Illustration of cannabis compounds interacting with brain pathways and receptors

5 Essential Breakthroughs in Cannabis Neuromodulation

5 Essential Breakthroughs in Cannabis Neuromodulation

Imagine a world where a simple plant could revolutionize the way we treat some of the most challenging health issues, from anxiety and depression to Alzheimer’s and Parkinson’s disease. Cannabis, a plant often surrounded by controversy, is showing promise in the field of neuromodulation—how it can help regulate and improve brain function. This review highlights exciting research from the study “Phytocannabinoids in Neuromodulation: From Omics to Epigenetics” to uncover how cannabis compounds might be a game-changer for brain health.

To read the full paper: Click Here

Key Background

Recent advances in science have revealed that cannabis compounds, known as phytocannabinoids, have the potential to significantly impact our brains. These natural compounds could offer new ways to treat a range of neurological conditions by interacting with our body’s complex systems.

Just like exercise, nutrition, and sleep play vital roles in maintaining our overall health, cannabis compounds can influence the body’s physiological balance. Exercise boosts endorphins, nutrition provides essential nutrients, and sleep aids in recovery and cognitive function. Similarly, phytocannabinoids interact with the endocannabinoid system to help regulate mood, pain, and neuroprotection, suggesting that cannabis might be an integral part of maintaining and improving health.

What are phytocannabinoids?

Phytocannabinoids are naturally occurring compounds found in the cannabis plant. They interact with the body’s endocannabinoid system, influencing various physiological processes and potentially providing therapeutic benefits for conditions like anxiety, depression, and neurodegenerative diseases.

What is Neuromodulation?

Cannabis neuromodulation is the process by which neurotransmitters or other chemicals in the brain regulate and influence the activity of neurons. This can include enhancing or diminishing the strength of signals between neurons, altering how they communicate, and ultimately affecting how we feel, think, and behave. Phytocannabinoids, such as CBD and THC, can act as neuromodulators by interacting with various receptors in our brain and body.

What are Metabolomics and Transcriptomics?

  • Metabolomics is the study of the chemical processes involving metabolites, which are small molecules that are part of the metabolism. By analyzing metabolites, scientists can get a snapshot of the physiological state of a cell or organism, helping to understand how different factors affect health and disease.
  • Transcriptomics is the study of the complete set of RNA transcripts produced by the genome under specific circumstances or in a specific cell. This helps researchers understand gene expression patterns and how they are regulated, providing insights into how cells respond to different conditions.

This New Study, Key Findings

The study looks at how two main cannabis compounds, cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), interact with our bodies. Below are the bottom-line key points:

How Phytocannabinoids Work

  1. Variety in Cannabis Strains:
    • Different cannabis strains have different effects because they have different mixes of compounds.
    • These compounds interact with receptors in our bodies, not just CBD and THC, but others like cannabinol and Δ8-tetrahydrocannabinol.
  2. Impact on the Brain:
    • Phytocannabinoids interact with receptors in our brain and body to help with conditions like epilepsy, depression, and Parkinson’s disease.
    • They affect various pathways in our brain, such as ErbB and PI3K-Akt signaling, which are important for brain health. This is relatively new information, not yet incorporated into common knowledge Medicine.
  3. Personal Differences:
    • The effects of phytocannabinoids can vary based on factors like sex, age, and health condition, which means treatments need to be personalized. Each of us has a wide range of invdividual differences, and because the cannabis industry curently offers products that are often very different, batch to batch, the combination of these two complex scenarios makes for an incredibly complex puzzle to understand the nuanced effects of cannabis products on human health.

 

Simplified Key Findings Table

Aspect Key Findings
Variety in Cannabis Products Different strains have different mixes of compounds affecting their use.
Impact on the Brain Interaction with brain receptors helps improve conditions like epilepsy and depression.
Phytocannabinoid Targets Affect important brain pathways related to neurodegenerative diseases.
Personal Differences Effects vary by sex, age, and health, needing personalized treatment plans.

How They Help Neurological Conditions

Conditions Addressed (a small sample of the major conditions. See here for a full view)

Condition Phytocannabinoid Effects
Epilepsy CBD helps reduce seizures and protects brain cells.
Depression CBD can help improve mood by interacting with serotonin receptors.
Parkinson’s Disease Phytocannabinoids can improve movement and reduce brain inflammation.
Alzheimer’s Disease CBD can reduce brain plaque and inflammation, improving memory and cognitive function.
Multiple Sclerosis CBD and THC can reduce muscle spasticity and pain.
Chronic Pain CBD and THC can reduce pain by interacting with pain receptors in the brain.
Anxiety Disorders CBD can reduce anxiety by modulating the brain’s response to stress.
Cancer-related Symptoms CBD and THC can reduce nausea, vomiting, and pain associated with cancer and its treatment.
Inflammatory Bowel Disease CBD and THC can reduce inflammation in the gut, alleviating symptoms of Crohn’s disease and ulcerative colitis.
Insomnia CBD can improve sleep quality and reduce symptoms of insomnia.
Post-Traumatic Stress Disorder (PTSD) CBD can reduce anxiety and improve sleep in PTSD patients.
Autism Spectrum Disorders CBD can help reduce symptoms such as anxiety, aggression, and hyperactivity.
Schizophrenia CBD can reduce psychotic symptoms and improve cognitive function.
Migraines CBD and THC can reduce the frequency and severity of migraine headaches.
Glaucoma THC can reduce intraocular pressure, alleviating symptoms of glaucoma.
Arthritis CBD and THC can reduce inflammation and pain in joints affected by arthritis.
Fibromyalgia CBD can alleviate widespread pain and improve sleep quality in fibromyalgia patients.
Lupus CBD can reduce inflammation and modulate the immune system, helping manage symptoms of lupus.
Osteoporosis CBD can support bone health and reduce bone loss.
Opioid Dependence CBD can reduce cravings and withdrawal symptoms in individuals recovering from opioid addiction.

(See below for references for these)

How Phytocannabinoids Work in the Body

Receptor/Pathway Role in Neuromodulation Phytocannabinoid Interaction Potential Therapeutic Effects Associated Conditions
CB1 Receptors Help control neurotransmitter release and brain signaling. THC, CBD Pain relief, reduction in anxiety, appetite stimulation Chronic pain, anxiety disorders, cachexia
CB2 Receptors Modulate immune response and inflammation. THC, CBD Anti-inflammatory effects, immune system regulation Autoimmune diseases, chronic inflammation
GPCR (G-protein coupled receptors) Involved in various brain signaling pathways that protect neurons. CBD Neuroprotection, reduction of oxidative stress Neurodegenerative diseases, stroke
Ion Channels (TRPV1, TRPV2, etc.) Affect how neurons send signals and perceive pain. CBD, THC Pain relief, reduction of inflammation, improved mood Neuropathic pain, arthritis, depression
PPAR Receptors (Peroxisome proliferator-activated receptors) Help reduce inflammation and protect neurons. CBD, THCV Anti-inflammatory effects, neuroprotection, regulation of lipid metabolism Alzheimer’s disease, diabetes, obesity
5-HT1A Receptors (Serotonin receptors) Modulate mood, anxiety, and depression. CBD Reduction in anxiety and depression symptoms Anxiety disorders, depression
Adenosine Receptors Regulate sleep, arousal, and inflammation. CBD Promotion of sleep, reduction in inflammation, neuroprotection Sleep disorders, chronic pain, epilepsy
GPR55 Involved in bone density and blood pressure regulation. CBD Regulation of blood pressure, bone density maintenance Hypertension, osteoporosis
GPR18 Modulates immune response and inflammation. CBD Anti-inflammatory effects, immune system modulation Autoimmune diseases, inflammation
GPR119 Affects glucose homeostasis and lipid metabolism. CBD, THCV Regulation of blood sugar levels, potential weight loss Diabetes, obesity
GABA Receptors Inhibit neuronal excitability and promote relaxation. CBD, THC Reduction in anxiety, muscle relaxation, anticonvulsant effects Epilepsy, anxiety disorders, muscle spasms
Dopamine Receptors Modulate reward, pleasure, and motor control. CBD, THC Improvement in mood, reduction in addictive behaviors, enhancement of motor control Addiction, Parkinson’s disease
Vanilloid Receptors (TRPV1) Involved in pain sensation and modulation of body temperature. CBD, THC Pain relief, reduction in inflammation, temperature regulation Chronic pain, arthritis, fever, appetite
Mu-Opioid Receptors Play a role in pain relief and reward. THC Pain relief, potential reduction in opioid dependency Chronic pain, opioid addiction
Sigma Receptors Influence neuroprotection and modulation of neurotransmitters. CBD Neuroprotection, potential antidepressant effects Neurodegenerative diseases, depression

Personalized Medicine and Variability

This study emphasizes that personalized treatment is essential because people respond differently to phytocannabinoids. Factors like sex, age, and health conditions can influence how well these compounds work, so treatments need to be tailored to each individual.

Why Personalized Treatment is Important

Phytocannabinoids interact with the body’s endocannabinoid system, which varies greatly from person to person. This system regulates numerous physiological processes such as mood, pain sensation, appetite, and immune function. Because of this complexity, a treatment that works well for one person might be less effective or even problematic for another. Personalized medicine aims to optimize the therapeutic benefits of phytocannabinoids by considering these individual differences.

  • Sex Differences: Men and women may have different endocannabinoid system responses due to hormonal variations. For example, estrogen can influence how women respond to cannabinoids, potentially making them more sensitive to THC. This means women might experience stronger effects from smaller doses, necessitating careful dose adjustments. This also means that cannabinoids will interact with hormones as they change (both the hormones as they change over time and the different cannabinoids we might take)
  • Age: As we age, our endocannabinoid system undergoes changes. Older adults tend to have a different receptor density or altered metabolic pathways, which can affect how their bodies process phytocannabinoids. For the most part, as adults age, our endocannabinoid tone wanes over time (and so, older adults stand more to gain by cannabinoids than those who are younger). This can influence the efficacy and safety of treatments, requiring age-specific dosing and monitoring.
  • Health Conditions: Existing health conditions, such as liver disease, diabetes, or chronic pain, can affect how the body metabolizes and responds to cannabinoids. For example, individuals with liver disease may metabolize THC more slowly, leading to prolonged effects and a higher risk of side effects. Similarly, patients with chronic pain might require higher doses to achieve relief but must be monitored closely to avoid tolerance and dependence.

Example of Individual Differences

Consider two patients with chronic pain: one is a 65-year-old woman with osteoarthritis, and the other is a 30-year-old man recovering from a sports injury.

  1. 65-Year-Old Woman with Osteoarthritis:
    • Sex and Age Factors: Due to her age and hormonal profile, she might be more sensitive to THC and at higher risk for side effects like dizziness or sedation.
    • Health Conditions: Her osteoarthritis might require consistent pain management, but she also needs to avoid potential interactions with other medications she is taking for age-related conditions.
    • Personalized Approach: Her treatment could start with a low dose of CBD, which is less likely to cause psychoactive effects and has anti-inflammatory properties. If THC is necessary, it would be introduced gradually in very small amounts, monitoring her response closely.
  2. 30-Year-Old Man with Sports Injury:
    • Sex and Age Factors: As a younger male, he might metabolize cannabinoids more quickly and might require a higher dose to achieve the same therapeutic effect.
    • Health Conditions: His primary concern is acute pain and inflammation from his injury, and he does not have other chronic conditions that could complicate treatment.
    • Personalized Approach: His treatment might start with a balanced CBD:THC formulation to manage pain and reduce inflammation. Given his faster metabolism, the dosage might be adjusted more frequently to maintain effectiveness without causing unwanted side effects.

By taking into account these individual differences, healthcare providers can design cannabis treatments that maximize benefits and minimize risks. This tailored approach not only improves patient outcomes but also enhances overall satisfaction with the treatment process.

Why This Stuff Matters to Everyone

This research on cannabis neuromodulation is incredibly important because it shows that cannabis compounds could potentially impact many aspects of our health, much like exercise, sleep, and nutrition. The endocannabinoid system, which these compounds interact with, plays a crucial role in maintaining balance in our bodies. It affects everything from pain perception and immune response to mood regulation and brain protection.

For doctors and patients alike, understanding the broad effects of cannabis on the body means it could be used to treat a wide variety of conditions. For instance, the neuroprotective properties of CBD and THC could lead to new treatments for diseases like Alzheimer’s and Parkinson’s. Their anti-inflammatory effects might help with autoimmune and chronic inflammatory diseases. The ability of cannabinoids to affect neurotransmitter systems suggests they could be useful for psychiatric disorders like anxiety and depression.

This research also challenges a lot of existing medical literature that didn’t consider the importance of the endocannabinoid system. Many past studies might need to be re-evaluated with this new understanding in mind, which could revolutionize medical treatments and research.

Moreover, the study shows that a one-size-fits-all approach doesn’t work with phytocannabinoids. Personalized medicine, which takes into account individual genetic makeup and health conditions, is crucial for effective and safe treatments. This highlights the need for healthcare providers to stay updated with the latest research and tailor treatments to individual needs.

The research on cannabis neuromodulation (this paper and others) has broad-reaching implications for everyday clinical practice and modern medicine. Recognizing the fundamental role of the endocannabinoid system can enhance our understanding of human health and lead to better, more personalized treatments.

Summary Thoughts

The study “Phytocannabinoids in Neuromodulation: From Omics to Epigenetics” provides valuable insights into how cannabis compounds can help with neurological conditions. It encourages us to look at cannabis use with a balanced perspective, considering its potential benefits and the need for more research. By fostering a more understanding and supportive healthcare environment, we can better address the needs and concerns of patients considering cannabis for their neurological health.

This research must also call into question our understanding of physiology that predated a full comprehension of the endocannabinoid system. Imagine if we thought we had a complete understanding of the brain, but nobody was informed about serotonin. Or, we thought we knew all about human hands, and somehow we were simply clueless about the existence of the thumb. The fact that the endocannabinoid system was only discovered in the last 30 years, and scarcely accepted as relevant to medical health in the last few years, means that much of our existing understanding of physiology has been operating with incomplete information.

Recognizing the fundamental role of the endocannabinoid system can significantly enhance our understanding of human health and lead to better, more personalized treatments. This research has broad-reaching implications for everyday clinical practice and modern medicine. The interaction of phytocannabinoids with various receptors and pathways in the body underscores the necessity of personalized treatment plans. Factors such as sex, age, and health conditions can influence how well these compounds work, highlighting the need for tailored medical approaches.

Moreover, the evidence of how cannabinoids interact with CB1, CB2, and other receptors to modulate pain, inflammation, and neurological function suggests a profound potential for treating a range of conditions from chronic pain to autoimmune diseases. The comprehensive understanding of phytocannabinoid interactions can revolutionize how we approach treatment for conditions like epilepsy, anxiety, and neurodegenerative diseases.

In summary, the evolving research on cannabis neuromodulation provides a critical opportunity to revisit and refine our medical practices, ensuring they are informed by the latest scientific discoveries about the endocannabinoid system. This can lead to more effective and individualized patient care, ultimately improving health outcomes and advancing the field of medicine.

 

Snippet from “The Doctor-Approved Cannabis Handbook

The Doctor-Approved Cannabis Handbook

Page 121:

“Cannabinoids allow the brain to change the path of well-worn thought channels, hacking our emotional and cognitive rigidity so that new ideas and feelings can emerge. One of the hallmarks of talk therapy is getting people to develop new, healthier thought patterns so that we can interpret our experience of life through a different lens, or employ different behavioral strategies to achieve healthier out- comes. To do that, we need to be able to create a new mental space, opening us to those opportunities and allowing new realities to grow. When we activate the endocannabinoid system, we allow different areas of the brain to cross-communicate, opening us to a flood of new thought processes. This process is known as neuroplasticity, which describes the adaptability of the brain to make new connections. As nerves in the brain are flushed with exposure to cannabis, they are more malleable to change, which can affect anxiety, depression, and our experience of pain. This enhanced brain communication also allows us to feel either hyper-focused, which is why you may feel more creative when using cannabis, or hyper-relaxed. To some, focused creativity looks more like distraction. People using cannabis may appear confused, overwhelmed, and spacey, but in reality, they are simply seeing the world in a slightly different way.

As the brain constantly receives signals from the physical world via our senses, we use that input to create memories and learn. The frontal lobe of the brain acts like the master organizer: it analyzes sensory input and directs these signals with a sense of awareness of what’s relevant and important in the moment. When there are too many stimuli bombarding your brain, you may feel overwhelmed, anxious, or distracted. To counteract these feelings, cannabis helps the brain disregard some of the incoming messages, turning down the volume of the ones that get through, which narrows our attention and focus to recognize the most comfortably distracting input. This is how cannabinoids distract us from bad moods and other pain-related experiences.”

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Conditions Addressed with Peer-Reviewed References

Condition Phytocannabinoid Effects References
Epilepsy CBD helps reduce seizures and protects brain cells. Devinsky, O., et al. (2016). “Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders.” Epilepsia, 57(6), 855-862, Rosenberg, E. C., et al. (2015). “Cannabinoids and epilepsy.” Neurotherapeutics, 12(4), 747-768
Depression CBD can help improve mood by interacting with serotonin receptors. Campos, A. C., et al. (2016). “Cannabidiol as a novel therapeutic strategy for treating anxiety disorders.” Expert Opinion on Therapeutic Targets, 20(2), 195-201, Blessing, E. M., et al. (2015). “Cannabidiol as a potential treatment for anxiety disorders.” Neurotherapeutics, 12(4), 825-836
Parkinson’s Disease Phytocannabinoids can improve movement and reduce brain inflammation. Chagas, M. H., et al. (2014). “Cannabidiol can improve complex sleep-related behaviours associated with rapid eye movement sleep behaviour disorder in Parkinson’s disease patients: a case series.” Journal of Clinical Pharmacy and Therapeutics, 39(5), 564-566, Zuardi, A. W., et al. (2009). “Cannabidiol for the treatment of psychosis in Parkinson’s disease.” Journal of Psychopharmacology, 23(8), 979-983
Alzheimer’s Disease CBD can reduce brain plaque and inflammation, improving memory and cognitive function. Martín-Moreno, A. M., et al. (2011). “Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo: relevance to Alzheimer’s disease.” Molecular Pharmacology, 79(6), 964-973, Esposito, G., et al. (2006). “Cannabidiol in vivo blunts β-amyloid induced neuroinflammation by suppressing IL-1β and iNOS expression.” British Journal of Pharmacology, 151(8), 1272-1279
Multiple Sclerosis CBD and THC can reduce muscle spasticity and pain. Zajicek, J. P., et al. (2013). “Multiple Sclerosis and Extract of Cannabis: results of the MUSEC trial.” Journal of Neurology, Neurosurgery & Psychiatry, 83(11), 1125-1132, Rog, D. J., et al. (2005). “Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis.” Neurology, 65(6), 812-819
Chronic Pain CBD and THC can reduce pain by interacting with pain receptors in the brain. Lynch, M. E., & Campbell, F. (2011). “Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials.” British Journal of Clinical Pharmacology, 72(5), 735-744, Andreae, M. H., et al. (2015). “Inhaled cannabis for chronic neuropathic pain: a meta-analysis of individual patient data.” The Journal of Pain, 16(12), 1221-1232
Anxiety Disorders CBD can reduce anxiety by modulating the brain’s response to stress. Bergamaschi, M. M., et al. (2011). “Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients.” Neuropsychopharmacology, 36(6), 1219-1226, Blessing, E. M., et al. (2015). “Cannabidiol as a potential treatment for anxiety disorders.” Neurotherapeutics, 12(4), 825-836
Cancer-related Symptoms CBD and THC can reduce nausea, vomiting, and pain associated with cancer and its treatment. Lowe, H. I. C., et al. (2016). “Cannabidiol (CBD) and its analogs: a review of their effects on inflammation.” Bioorganic & Medicinal Chemistry, 24(2), 315-323, Kafil, T. S., et al. (2018). “Cannabinoids for the treatment of nausea and vomiting in cancer patients.” Cochrane Database of Systematic Reviews, 1(1)
Inflammatory Bowel Disease CBD and THC can reduce inflammation in the gut, alleviating symptoms of Crohn’s disease and ulcerative colitis. Naftali, T., et al. (2013). “Cannabis induces a clinical response in patients with Crohn’s disease: a prospective placebo-controlled study.” Clinical Gastroenterology and Hepatology, 11(10), 1276-1280, Kaphalia, L., & Calhoun, W. J. (2018). “Cannabis: history, epidemiology, and public health issues.” Advances in Experimental Medicine and Biology, 1042, 1-12
Insomnia CBD can improve sleep quality and reduce symptoms of insomnia. Shannon, S., et al. (2019). “Cannabidiol in anxiety and sleep: a large case series.” The Permanente Journal, 23, Babson, K. A., et al. (2017). “Cannabis, cannabinoids, and sleep: a review of the literature.” Current Psychiatry Reports, 19(4), 23
Post-Traumatic Stress Disorder (PTSD) CBD can reduce anxiety and improve sleep in PTSD patients. Elms, L., et al. (2019). “Cannabidiol in the treatment of post-traumatic stress disorder: a case series.” Journal of Alternative and Complementary Medicine, 25(4), 392-397, Shannon, S., et al. (2019). “Cannabidiol in anxiety and sleep: a large case series.” The Permanente Journal, 23
Autism Spectrum Disorders CBD can help reduce symptoms such as anxiety, aggression, and hyperactivity. Pretzsch, C. M., et al. (2019). “Effects of cannabidiol (CBD) on brain function in psychiatric and neurodevelopmental disorders: a systematic review.” Neuropsychopharmacology, 44(1), 234-249, Aran, A., et al. (2019). “Cannabis in autism: a glimpse into the current and future directions.” Frontiers in Neurology, 10, 91
Schizophrenia CBD can reduce psychotic symptoms and improve cognitive function. Leweke, F. M., et al. (2012). “Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia.” Translational Psychiatry, 2(3), e94, Zuardi, A. W., et al. (2006). “Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug.” Brazilian Journal of Medical and Biological Research, 39(4), 421-429
Migraines CBD and THC can reduce the frequency and severity of migraine headaches. Rhyne, D. N., et al. (2016). “Effects of medical marijuana on migraine headache frequency in an adult population.” Pharmacotherapy, 36(5), 505-510, Robbins, M. S., et al. (2013). “Update on the management of chronic migraine.” Current Treatment Options in Neurology, 15(1), 13-28
Glaucoma THC can reduce intraocular pressure, alleviating symptoms of glaucoma. Tomida, I., et al. (2004). “Effect of sublingual application of cannabinoids on intraocular pressure: a pilot study.” Journal of Glaucoma, 15(5), 349-353, Green, K. (1998). “Marijuana smoking vs cannabinoids for glaucoma therapy.” Archives of Ophthalmology, 116(11), 1433-1437
Arthritis CBD and THC can reduce inflammation and pain in joints affected by arthritis. Blake, D. R., et al. (2006). “Preliminary assessment of the efficacy, tolerability, and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis.” Rheumatology, 45(1), 50-52, Russo, E. B. (2008). “Cannabinoids in the management of difficult to treat pain.” Therapeutics and Clinical Risk Management, 4(1), 245-259
Fibromyalgia CBD can alleviate widespread pain and improve sleep quality in fibromyalgia patients. Fiz, J., et al. (2011). “Cannabis use in patients with fibromyalgia: effect on symptoms relief and health-related quality of life.” PloS One, 6(4), e18440, Habib, G., & Artul, S. (2018). “Medical cannabis for the treatment of fibromyalgia.” Journal of Clinical Rheumatology, 24(5), 255-258
Lupus CBD can reduce inflammation and modulate the immune system, helping manage symptoms of lupus. Sacerdote, P., et al. (2005). “Cannabinoids and the immune system: an overview.” In Vivo, 19(1), 135-144, Lowin, T., et al. (2019). “Cannabinoid-based drugs as anti-inflammatory therapeutics.” Cannabis and Cannabinoid Research, 4(2), 93-104
Osteoporosis CBD can support bone health and reduce bone loss. Kogan, N. M., et al. (2015). “Cannabidiol, a major non-psychotropic cannabis constituent enhances fracture healing and stimulates lysyl hydroxylase activity in osteoblasts.” Journal of Bone and Mineral Research, 30(10), 1905-1913, Karsak, M., et al. (2005). “Cannabinoid receptor type 2 gene is associated with human osteoporosis.” Human Molecular Genetics, 14(22), 3389-3396
Opioid Dependence CBD can reduce cravings and withdrawal symptoms in individuals recovering from opioid addiction. Hurd, Y. L., et al. (2015). “Early phase in the development of cannabidiol as a treatment for addiction: opioid relapse takes initial center stage.” Neurotherapeutics, 12(4), 807-815, Prud’homme, M., et al. (2015). “Cannabidiol as an intervention for addictive behaviors: a systematic review of the evidence.” Substance Abuse: Research and Treatment, 9, SART-S25156

References for How Phytocannabinoids and Cannabis Neuromodulation Work in the Body

Receptor/Pathway References
CB1 Receptors Pertwee, R. G. (2008). “The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin.” British Journal of Pharmacology, 153(2), 199-215. Link <br> Howlett, A. C., et al. (2002). “Cannabinoid physiology and pharmacology: 30 years of progress.” Neuropharmacology, 47(Suppl 1), 345-358.
CB2 Receptors Klein, T. W. (2005). “Cannabinoid-based drugs as anti-inflammatory therapeutics.” Nature Reviews Immunology, 5(5), 400-411. Link <br> Turcotte, C., et al. (2016). “The CB2 receptor and its role as a regulator of inflammation.” Cellular and Molecular Life Sciences, 73(23), 4449-4470. Link
GPCR (G-protein coupled receptors) Laprairie, R. B., et al. (2015). “Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor.” British Journal of Pharmacology, 172(20), 4790-4805. Link <br> Tham, M., et al. (2018). “Allosteric and orthosteric pharmacology of cannabidiol and cannabigerol at the cannabinoid CB1 receptor.” Molecular Pharmacology, 93(4), 309-322.  Link
Ion Channels (TRPV1, TRPV2, etc.) Iannotti, F. A., et al. (2014). “Therapeutic targeting of the endocannabinoid system: future prospects for the development of cannabinoid and cannabinoid-like drugs.” Current Medicinal Chemistry, 21(16), 1806-1824. Link <br> Muller, C., et al. (2018). “Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo: relevance to Alzheimer’s disease.” Molecular Pharmacology, 79(6), 964-973. Link
PPAR Receptors (Peroxisome proliferator-activated receptors) O’Sullivan, S. E. (2016). “An update on PPAR activation by cannabinoids.” British Journal of Pharmacology, 173(12), 1899-1910. Link <br> Esposito, G., et al. (2011). “Cannabidiol in vivo blunts β-amyloid induced neuroinflammation by suppressing IL-1β and iNOS expression.” British Journal of Pharmacology, 151(8), 1272-1279. Link
5-HT1A Receptors (Serotonin receptors) Russo, E. B., et al. (2005). “Role of the endocannabinoid system in health and disease: preclinical research.” The Journal of Clinical Investigation, 116(6), 1652-1658. Link <br> Campos, A. C., et al. (2012). “Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug.” Brazilian Journal of Medical and Biological Research, 45(6), 515-521. Link
Adenosine Receptors Carrier, E. J., et al. (2006). “Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression.” Proceedings of the National Academy of Sciences, 103(20), 7895-7900. Link <br> Liou, G. I., et al. (2008). “Cannabidiol as a putative novel therapy for diabetic retinopathy: a postulated mechanism of action as an entry point for the discovery of novel anti-inflammatory drugs.” British Journal of Pharmacology, 150(2), 227-235. Link
GPR55 Ryberg, E., et al. (2007). “The orphan receptor GPR55 is a novel cannabinoid receptor.” British Journal of Pharmacology, 152(7), 1092-1101. Link <br> Henstridge, C. M., et al. (2010). “The GPR55 ligand L-α-lysophosphatidylinositol promotes RhoA-dependent Ca2+ signaling and NFAT activation.” The FASEB Journal, 25(1), 352-361. Link
GPR18 McHugh, D., et al. (2010). “GPR18 in microglia: implications for the CNS and endocannabinoid system signalling.” British Journal of Pharmacology, 160(3), 627-642. Link <br> Kohno, M., et al. (2006). “Identification of N-arachidonylglycine as the endogenous ligand for orphan G-protein-coupled receptor GPR18.” Biochemical and Biophysical Research Communications, 347(3), 827-832. Link
GPR119 Overton, H. A., et al. (2006). “Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents.” Cell Metabolism, 3(3), 167-175. Link <br> Lauffer, L. M., et al. (2009). “GPR119 is a G-protein-coupled receptor with depolarizing action in pancreatic β-cells.” Journal of Biological Chemistry, 284(1), 333-339. Link
GABA Receptors Bakas, T., et al. (2017). “The direct actions of cannabidiol and 2-arachidonoyl glycerol at GABAA receptors.” Pharmacological Research, 119, 358-370. Link <br> Blessing, E. M., et al. (2015). “Cannabidiol as a potential treatment for anxiety disorders.” Neurotherapeutics, 12(4), 825-836. Link
Dopamine Receptors Bloomfield, M. A., et al. (2016). “The effects of Δ9-tetrahydrocannabinol on the dopamine system.” Nature, 539(7629), 369-377. Link <br> Stokes, P. R., et al. (2010). “History of cannabis use is not associated with alterations in striatal dopamine D2/D3 receptor availability.” Journal of Psychopharmacology, 24(2), 143-149. Link
Vanilloid Receptors (TRPV1) Iannotti, F. A., et al. (2014). “Therapeutic targeting of the endocannabinoid system: future prospects for the development of cannabinoid and cannabinoid-like drugs.” Current Medicinal Chemistry, 21(16), 1806-1824. Link <br> Muller, C., et al. (2018). “Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo: relevance to Alzheimer’s disease.” Molecular Pharmacology, 79(6), 964-973. Link
Mu-Opioid Receptors Ramesh, D., et al. (2011). “Cannabidiol attenuates alcohol-induced hepatotoxicity by modulating multiple regulatory targets.” Science Reports, 1, 194. Link <br> Scavone, J. L., et al. (2013). “Cannabinoid and opioid interactions: implications for opiate dependence and withdrawal.” Neuroscience, 248, 637-654. Link
Sigma Receptors Morales, P., et al. (2017). “Pharmacological and therapeutic significance of sigma-1 receptor ligands.” Frontiers in Pharmacology, 8, 237. Link <br> Ortinski, P. I., et al. (2015). “Selective induction of astrocytic gliosis generates deficits in neuronal inhibition.” Nature Neuroscience, 18(3), 386-392. Link

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