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Cannabidiol alleviates neurological deficits after traumatic brain injury by improving intracranial lymphatic drainage

Abstract

Traumatic brain injury (TBI)—a severe clinical problem—is compounded by a lack of effective treatments and impeded intracranial metabolic waste clearance. The glymphatic system and meningeal lymphatic vessels are instrumental in TBI pathophysiology and crucial for clearing harmful substances. Cannabidiol (CBD) has the potential to address metabolic imbalances and improve cognitive functions in neurodegenerative diseases, but its specific effect on TBI remains unclear. Using a fluid percussion injury model, we adopted a comprehensive approach that included behavioral testing, various imaging techniques, and deep cervical lymph node (dCLN) ligation to evaluate CBD’s effects on neurological outcomes and lymphatic clearance in a TBI mouse model. Our results demonstrated that CBD markedly enhanced motor, memory, and cognitive functions, correlating with reduced levels of detrimental neural proteins. CBD also expedited the removal of intracranial tracers, increased cerebral blood flow, and improved tracer migration from lymphatic vessels to dCLNs. Intriguingly, CBD treatment modified aquaporin-4 polarization and diminished neuroinflammatory indicators. A key observation was that disrupting efferent lymphatic channels nullified CBD’s positive effects on waste removal and cognitive enhancements, whereas its anti-inflammatory benefits continued. This finding suggests that CBD’s ability to improve waste clearance may operate via the lymphatic system, thereby improving neurological outcomes in TBI patients. Therefore, our study underscores CBD’s potential therapeutic role in TBI management.

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Antitumor Effects of Cannabis sativa Bioactive Compounds on Colorectal Carcinogenesis

Abstract

Cannabis sativa is a multipurpose plant that has been used in medicine for centuries. Recently, considerable research has focused on the bioactive compounds of this plant, particularly cannabinoids and terpenes. Among other properties, these compounds exhibit antitumor effects in several cancer types, including colorectal cancer (CRC). Cannabinoids show positive effects in the treatment of CRC by inducing apoptosis, proliferation, metastasis, inflammation, angiogenesis, oxidative stress, and autophagy. Terpenes, such as β-caryophyllene, limonene, and myrcene, have also been reported to have potential antitumor effects on CRC through the induction of apoptosis, the inhibition of cell proliferation, and angiogenesis. In addition, synergy effects between cannabinoids and terpenes are believed to be important factors in the treatment of CRC. This review focuses on the current knowledge about the potential of cannabinoids and terpenoids from C. sativa to serve as bioactive agents for the treatment of CRC while evidencing the need for further research to fully elucidate the mechanisms of action and the safety of these compounds.

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CBD could reverse opioid overdoses

FOR IMMEDIATE RELEASE

INDIANAPOLIS, March 28, 2023 — There’s been a recent push in the U.S. to make naloxone — a fast-acting opioid antidote — available without a prescription. This medication has saved lives, but it’s less effective against powerful synthetic opioids, such as fentanyl. In an interesting twist, researchers are now looking to cannabidiol (CBD), a component of marijuana, as a possible alternative to the popular antidote. Today, a team reports compounds based on CBD that reduce fentanyl binding and boost the effects of naloxone.

The researchers will present their results at the spring meeting of the American Chemical Society (ACS). ACS Spring 2023 is a hybrid meeting being held virtually and in-person March 26–30, and features more than 10,000 presentations on a wide range of science topics.

“Fentanyl-class compounds account for more than 80% of opioid overdose deaths, and these compounds aren’t going anywhere — it’s just too much of an economic temptation for dealers,” says Alex Straiker, Ph.D., the project’s co-principal investigator. “Given that naloxone is the only drug available to reverse overdoses, I think it makes sense to look at alternatives.”

A new option could take one of two forms, according to Michael VanNieuwenhze, Ph.D., the other co-principal investigator for the project.

“Ideally, we would like to discover a more potent replacement for naloxone,” VanNieuwenhze says. “However, finding something that works synergistically with it, reducing the amount needed to treat an overdose, would also be a success.”

Jessica Gudorf, a graduate student in VanNieuwenhze’s group, is presenting the work at the meeting. All of the researchers are at Indiana University Bloomington.

Opioids are a class of compounds that are prescribed to treat pain and are sometimes sold illegally. If taken in excess, the drugs can interfere with breathing, making them potentially lethal. The U.S. Centers for Disease Control and Prevention estimates that more than half a million people died from overdoses involving opioids between 1999 and 2020. That toll continues to climb.

Compared to other compounds in this class, such as heroin or morphine, fentanyl and its other synthetic relatives bind more tightly to opioid receptors in the brain. Naloxone reverses an overdose by competing with the drug molecules for the same binding sites on the receptors. But because fentanyl binds so readily, it has a leg up on naloxone, and growing evidence suggests that reversing these kinds of overdoses may require multiple doses of the antidote.

At this point, researchers have exhaustively studied the strategy naloxone takes, but they have yet to find any way to improve on its performance, Gudorf says. “Our work opens the door to making new blockers that work through a different mechanism,” she explains.

Earlier research suggesting that CBD can interfere with opioid binding inspired the current effort. In research published in 2006, a group based in Germany concluded that CBD hampered opioid binding indirectly, by altering the shape of the receptor. When used with naloxone, they found CBD accelerated the medication’s effect, forcing the receptors to release opioids.

To augment these effects, Gudorf altered CBD’s structure to generate derivatives. Taryn Bosquez-Berger, a graduate student in Straiker’s group, tested these new compounds in cells with a substance called DAMGO, an opioid used only in lab studies. To measure their success, she monitored a molecular signal that diminishes when this type of drug binds. Armed with feedback from these experiments, Gudorf refined the structures she generated.

In the end, they narrowed the field to 15, which they tested at varying concentrations against fentanyl, with and without naloxone. Several derivatives could reduce fentanyl binding even at what Bosquez-Berger described as “incredibly low” concentrations, while also outperforming naloxone’s opioid-blocking performance. Two of these also showed a synergistic effect when combined with the antidote.

The team has since begun testing the most successful derivatives in mice. In these experiments, they are investigating whether these compounds alter behaviors associated with taking fentanyl.

“We hope our approach leads to the birth of new therapeutics, which, in the hands of emergency personnel, could save even more lives,” Bosquez-Berger says.

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Cannabidiol goes nuclear: The role of PPARγ

Abstract

Background

Cannabidiol (CBD) is one of the main phytocannabinoids found in Cannabis sativa. In contrast to Δ9-tetrahydrocannabinol, it has a low affinity for cannabinoid receptors CB1 and CB2, thereby it does not induce significant psychoactive effects. However, CBD may interact with other receptors, including peroxisome proliferator-activated receptor gamma (PPARγ). CBD is a PPARγ agonist and changes its expression. There is considerable evidence that CBD’s effects are mediated by its interaction with PPARγ. So, we reviewed studies related to the interaction of CBD and PPARγ.

Methods

In this comprehensive literature review, the term ‘cannabidiol’ was used in combination with the following keywords including ‘PPARγ’, ‘Alzheimer’s disease’, ‘Parkinson’s disease’, ‘seizure’, ‘multiple sclerosis’, ‘immune system’, ‘cardiovascular system’, ‘cancer’, and ‘adipogenesis’. PubMed, Web of Science, and Google Scholar were searched until December 20, 2022. A total of 78 articles were used for the reviewing process.

Results

CBD, via activation of PPARγ, promotes significant pharmacological effects. The present review shows that the effects of CBD on Alzheimer’s disease and memory, Parkinson’s disease and movement disorders, multiple sclerosis, anxiety and depression, cardiovascular system, immune system, cancer, and adipogenesis are mediated, at least in part, via PPARγ.

Conclusion

CBD not only activates PPARγ but also affects its expression in the body. It was suggested that the late effects of CBD are mediated via PPARγ activation. We suggested that CBD’s chemical structure is a good backbone for developing new dual agonists. Combining it with other chemicals enhances their biological effectiveness while reducing their dosage. The present study indicated that PPARγ is a key target for CBD, and its activation by CBD should be considered in all future studies.

Graphical abstract

Introduction

Cannabis sativa is a medicinal plant with many active compounds, including Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) (Martínez et al., 2020). Δ9-THC is a phytocannabinoid with psychoactive properties, while CBD is devoid of such properties. However, CBD has been used in the treatment of a wide range of diseases and disorders, such as psychosis, depression, epilepsy, anxiety, addiction, multiple sclerosis, cardiovascular and inflammatory diseases, rheumatoid arthritis, emesis, Parkinson’s, Alzheimer’s, and Huntington’s diseases (Melas et al., 2021; Premoli et al., 2019; Rock et al., 2012; Rudroff and Sosnoff, 2018; Stanley et al., 2013; Verrico et al., 2020). This wide range of applications suggests diverse cellular targets for CBD. Indeed, CBD has a rich pharmacology with numerous biological targets. After FDA approval of Epidiolex® for the treatment of Dravet and Lennox-Gastaut syndromes (Devinsky et al., 2017; Thiele et al., 2018) and the recent legalization of commercial hemp, CBD has gained much more attention. Its applications in the treatment of anxiety (Berger et al., 2022), post-traumatic stress disorder (PTSD) (Das et al., 2013), psychosis (Devinsky et al., 2014), cognitive dysfunction (McCartney et al., 2022), and dementia (Kłosińska and Leszko, 2022) have been reported with positive results.

It was reported that consumption of a marijuana cigarette (1 g) elevates CBD concentration up to 0.056 μg/ml in the serum (Pacifici et al., 2020). Cannabinoids and endocannabinoids (e.g., anandamide and 2-arachidonoylglycerol) act primarily on two cannabinoid receptors, the CB1 and CB2 receptors (Hajizadeh Moghaddam et al., 2013). Although CBD has little or no binding affinity for these targets (Navarro et al., 2018). So, the discovery of biological targets other than CB1 and CB2 has been pursued in many recent studies. CBD binds various receptors, including the orphan G protein-coupled receptors; GPR3, GPR6, GPR12, and GPR55 (Laun et al., 2019; Whyte et al., 2009), α2 adrenergic, (Cascio et al., 2010), dopamine D2 (Seeman, 2016), γ-aminobutyric acid type A (GABAA) (Bakas et al., 2017), adenosine A2A (Carrier et al., 2006), glycine (Ahrens et al., 2009), serotonin 5-HT1A (Galaj et al., 2020), and μ- and δ-opioid receptors (Kathmann et al., 2006). It also binds T-type (Ross et al., 2008) and l-type voltage-regulated Ca2+ channels (Isaev et al., 2022), and peroxisome proliferator-activated receptor gamma (PPARγ) (Mlost et al., 2021), and has significant modulatory effects on various transient potential (TRP) channels (Etemad et al., 2022).

PPARγ belongs to a family of nuclear receptors having three subtypes: PPARα, PPARβ/δ, and PPARγ. They participate in several cellular functions, including respiration, metabolism, differentiation, and development (Mirza et al., 2019) and serve as the main regulators of energy homeostasis and glucose and lipid metabolism. PPARγ has two distinct isoforms designated as PPARγ1 and PPARγ2. PPARγ1 is expressed in almost all tissues, while PPARγ2 is expressed almost exclusively in the adipose tissue (Ahmadian et al., 2013). Due to its different structure, PPARγ2 has 5- to 10-fold ligand-independent activation compared to PPARγ1, with an important role in effective adipogenesis (Wu et al., 2020). Several endogenous ligands for PPARγ have been identified, mainly belonging to unsaturated fatty acids, including petroselinic acid, arachidonic acid, linolenic acid, and linoleic acid (Kliewer et al., 1997). PPARγ ligands promote PPARγ heterodimer with another nuclear receptor, the retinoid X receptor (RXR). The functions of PPARγ get altered by the binding ligand shape and the presence of coactivator or corepressor proteins. When no ligand is present, PPARγ and RXR heterodimer binds with the corepressor and suppress gene transcription (Privalsky, 2004). In contrast, specific ligands lead to recruitment of the coactivator and release the corepressor that induces activation of the basal transcriptional machinery. So, PPARγ changes the expression of various genes implicated in glucose homeostasis, insulin release, lipid metabolism, inflammation, and immunity (Fig. 1) (Ahmadian et al., 2013). PPARγ activates nuclear erythroid 2-related factor (Nrf2), which provokes the expression of major antioxidant proteins such as glutathione S-transferase (GST), catalase (CAT), heme-oxygenase-1 (HO-1), and manganese-dependent superoxide dismutase (Mn-SOD) (Hussein et al., 2019; Nguyen et al., 2009). PPARγ also inhibits the transcriptional activities of several transcription factors including activator protein 1 (AP-1), signal transducer and activator of transcription (STAT), nuclear factor-kappa B (NF-kB), and cell signaling proteins, including mitogen-activated protein (MAP) kinases (Carvalho et al., 2021). NF-kB has a crucial role in the activation of various pro-inflammatory gene expressions such as tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), interleukin-1 (IL-1), IL-6, and IL-12 (Liu et al., 2017). PPARγ agonists (thiazolidinediones) such as pioglitazone and rosiglitazone are used for treating type II diabetes. However, they have been used in the treatment of various diseases such as cancer (Yee et al., 2007), Alzheimer’s disease (Sato et al., 2011), depression (Kemp et al., 2014), and rheumatoid arthritis (Ormseth et al., 2013). This wide range of clinical applications is in accordance with multiple PPARγ cellular targets that were mentioned previously.

However, thiazolidinediones may exacerbate congestive heart failure in some patients (Chaggar et al., 2009). These drugs may increase the risk of bladder cancer and bone fractures (Murphy and Rodgers, 2007; Tseng, 2014). The underlying mechanism is not well established, but it may result from activation of PPARγ. PPARγ activation alters tumor growth and progression in non-adipose cells. Its activation in bone creates an imbalance in bone remodeling, including changes in bone marrow structure and function. Thiazolidinediones may also impair bone function by reducing estrogen synthesis (Murphy and Rodgers, 2007).

CBD is an agonist of the PPARγ (Granja et al., 2012) and has little or no affinity for PPARα (D’Aniello et al., 2019). Likewise, some cannabinoids, such as THC (O’Sullivan et al., 2005) and the endocannabinoids 2-arachidonoylglycerol and anandamide, have affinities for PPARγ (Gasperi et al., 2007). CBD not only binds PPARγ but also changes its expression (Hegde et al., 2015; O’Sullivan et al., 2009). Considering the safety and tolerability of CBD in clinical practice (McCartney et al., 2022; O’Brien et al., 2022) and its growing consumption (Rapin et al., 2021), we have to expand our knowledge regarding the biological targets of CBD. Considerable evidence shows that PPARγ is a key target for CBD. Indeed, many effects of CBD can be prevented by PPARγ antagonists. Based on these findings, for the first time, we aimed to review the studies related to the interaction of CBD and PPARγ and discuss the importance of such interaction in pre-clinical and clinical studies.

Section Snippets

Search Strategy

In this comprehensive literature review, the term ‘cannabidiol’ was used in combination with the following keywords including ‘PPARγ’, ‘Alzheimer’s disease’, ‘Parkinson’s disease’, ‘seizure’, ‘multiple sclerosis’, ‘immune system’, ‘cardiovascular system’, ‘cancer’, ‘adipogenesis’. PubMed, Web of Science, Scopus, and Google Scholar were used as electronic databases. No time limitation (up to December 20, 2022) was considered in this review. The search strategy used for the present article…

CBD and PPARγ interaction in the cardiovascular system

CBD has been reported as a vasorelaxant agent that reduces mean arterial blood pressure without affecting the heart rate (Walsh et al., 2010). The vasorelaxant effect of CBD on human mesenteric arteries has been reported (Stanley et al., 2015). The respective molecular basis was investigated in the isolated rat small mesenteric arteries (sMAs) and human pulmonary arteries (hPAs) (Baranowska-Kuczko et al., 2020). The results showed that CBD promoted a full concentration- and time-dependent…

CBD and PPARγ interaction in the immune system

PPARγ expression may alter under inflammatory conditions (Wahli and Michalik, 2012). It inhibits gene expression of various pro-inflammatory mediators, including NO, IL-1β, IL-6, TNF-α, iNOS, and COX-2 via NF-κB inhibition (Liu et al., 2017). In addition, PPARγ promotes macrophage differentiation to the anti-inflammatory M2 phenotype and suppresses the pro-inflammatory M1 phenotype (Bouhlel et al., 2007). PPARγ receptor has been associated with cell apoptosis, proliferation, and reduction of

CBD and PPARγ interaction in viral infections

In recent years, CBD has received more attention as an antiviral agent. It has an antiviral effect on Kaposi’s sarcoma-associated herpes virus (Maor et al., 2012) and hepatitis C virus, but not on hepatitis B virus (Lowe et al., 2017). CBD’s anti-inflammatory and analgesic properties make it plausible for use in oral and genital herpes, shingles, and Ebola (Mabou Tagne et al., 2020). CBD also potentiated the antiviral effects of terpenes against human Coronavirus E229 (Chatow et al., 2021). A…

CBD and PPARγ interaction in cancer

Successful treatment of cancer remains one of the major problems of human health. Many studies show that CBD has beneficial effects on cancer cells both in vitro and in vivo. CBD exhibited anti-proliferative properties against colon, breast, cervix, glioma, prostate, ovary, leukemia, and thyroid cancer cells (Massi et al., 2013). The main mechanisms underlying the anticancer effects of CBD are inhibition of intercellular adhesion molecule-1 (ICAM-1)-dependent cell invasion, reduction in…

CBD and PPARγ interaction in adipogenesis

PPARγ has a crucial role in white adipose tissue adipogenesis and is considered a “master regulator” of adipogenesis (Wafer et al., 2017). Mutations within the PPARγ gene have been associated with severe lipodystrophy, insulin resistance, and diabetes in humans (Agostini et al., 2006). Considering the crucial role of PPARγ in adipogenesis, the effect of CBD on adipogenesis in human and mouse multipotent MSCs was assessed. The results revealed that CBD promoted the differentiation of MSCs and…

Conclusion and perspectives

PPARγ receptors are attractive drug targets as they modulate various physiological processes. They may offer a promising target for treating diseases such as AD due to their variable expression during selected diseases (de la Monte and Wands, 2006). PPARγ agonists are a class of anti-diabetic drugs whose applications are beyond their glucose-lowering effects; breast cancer (Yee et al., 2007), rheumatoid arthritis (Ormseth et al., 2013), high blood pressure (Piché et al., 2018), endothelial…

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The Effect of Cannabis Plant Extracts on Head and Neck Squamous Cell Carcinoma and the Quest for Cannabis-Based Personalized Therapy

Simple Summary

The survival rate of head and neck cancer has only improved slightly over the last quarter century, raising the need for novel therapies to better treat this disease. This research examined the anti-tumor effects of 24 different types of cannabis extracts on head and neck cancer cells. Type III decarboxylated extracts with high levels of Cannabidiol (CBD) were the most effective in killing cancer cells. From these extracts, the specific active molecules were recognized. Combining CBD with Cannabichromene (CBC) in a 2:1 ratio made the effect even stronger. These findings can help doctors match cannabis extracts to treat head and neck cancer. CBD extracts enriched with the non-psychoactive CBC can offer patients more effective treatment. Further research is needed to develop new topical treatments from such extracts.

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CBD & Colorectal Cancer

A collection and occasional review of research on the effects of CBD on Colorectal Cancer. Since CBD has been found to down regulate Id-1 we also include research on Id-1 and colorectal cancer. Listed below in chronological order.

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CBD & Cervical Cancer

Pre-clinical evidence

A collection and occasional review of research on the effects of CBD on Cervical Cancer. Since CBD has been found to down regulate Id-1 we also include research on Id-1 and cervical cancer. Listed below in chronological order.

These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.

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CBD & Gastric Cancer

Here we take a look at the available research and anecdotal evidence supporting the use of CBD against gastric cancer.

Pre-clinical evidence

Two in vitro studies published in 2019 show cell cycle arrest and apoptosis in gastric cancer with no effect on normal healthy cells.

Anecdotal Evidence

Phil was diagnosed with advanced, HER2-positive, stage IV gastric cancer in late 2021. In addition to herceptin, cisplatin, and xeloda, Phil took high dose CBD oil. Phil and his wife Kim were recently interviewed by “Hope For Stomach Cancer”

It’s worth mentioning that in addition to my doctor-prescribed treatments, I was using high-dose CBD on the side to help manage my symptoms. I had great success with this. I feel like some of the miraculous improvements we saw can be attributed to using CBD. 

— Phil Lago, Interview with Hope For Stomach Cancer

Phil was diagnosed in late October 2021 and started taking CBD at the end of November 2021. In March of 2022 Phil had another endoscopy with amazing results.

Phil takes approximately 200mg of high potency CBD 3 times daily.

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What is CBDV?

What is CBDV? Learn all about this newly available phytocannabinoid…what it is, who might benefit from its medicinal properties and more…

After witnessing the incredible medical benefits of cannabis in thousands of my patients, both adults and children, over the last 14 years, I feel people must know the truth about medical cannabis. It is safe, effective and well-tolerated for most who use it medically. Subscribe to my YouTube channel to learn about your endocannabinoid system, the cannabis plant and how to use cannabis as medicine.