and Cannabinoids https://www.ncbi.nlm.nih.gov/books/NBK425767/
32. Medical marijuana https://www.mayoclinic.org/healthy-lifestyle/consumer-health/in-depth/medical-marijuana/art-20137855
33. Human Metabolites of Cannabidiol: A Review on Their Formation, Biological Activity, and Relevance in Therapy https://www.liebertpub.com/doi/10.1089/can.2015.0012
34. Cannabinoids https://adf.org.au/drug-facts/cannabinoids/
35. Cannabinoid Metabolites as Inhibitors of Major Hepatic CYP450 Enzymes, with Implications for Cannabis-Drug Interactions https://dmd.aspetjournals.org/content/49/12/1070
36. FDA and Cannabis: Research and Drug Approval Process https://www.fda.gov/news-events/public-health-focus/fda-and-cannabis-research-and-drug-approval-process
37. FDA Regulation of Cannabis and Cannabis-Derived Products, Including Cannabidiol (CBD) https://www.fda.gov/news-events/public-health-focus/fda-regulation-cannabis-and-cannabis-derived-products-including-cannabidiol-cbd
38. Safety and tolerability of natural and synthetic cannabinoids in adults aged over 50 years: A systematic review and meta-analysis https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1003524
39. Preparation and Distribution of Cannabis and Cannabis-Derived Dosage Formulations for Investigational and Therapeutic Use in the United States https://www.frontiersin.org/articles/10.3389/fphar.2016.00285/full

 

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