Entourage effects of Cannabis plant for pain management, Review of current understanding, based on Scientifically Published Literature.
Syed Arshad Raza Ahmed
Nutraceuticals, Cosmaceuticals, Formulation / clinical evaluation & Business Development Expert with 15+ years of Experience.
Introduction:
Cannabis has been used for centuries for its potential medicinal properties, including pain relief.
The entourage effect is a phenomenon that suggests the synergistic interaction of various compounds in cannabis, including cannabinoids, terpenes, and other phytochemicals, contributes to its therapeutic effects. Entourage effect proposes that the combination of multiple compounds in cannabis may have more significant therapeutic benefits than isolated compounds alone. (1,2,3,4,5).
The synergistic interaction between cannabinoids, terpenes, and other phytochemicals modulates the endocannabinoid system, influences neurotransmitter activity, and exhibits anti-inflammatory, analgesic, anxiolytic, and neuroprotective effects.
Cannabinoids, Terpenes and Pain:
Cannabinoids, including Cannabidiol (CBD) and Delta-9-tetrahydrocannabinol (THC), Cannabigerol(CBG) have been studied for their potential benefits in pain management. The entourage effect has shown promise in various types of pain as chronic pain, cancer related pain Multiple Sclerosis (MS)-Related Pain and Neuropathic Pain. (1,2,3,4,5)
Entourage Effects in Pain Management:
Enhanced Analgesic Effects:
Combining cannabinois and terpenes resulted in superior pain relief compared to THC, CBD and terpenes alone. (89,90)
Synergistic Anti-inflammatory Effects:
Anti-inflammatory effects of terpenes and cannabinoids combined produced enhanced anti-inflammatory effects compared to individual compounds (91).
Effects on Chronic Pain: A substantial body of literature suggests that cannabinoids can be effective in managing chronic pain conditions such as neuropathic pain, fibromyalgia, and chronic non-cancer pain. A review in 2015 analyzed multiple studies and concluded that cannabinoids, particularly CBD, showed promise in reducing chronic pain and improving quality of life.6
Effects on Cancer-Related Pain: Cannabinoids have demonstrated potential in managing pain associated with cancer and its treatments. Studies have shown that cannabinoids, either alone or in combination with opioids, can help reduce cancer-related pain. Cannabinoids, particularly THC and nabiximols (a combination of THC and CBD), were effective in treating cancer pain. 7
Effects on Multiple Sclerosis (MS)-Related Pain: Cannabinoids have shown promise in managing pain associated with multiple sclerosis. Studies have found that cannabinoids, such as THC and nabiximols, can help alleviate MS-related pain, including neuropathic pain and spasticity. Finding of systematic review in 2018 concluded that cannabinoids had significant benefits in reducing MS-related pain.8
Cannabidiol (CBD):
Cannabidiol (CBD) has been studied for its potential benefits in pain management. Cannabidiol exerts its benefits in pain management through following pharmacological effects:
Anti-Inflammatory Effects: CBD possesses anti-inflammatory properties, , which can help reduce inflammation and associated pain, By interacting with the body's endocannabinoid system and other signaling pathways, CBD may help alleviate pain caused by inflammatory conditions like arthritis or muscle soreness. Cannabidiol can also help regulate immune responses. It has been shown to suppress the production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β). By reducing the release of these inflammatory molecules, CBD may help mitigate excessive inflammation. (9)
Chronic inflammation is associated with various diseases, including arthritis, cardiovascular disorders, and neurodegenerative conditions.
CBD's Mechanisms of Action:
CBD interacts with the endocannabinoid system (ECS), which regulates immune responses and inflammation. Although CBD does not directly bind to cannabinoid receptors, it influences them indirectly. CBD's anti-inflammatory effects are believed to occur through multiple pathways, including:
Inhibition of inflammatory mediators:
CBD has been shown to suppress the production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), which are involved in promoting inflammation.
In Vitro & Animal Studies:
CBD administration to rats with induced arthritis reduced joint inflammation and associated pain (10).
CBD treatment reduced joint swelling and immune cell infiltration in a rat model of arthritis (11).
CBD inhibited the production of inflammatory molecules and reduced the activation of immune cells in human cell cultures (12).
CBD reduced the release of pro-inflammatory cytokines and prevented microglial cell activation in cell cultures (13).
Results of Human Clinical Trials:
CBD's effects in patients with ulcerative colitis are investigated, and ?found that CBD treatment led to a significant decrease in disease activity index scores, indicating reduced inflammation in the colon (14).
CBD's effects on pain and inflammation in patients with multiple sclerosis are examined in a clinical trial. The study reported a reduction in pain and improved inflammatory markers in the CBD-treated group (15).
Modulation of immune responses:
CBD can influence the behavior and function of immune cells, such as macrophages and lymphocytes, which play a role in the inflammatory response. Studies suggest that CBD can suppress immune cell activation and migration. CBD also interacts with the endocannabinoid system (ECS), which is involved in regulating immune function. CBD influences immune responses through various mechanisms, including:
Immune Cell Activation and Function:
CBD has been shown to modulate the behavior and function of immune cells. It can suppress the activation of immune cells, such as macrophages and lymphocytes, which play a vital role in the immune response. Studies have demonstrated CBD's ability to reduce the production of pro-inflammatory cytokines and chemokines, which are involved in immune cell communication and inflammation.(16)
Immunomodulatory Effects:
CBD can modulate immune responses by influencing the balance between pro-inflammatory and anti-inflammatory signals. It has been reported to enhance the production of anti-inflammatory cytokines, such as interleukin-10 (IL-10), which can help regulate the immune system's response and promote immune homeostasis.(20)
Scientific Evaluation studies Supporting CBD's Modulation of Immune Responses:
In Vitro & Animal Studies:
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Results of Human Clinical Trials:
Anti-oxidant Property: ?
Oxidative stress, an imbalance between the production of reactive oxygen species (ROS) and the body's antioxidant defense system, plays a significant role in the pathogenesis of various diseases. CBD possesses antioxidant properties, enabling it to scavenge harmful free radicals and reduce oxidative stress. By reducing oxidative stress, CBD may also help alleviate inflammation.
CBD's Effects on Oxidative Stress:
Free radicals are highly reactive molecules that can cause cellular damage and contribute to the development of various diseases. CBD's antioxidant activity helps neutralize these free radicals, protecting cells from oxidative damage.
Induction of Endogenous Antioxidant Defense:
CBD can stimulate the expression and activity of endogenous antioxidant enzymes, such as superoxide dismutase (SOD) and catalase. These enzymes play a crucial role in the body's defense against oxidative stress by converting harmful ROS into less reactive molecules.
In Vitro & Animal Studies:
Human Studies:
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Neuropathic pain relief:
Neuropathic pain, a complex chronic pain condition resulting from damage or dysfunction of the nervous system, is challenging to treat effectively. Cannabidiol has emerged as a potential therapeutic option for neuropathic pain relief.
CBD's Mechanisms of Action in Neuropathic Pain Relief: CBD interacts with various molecular targets in the body, enabling it to modulate neuropathic pain. The mechanisms by which CBD exerts its analgesic effects include:
Interaction with Cannabinoid Receptors:
CBD indirectly interacts with cannabinoid receptors, particularly the cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2). By modulating these receptors' activity, CBD can influence pain perception and reduce neuropathic pain symptoms.(62)
Activation of Non-Cannabinoid Receptors:
CBD interacts with non-cannabinoid receptors, such as the transient receptor potential vanilloid type 1 (TRPV1) and the serotonin 5-HT1A receptor. Activation of these receptors contributes to the analgesic effects of CBD by regulating pain transmission and modulating neurotransmitter release.(63)
Anti-Inflammatory and Neuroprotective Effects:
CBD possesses anti-inflammatory properties, which can help reduce inflammation associated with neuropathic pain. Additionally, CBD exhibits neuroprotective effects by preserving neuronal health and function, potentially mitigating the development and progression of neuropathic pain.
Scientific Evidence Supporting CBD's Neuropathic Pain Relief:
Preclinical Studies:
Human Clinical Trials:
Meta-Analysis:
Delta-9-Tetrahydrocannabinol (THC) in Pain Management:
Pain is a complex and prevalent condition, and THC, a psychoactive compound found in cannabis, has shown potential analgesic properties.
Scientific literature suggests that THC has potential analgesic effects and may be beneficial in pain management. THC interacts with cannabinoid receptors, primarily CB1 receptors, in the central nervous system, modulating pain perception and providing pain relief. Clinical studies have demonstrated the efficacy of THC in various pain conditions, including neuropathic pain, cancer-related pain, and chronic non-cancer pain.(31,32,33,34,35,36,37)
Neuropathic Pain Relief by Delta-9-Tetrahydrocannabinol THC:
Neuropathic pain is a complex and debilitating condition caused by damage or dysfunction of the nervous system. It is often resistant to conventional pain medications, making it challenging to manage effectively.
Mechanisms of Action in Neuropathic Pain Relief:
THC interacts with the endocannabinoid system, which plays a crucial role in pain modulation and homeostasis within the body. The mechanisms by which THC exerts its analgesic effects in neuropathic pain include:
Activation of Cannabinoid Receptors: THC binds to and activates cannabinoid receptors, primarily the cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2). By modulating these receptors' activity, THC can regulate pain perception and reduce neuropathic pain symptoms.(64)
Modulation of Neurotransmitter Release: THC can influence the release of various neurotransmitters involved in pain transmission, such as gamma-aminobutyric acid (GABA), glutamate, and serotonin. By altering the balance of these neurotransmitters, THC may help modulate pain signals in the central nervous system.(65)
Anti-Inflammatory Effects:
Chronic inflammation often accompanies neuropathic pain conditions. THC possesses anti-inflammatory properties, which can help reduce inflammation and alleviate pain symptoms associated with neuroinflammation.(66)
Scientific Evidence Supporting THC's Neuropathic Pain Relief:
Preclinical Studies:
THC reduced mechanical allodynia (hypersensitivity to non-painful stimuli) and improved thermal hyperalgesia (increased sensitivity to painful stimuli) in a rat model of neuropathic pain (38).
THC administration reduced neuropathic pain behaviors in a mouse model of peripheral nerve injury (39).
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Human Clinical Trials:
THC treatment significantly reduced pain intensity compared to placebo in patients with neuropathic pain conditions reported by randomized controlled trial. (40)
Meta analysis:
A systematic review and meta-analysis reported that THC treatment provided significant pain relief in patients with various neuropathic pain conditions (41).
Combination Therapy:
THC has been shown to enhance the analgesic effects of other cannabinoids, such as cannabidiol (CBD). A combination of THC and CBD provided greater pain relief than THC alone in patients with neuropathic pain (42).
Chronic Pain Relief by Delta-9-Tetrahydrocannabinol (THC):
Delta-9-tetrahydrocannabinol (THC), the primary psychoactive compound found in cannabis, has gained attention as a potential therapeutic option for chronic pain relief.
Mechanisms of Action in Chronic Pain Relief:
THC interacts with the endocannabinoid system, Mechanisms by which THC exerts its analgesic effects in chronic pain include:
Activation of Cannabinoid Receptors:
THC binds to and activates cannabinoid receptors, primarily the cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2). By modulating these receptors' activity, THC can regulate pain perception and reduce chronic pain symptoms.(67,68)
Modulation of Neurotransmitter Release:
THC can influence the release of various neurotransmitters involved in pain transmission, such as gamma-aminobutyric acid (GABA), glutamate, and serotonin. By altering the balance of these neurotransmitters, THC may help modulate pain signals in the central nervous system.(65)
Anti-Inflammatory Effects:
Chronic pain conditions often involve inflammation. THC possesses anti-inflammatory properties, which can help reduce inflammation and alleviate pain symptoms associated with inflammatory processes.(66)
Scientific Evidence Supporting THC's Chronic Pain Relief:
Preclinical Studies:
THC administration reduced pain responses in a rat model of chronic inflammatory pain (43). THC treatment reduced mechanical allodynia (hypersensitivity to non-painful stimuli) in a mouse model of neuropathic pain (44).
Human Clinical Trials:
A randomized controlled study reported that THC treatment resulted in a significant reduction in pain intensity compared to placebo (45).
Meta analysis:
A systematic review and meta-analysis, analyzed the available clinical trials on cannabinoids for chronic pain, concluded that THC-based medicines provided significant pain relief in patients with various chronic pain conditions (46).
THC has been shown to enhance the analgesic effects of other cannabinoids, such as cannabidiol (CBD). Combination provided greater pain relief than either compound alone (47).
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Cancer Related Pain Relief by Delta-9-Tetrahydrocannabinol (THC):
Cancer-related pain is a significant symptom experienced by many cancer patients and can be challenging to manage effectively. Delta-9-tetrahydrocannabinol (THC), has emerged as a potential therapeutic option for alleviating cancer-related pain.
Mechanisms of Action in Cancer-Related Pain Relief:
THC interacts with the endocannabinoid system, a complex network of receptors and endogenous cannabinoids involved in pain modulation. The mechanisms by which THC exerts its analgesic effects in cancer-related pain include:
Activation of Cannabinoid Receptors: THC binds to and activates cannabinoid receptors, particularly the cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2). By modulating these receptors' activity, THC can regulate pain perception and alleviate cancer-related pain.(69)
Modulation of Neurotransmitter Release: THC can influence the release of various neurotransmitters involved in pain transmission, such as gamma-aminobutyric acid (GABA), glutamate, and serotonin. By modulating the balance of these neurotransmitters, THC may help regulate pain signals in the central nervous system.(70,71)
Psychological and Mood Effects: Cancer-related pain can be influenced by psychological factors, such as anxiety and depression. THC's psychoactive properties may contribute to its pain-relieving effects by reducing anxiety, improving mood, and enhancing overall well-being.
Scientific Evidence Supporting THC's Cancer-Related Pain Relief:
Clinical Trials:
THC:CBD extract and THC extract significantly reduced pain intensity compared to placebo in patients with intractable cancer-related pain (48).
THC:CBD spray provided a significant reduction in pain intensity and improved sleep quality in cancer patients with moderate to severe pain. ?(49).
Systematic Reviews and Meta-Analyses:
Cannabinoids, including THC, were effective in reducing cancer-related pain (50).
Cannabinoids, including THC, could be considered as an adjuvant analgesic for cancer pain (51).
Expert Recommendations:
The American Society of Clinical Oncology (ASCO) has provided a position statement supporting the use of cannabinoids, including THC, for cancer-related pain management. ASCO recommends considering cannabinoids as an option when standard treatment is insufficient or associated with adverse effects (52).
Cannabigerol CBG:
Cannabigerol (CBG) is a non-psychoactive cannabinoid found in the Cannabis sativa plant. While much of the research on cannabinoids has focused on tetrahydrocannabinol (THC) and cannabidiol (CBD), CBG has recently gained attention for its potential therapeutic effects, including pain relief.
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CBG's Mechanisms of Action in Pain Relief:
CBG interacts with various molecular targets in the body, enabling it to modulate pain. The mechanisms by which CBG exerts its analgesic effects include:
Interaction with Cannabinoid Receptors:
CBG interacts with cannabinoid receptors, particularly the cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2). By influencing these receptors' activity, CBG can modulate pain perception and reduce pain symptoms.(72)
Activation of Non-Cannabinoid Receptors: CBG interacts with non-cannabinoid receptors, such as the transient receptor potential vanilloid type 1 (TRPV1) and the serotonin 5-HT1A receptor. Activation of these receptors contributes to CBG's analgesic effects by regulating pain transmission and modulating neurotransmitter release.(73,74)
Anti-Inflammatory Effects: CBG possesses anti-inflammatory properties, which can help reduce inflammation associated with pain. By suppressing the release of pro-inflammatory molecules and modulating the immune response, CBG may alleviate pain symptoms linked to inflammation.(75,76)
Scientific Evidence Supporting CBG's Pain Relief:
Preclinical Studies:
A study published in the journal Pharmacology, Biochemistry, and Behavior found that CBG reduced pain responses in a mouse model of inflammatory pain (53).
Another study published in the journal ACS Chemical Neuroscience demonstrated that CBG exerted analgesic effects in a rat model of neuropathic pain (54).
Human Clinical Trials:
Although human clinical trials specifically investigating CBG's pain-relieving effects are limited, a study published in the journal European Journal of Pain examined the effects of a combination of THC, CBD, and CBG on cancer-related pain. The study reported that the combination treatment significantly reduced pain intensity in cancer patients (55).
Synergistic Effects:
CBG has been shown to enhance the analgesic effects of other cannabinoids. A study published in the journal Cannabis and Cannabinoid Research demonstrated that CBG enhanced the pain-relieving effects of CBD in a rat model of chronic pain (56).
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Cannabis Terpenes Effects and Roles in Pain Management:
Terpenes are aromatic compounds found in various plants, including cannabis. These compounds contribute to the distinct smells and flavors associated with different cannabis strains. Cannabis plants contain numerous terpenes, and their presence can vary depending on the strain and growing conditions. Some common terpenes found in cannabis include:
Myrcene: Myrcene is known for its sedative and relaxing effects. It has been reported to have analgesic properties and may enhance the effects of cannabinoids by increasing their absorption through the skin, mucous membranes, and gastrointestinal tract.
Limonene: Limonene is associated with a citrusy aroma and is believed to have anti-inflammatory properties. It may also enhance the permeability of cell membranes, potentially facilitating the absorption of cannabinoids.
Pinene: Pinene is commonly found in coniferous trees and has been studied for its anti-inflammatory and analgesic effects. It may also have a bronchodilator effect, which can be beneficial for respiratory conditions associated with pain.
Caryophyllene: Caryophyllene is the only terpene known to directly interact with CB2 receptors, leading to anti-inflammatory effects. It has shown promise in preclinical studies for its potential analgesic properties.
Terpenes, Cannabinoid Receptors, and Pain Relief:
Terpenes can influence the activity of cannabinoids through following mechanisms:
Entourage Effect:
Terpenes, along with cannabinoids, may synergistically enhance the therapeutic effects of each other. This synergy, known as the entourage effect, suggests that the combined presence of terpenes and cannabinoids can result in more significant pain relief than individual compounds alone.(77,78,79,80)
Modulation of Receptor Activity:
?Some terpenes, such as caryophyllene, may interact directly with cannabinoid receptors, particularly CB2 receptors. By activating these receptors, terpenes can potentially reduce inflammation and alleviate pain associated with inflammatory conditions. (81,82,83,84,86,87,88)
Conclusion:
The entourage effects resulting from the combination of cannabinoids and terpenes in the cannabis plant have shown promising potential in pain management. The synergistic interactions between these compounds may enhance their analgesic and anti-inflammatory properties, leading to improved therapeutic outcomes
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