How Does CBD Work - April 2024

How CBD Works in the Human Body

CBD or cannabidiol is derived from the hemp plant⁽⁴⁾. Unlike other cannabinoids such as tetrahydrocannabinol (THC), CBD does not produce a psychoactive or “high” effect.

CBD and THC are the most prevalent cannabinoids present in cannabis. Medical marijuana has far more THC than hemp, which is rich in CBD.

Two members of the G-protein coupled receptor family, CB1 and CB2 receptors mediate the biological effects of cannabinoids, the principal ingredients of cannabis⁽⁵⁾. 

The CB1R is the predominant subtype in the central nervous system and has attracted considerable interest as a possible therapeutic target in various pathological situations, such as neuropsychological disorders and neurodegenerative illnesses.

 In addition, cannabinoids may affect signal transduction pathways and exhibit powerful effects at peripheral locations. 

However, even though cannabinoids offer medicinal promise, their psychotropic effects have substantially restricted their use in clinical practice. 

What Is the Endocannabinoid System?

The endocannabinoid system (ECS) has a significant role in the central nervous system development, neuronal plasticity, and endogenous and environmental dama​​ge⁽⁶⁾. The ECS consists of cannabinoid receptors, endogenous cannabinoids, and enzymes.

How Does CBD Interact With Cannabinoid Receptors?

Cannabinoids engage with the cannabinoid receptors, such as CB1. Exogenous cannabinoids, including tetrahydrocannabinol, affect cannabinoid receptors.

Due to the widespread societal use of cannabis and the involvement of endocannabinoids in many biological processes, much is known about the ECS’s physiological and pathological functions. 

Serotonin Receptors

Serotonin receptors affect various biological and neurological processes, including aggression, anxiety, hunger, cognition, learning, memory, mood, nausea, sleep, and thermoregulation⁽⁷⁾.

5-HT1A receptors are a subtype of serotonin receptors found in the presynaptic and postsynaptic membranes.

5-HT1A receptors are G-protein-coupled receptors that exert their actions by inhibiting adenylyl cyclase and other second messenger cascades via Gi/Go proteins. These proteins mediate both excitatory and inhibitory neurotransmission.

Chemical messengers are neurotransmitters⁽⁸⁾. They convey communications between nerve, muscle, and gland cells. These signals let individuals move their limbs, sense sensations, keep the heart pumping, and take in and react to all body and environmental information.

Meanwhile, excitatory neurotransmitters “excite” the neuron, causing it to fire off messages throughout the body⁽⁹⁾.

Vanilloid Receptors

The peripheral terminals of specialized sensory neurons, called nociceptors, primarily detect painful sensations(¹⁰⁾. These small-diameter neurons communicate this information to the central nervous system, resulting in an experience of pain or discomfort. 

The capsaicin (vanilloid) receptor is an excitatory ion channel expressed on nociceptors and plays a crucial role in transmitting heat and inflammatory pain. 

Research on the vanilloid receptor gene knockout mice confirms the channel’s role in pain sensation and responsiveness to noxious stimuli after tissue damage⁽¹¹⁾. 

Missing the VR1 gene underlines the significance of this channel in pain perception, particularly heat-evoked pain perception.

GPR55—Orphan Receptors

GPR55 is an orphan G-protein-coupled receptor (GPCR) expressed in the CNS and immune system⁽¹²⁾. This cannabinoid receptor’s most widely acknowledged endogenous agonist is lysophosphatidylinositol. 

Lysophosphatidylinositol, or LPI, is a bioactive lipid produced by the PLA (phospholipase A) family of lipases that are thought to have a significant role in physiological and pathological processes⁽¹³⁾.

Owing to the overlapping ligand action with delta-9-THC and an endogenous cannabinoid (anandamide), GPR55 has also been identified as a possible cannabinoid receptor. However, its categorization remains disputed due to differences across studies.

PPARS – Nuclear Receptors

Peroxisome proliferator-activated receptors (PPARs) have been identified as promoters of peroxisome proliferation⁽¹⁴⁾. 

Numerous research from several disciplines has shown that PPARs are nuclear receptors that govern cellular and whole-body energy balance during lipid and glucose metabolism, cell proliferation, and cancer formation.  

The capacity of PPARs to alleviate metabolic disorders has garnered a great deal of interest in light of growing threats to human health and wellness. In prior research, researchers discovered that the diverse roles of PPARs may serve as potential therapeutic targets for obesity and atherosclerosis.

CBD as a Reuptake Inhibitor

Cannabidiol (CBD), the primary nonaddictive component of the cannabis plant that interacts with the serotonin (5-HT)1A receptor, may exhibit analgesic and anxiolytic properties, according to clinical trials⁽¹⁵⁾. 

However, CBD’s effects on 5-HT neuronal activity and models of neuropathic pain remain unclear.

Repeated CBD therapy’s low doses primarily promote analgesia through TRPV1 activation, lower anxiety via 5-HT1A receptor activation, and restore disrupted 5-HT neurotransmission under the circumstances of neuropathic pain.

TRPV1 proteins detect and regulate body temperature.

CBD as an Allosteric Modulator

Allosteric modulators are substances that bind to a specific receptor to modulate or change the receptor’s response to stimulus.

Cannabidiol modulated CB1 receptors as a noncompetitive negative allosteric modulator. In addition to actions not mediated by CB1 receptors, allosteric modulation may explain the in vivo effects of cannabidiol⁽¹⁶⁾.

Allosteric modulators of CB1 receptors have the potential to manage CNS and peripheral illnesses without the side effects of orthosteric agonism or antagonism.

What Conditions May CBD Be Used to Treat?

Johns Hopkins University showed some health benefits of CBD use⁽¹⁷⁾.

For individuals with various health conditions, such as epilepsy, chronic pain, and autism, those who use cannabidiol products reported improved quality of life and lower levels of anxiety and depression. These individuals also reported better sleep and mood.

Individuals who are not users showed improvements in their health measures after they started using medical cannabis, similar to those who were using cannabis.

Meanwhile, CBD may reduce pain caused by inflammation, arthritis, and nerve damage by interacting with neurotransmitters in the central nervous system⁽¹⁸⁾. In a four-week study, individuals with a nerve injury in the lower half of the body who applied topical CBD oil reported a substantial decrease in acute, stabbing pain.

What Else Does CBD Do?

The National Center for Health Research summarizes the potential health benefits of CBD from other clinical research⁽¹⁹⁾. Here are some of them:

• Chronic Pain Management 

Currently, studies are being conducted on individuals with chronic pain conditions to determine if CBD can help relieve their pain⁽²⁰⁾. In 2021, a survey was conducted on 253 patients from various pain management clinics to see how they managed their pain. Sixty-two percent of them reported using CBD for their pain relief.

According to the survey, over 60% of the participants who used CBD for pain relief claimed that they were able to decrease their use of opioid medication. Most participants also stated that they did not find the compound addictive or harmful.

Likewise, a 2019 study looked into the effects of CBD on the chronic pain of patients who were taking opioids⁽²¹⁾. 

The participants were between 30-65 years old and had been experiencing moderate to severe pain for at least three years. Out of the 94 patients who took CBD, 84 agreed to continue taking CBD gummies for eight weeks.

• Epilepsy 

Epidiolex is the only CBD medication currently authorized by the Food and Drug Administration (FDA) for medicinal reasons. Epidiolex is a prescription medication used to manage pediatric epilepsy, including Dravet syndrome (DS),  Lennox-Gastaut syndrome (LGS), and tuberous sclerosis complex (TSC)⁽²²⁾. 

In 2018, the FDA authorized Epidiolex based on four double-blind, placebo-controlled studies demonstrating that it might dramatically decrease the frequency of participants’ seizures⁽²³⁾. 

Users should not use any CBD medication other than Epidiolex to manage epilepsy and visit a physician to determine whether the product is safe and effective for their symptoms.

• Anxiety Disorders 

Research shows that CBD may be an alternative anxiety disorder therapy. Despite continuing clinical research, CBD is not an FDA-approved therapy for anxiety disorders⁽²⁴⁾.

A review was undertaken in 2020 to determine the safety and efficacy of CBD as an alternative pharmaceutical therapy for several anxiety-related diseases⁽²⁵⁾.

This research evaluated previously published studies, such as randomized controlled trials and case studies. It examined the spectrum of CBD usage among 285 individuals with anxiety disorders.

In this research, healthy volunteers and patients with a generalized anxiety disorder (GAD), social anxiety disorder (SAD), PTSD-related anxiety, and insomnia disorder received CBD therapy.

The analysis showed that CBD consumption consistently reduced anxiety symptoms, suggesting that CBD may be an alternate option for individuals receiving different anti-anxiety medications.

In addition, there is one cross-sectional study of CBD users focusing on self-perceived stress and anxiety problems⁽²⁶⁾. 

A total of 387 current or former CBD users responded to a 20-question online survey. The poll was sent through email databases and social media to CBD consumers. Participants reported demographic information, CBD usage patterns, reasons for use, and the effects of CBD on anxiety, sleep, and stress.

This study showed that CBD users manage self-perceived anxiety, stress, sleep, and other symptoms, often in low dosages. These patterns varied according to demographic factors. 

Low dosages, indicative of the general user, need further research to see how CBD users may affect mental health symptoms such as stress, anxiety, and sleep issues.

How Can Users Take CBD?

CBD is available in several forms, including oils, extracts, pills, patches, vapes, and topical skin applications⁽²⁷⁾. 

CBD topicals are intended for direct application to the skin. There are lotions, balms, creams, salves, and transdermal patches containing CBD.  

A CBD-infused topical oil, lotion, or cream may effectively reduce inflammation and relieve muscle and joint pain.

CBD edibles have an earthy flavor, such as CBD gummies, truffles, and even mints. However, individuals who want to avoid sugar and preservatives may choose to try a sublingual product. 

There are tinctures, sprays, oils, and lozenges among them. Tinctures are prepared by soaking cannabis flowers in alcohol or oil.

CBD may also enter the circulation directly via a sublingual patch, tincture, or spray meant to be applied under the tongue.

Research on animals published in the European Journal of Pain showed that the topical use of CBD may reduce arthritis-related pain and inflammation⁽²⁸⁾. Another study demonstrated how CBD may reduce difficult-to-manage inflammatory and neuropathic pain.

Also, consumers may smoke cannabis flowers in a joint, use a vaporizer with a CBD oil cartridge, or inhale CBD concentrates such as sugar waxes with any vape pen that includes a chamber for concentrates.

However, emerging research shows linkages to chronic lung illness, asthma, and cardiovascular disease to e-cigarette and tobacco use⁽²⁹⁾. 

Individuals may be exposing themselves to several compounds that they do not fully understand and that are likely hazardous.

Lastly, researchers have not conclusively determined the length of time that cannabidiol will remain within the body.

The time for CBD to take effect entirely may vary depending on the administration method. 

CBD edibles, oils, and capsules are estimated to work for six to eight hours after administration. While smoking and vaping CBD may take from two to four hours. Sublingual CBD may also take up from 2 to four hours. 

How Safe Is CBD Compared to Alternatives?

No direct studies show how safe CBD is as compared to alternatives. However, the evaluated research highlighted and expanded CBD‘s positive safety profile in humans⁽³⁰⁾. 

A more clinical study is required to determine whether CBD‘s influence and interactions with other medicines lead to good or negative consequences,  such as decreasing clobazam dosages and side effects in epilepsy.

Risks and Side Effects

CBD may enhance the blood concentration of blood-thinning and other medications by fighting for the liver enzymes responsible for their breakdown⁽³¹⁾. 

High doses of CBD may cause anomalies in liver-related blood tests in humans⁽³²⁾. Many over-the-counter medications, including acetaminophen (Tylenol), have a similar effect. 

Individuals consistently taking CBD should inform their healthcare professionals.

Meanwhile, the Mayo Clinic cited some side effects of CBD, such as dry mouth, reduced appetite, drowsiness, and fatigue⁽³³⁾.

Is CBD Legal?

Currently, the FDA does not regulate the safety and purity of CBD products as dietary supplements. 

The 2018 Farm Bill makes hemp legal in the United States⁽³⁴⁾. This bill permits the interstate transport of hemp-derived goods for business and other uses. There are also no prohibitions on the sale, transit, or possession of hemp-derived goods, provided that they are manufactured under the law.

CBD is widely available in the United States despite its uncertain legal status. CBD is legal in all fifty states but with varying restrictions⁽³⁵⁾. 

In December 2015, the FDA loosened regulatory restrictions for CBD experiments, allowing researchers to perform clinical studies⁽³⁶⁾. 

The prescription medicine Sativex, which contains CBD as its active component, is authorized for multiple sclerosis-related muscular stiffnesses and cancer pain⁽³⁷⁾. Epidiolex is approved for specific epilepsy and tuberous sclerosis in the United States.

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1. 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
2. An introduction to the endogenous cannabinoid system https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789136/
3. What Is Cbd And What Are Its Health Benefits? https://hub.jhu.edu/2020/01/03/what-is-cbd-2499-em1-art1-qa-health/
4. 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
5. Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877694/
6. An introduction to the endogenous cannabinoid system https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789136/
7. A Worldwide Yearly Survey of New Data in Adverse Drug Reactions https://www.sciencedirect.com/topics/neuroscience/5-ht-receptor
8. Neurotransmitters https://my.clevelandclinic.org/health/articles/22513-neurotransmitters
9. Ibid.
10. The Vanilloid Receptor: A Molecular Gateway to the Pain Pathway https://www.annualreviews.org/doi/10.1146/annurev.neuro.24.1.487
11. Ibid.
12. GPR55 https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/gpr55
13. Lysophosphatidylinositol Signalling and Metabolic Disease https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4812335/
14. PPARs as Nuclear Receptors for Nutrient and Energy Metabolism https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6680900/
15. Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319597/
16. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor https://pubmed.ncbi.nlm.nih.gov/26218440/
17. What Is Cbd And What Are Its Health Benefits? https://hub.jhu.edu/2020/01/03/what-is-cbd-2499-em1-art1-qa-health/
18. CBD Oil — Are the Benefits Claimed Too Good To Be True? https://health.clevelandclinic.org/cbd-oil-benefits/
19. How Safe is CBD? https://www.center4research.org/how-safe-is-cbd/
20. Ibid.
21. Ibid.
22. FDA Approves New Indication for Drug Containing an Active Ingredient Derived from Cannabis to Treat Seizures in Rare Genetic Disease https://docs.google.com/document/d/1ozQs1SF4y2UBjrykGHO3dbXFXtFsFR54DRbLpoT5dIw/edit#
23. Ibid.
24. How Safe is CBD? https://www.center4research.org/how-safe-is-cbd/
25. Ibid.
26. Reasons for cannabidiol use: a cross-sectional study of CBD users, focusing on self-perceived stress, anxiety, and sleep problems https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893882/
27. 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
28. Ibid.
29. 5 Vaping Facts You Need to Know https://www.hopkinsmedicine.org/health/wellness-and-prevention/5-truths-you-need-to-know-about-vaping
30. An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569602/
31. 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
32. Ibid.
33. What are the benefits of CBD — and is it safe to use? https://www.mayoclinic.org/healthy-lifestyle/consumer-health/expert-answers/is-cbd-safe-and-effective/faq-20446700
34. The Farm Bill, hemp legalization and the status of CBD: An explainer https://www.brookings.edu/blog/fixgov/2018/12/14/the-farm-bill-hemp-and-cbd-explainer/
35. 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
36. DEA Eases Requirements For FDA-Approved Clinical Trials On Cannabidiol https://www.dea.gov/press-releases/2015/12/23/dea-eases-requirements-fda-approved-clinical-trials-cannabidiol
37. 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

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