Cannabis and cannabinoids on treatment of inflammation: a patent review

The inflammatory process is a physiological response to a vast number harmful stimulus that takes place in order to restore homeostasis. Many drugs used in pharmacotherapy are effective to control inflammatory responses, however there is a range of adverse effects attributed to steroidal and non-steroidal anti-inflammatory drugs (NSAIDs).

In this sense, herbal medicine and derivatives gain more adepts because of their effectiveness and safety, showing the importance of medicinal plants, especially the Cannabis genus and the cannabinoid derivatives.
The aim of this prospection was to identify data related to patents involving Cannabis and cannabinoids for the treatment of inflammation.
A total of 370 patents were found, of which 17 patents met the inclusion criteria.
Although reports show synergistic effects of the plant components, patents involving Cannabis and cannabinoids focus on isolated substances (CBD e THC). However, patents related to Cannabis and cannabinoids are promising for future use of the plant or its derivatives on the treatment of inflammation.”
“Cannabis-based drugs have been shown to be effective in inflammatory diseases.”
“Cannabinoid-based drugs as anti-inflammatory therapeutics.”

The protective effects of β-caryophyllene on LPS-induced primary microglia M1/M2 imbalance: A mechanistic evaluation.

Life Sciences

“Neuroinflammation is observed as a routine characterization of neurodegenerative disorders such as dementia, multiple sclerosis (MS) and Alzheimer’s diseases (AD). Scientific evidence propounds both of the neuromodulatory and immunomodulatory effects of CB2 in the immune system. β-Caryophyllene (BCP) is a dietary selective CB2 agonist, which deserves the anti-inflammatory and antioxidant effects at both low and high doses through activation of the CB2 receptor.


In this study, we investigated the protective effects of a broad range concentration of BCP against LPS-induced primary microglia cells inflammation and M1/M2 imbalance and identifying the portion of the involvement of related signaling pathways on BCP effects using pharmacological antagonists of CB2, PPAR-γ, and sphingomyelinase (SMase).


The protective effects of BCP on LPS-induced microglia imbalance is provided by the M2 healing phenotype of microglia, releasing the anti-inflammatory (IL-10, Arg-1, and urea) and anti-oxidant (GSH) parameters and reducing the inflammatory (IL-1β, TNF-α, PGE2, iNOS and NO) and oxidative (ROS) biomarkers. Moreover, we showed that BCP exerts its effects through CB2receptors which overproduction of ceramides by SMase at middle to higher concentrations of BCP reduce the protective activity of BCP and results in the activation of the PPAR-γ pathway.


In conclusion, the low concentration of BCP has higher selective anti-inflammatory effects rather than high levels. On this occasion, BCP by modulating the microglia is able to have potential therapeutic effects in neuro-inflammation conditions and microglia cells such as MS and AD.”

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”

“Beta-caryophyllene is a dietary cannabinoid.”

β-caryophyllene and β-caryophyllene oxide-natural compounds of anticancer and analgesic properties.


Cancer Biology & Medicine

“Natural bicyclic sesquiterpenes, β-caryophyllene (BCP) and β-caryophyllene oxide (BCPO), are present in a large number of plants worldwide.

Both BCP and BCPO (BCP(O)) possess significant anticancer activities, affecting growth and proliferation of numerous cancer cells.

In addition, both compounds potentiate the classical drug efficacy by augmenting their concentrations inside the cells.

BCP is a phytocannabinoid with strong affinity to cannabinoid receptor type 2 (CB2 ), but not cannabinoid receptor type 1 (CB1 ). In opposite, BCP oxidation derivative, BCPO, does not exhibit CB1/2 binding, thus the mechanism of its action is not related to endocannabinoid system (ECS) machinery.

It is known that BCPO alters several key pathways for cancer development, such as mitogen-activated protein kinase (MAPK), PI3K/AKT/mTOR/S6K1 and STAT3 pathways. In addition, treatment with this compound reduces the expression of procancer genes/proteins, while increases the levels of those with proapoptotic properties.

The selective activation of CB2 may be considered a novel strategy in pain treatment, devoid of psychoactive side effects associated with CB1 stimulation. Thus, BCP as selective CB2 activator may be taken into account as potential natural analgesic drug.

Moreover, due to the fact that chronic pain is often an element of cancer disease, the double activity of BCP, anticancer and analgesic, as well as its beneficial influence on the efficacy of classical chemotherapeutics, is particularly valuable in oncology.

This review is focused on anticancer and analgesic activities of BCP and BCPO, the mechanisms of their actions, and potential therapeutic utility.”

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”

Identification of Psychoactive Degradants of Cannabidiol in Simulated Gastric and Physiological Fluid

“The flowering plants of the genus Cannabis, which mainly comprises the sativa and indica species, have been recognized for medical treatment for millennia.

Although Cannabis contains nearly 500 compounds from 18 chemical classes, its physiological effects derive mainly from a family of naturally occurring compounds known as plant cannabinoids or phytocannabinoids. Of the more than 100 phytocannabinoids that have been identified in Cannabis, among the most important and widely studied are its main psychoactive constituent, Δ9-tetrahydrocannabinol (Δ9-THC), and the most important nonpsychoactive component, cannabidiol (CBD). Other biologically active phytocannabinoids that have been isolated in Cannabis include Δ8-THC, cannabinol, Δ9-tetrahydrocannabivarin, and cannabidivarin.

In recent research, orally administered cannabidiol (CBD) showed a relatively high incidence of somnolence in a pediatric population. Previous work has suggested that when CBD is exposed to an acidic environment, it degrades to Δ9-tetrahydrocannabinol (THC) and other psychoactive cannabinoids. To gain a better understanding of quantitative exposure, we completed an in vitro study by evaluating the formation of psychoactive cannabinoids when CBD is exposed to simulated gastric fluid (SGF).

SGF converts CBD into the psychoactive components Δ9-THC and Δ8-THC. The first-order kinetics observed in this study allowed estimated levels to be calculated and indicated that the acidic environment during normal gastrointestinal transit can expose orally CBD-treated patients to levels of THC and other psychoactive cannabinoids that may exceed the threshold for a physiological response. Delivery methods that decrease the potential for formation of psychoactive cannabinoids should be explored.

Despite persistent challenges with dosing and administration, CBD-based therapies have a good safety profile and a potential for efficacy in the treatment of a variety of medical conditions. The rapidly evolving sciences of drug delivery and cannabinoid pharmacology may soon lead to breakthroughs that will improve access to the benefits of this pharmacological class of agents. In addition, current technologies, such as transdermal-based therapy, may be able to eliminate the potential for psychotropic effects due to this acid-catalyzed cyclization by delivering CBD through the skin and into the neutral, nonreactive environment of the systemic circulation.”

β-Caryophyllene, a phytocannabinoid attenuates oxidative stress, neuroinflammation, glial activation, and salvages dopaminergic neurons in a rat model of Parkinson disease.

“Parkinson disease (PD) is a neurodegenerative disease characterized by progressive dopaminergic neurodegeneration in the substantia nigra pars compacta (SNc) area.

The present study was undertaken to evaluate the neuroprotective effect of β-caryophyllene (BCP) against rotenone-induced oxidative stress and neuroinflammation in a rat model of PD.

The findings demonstrate that BCP provides neuroprotection against rotenone-induced PD and the neuroprotective effects can be ascribed to its potent antioxidant and anti-inflammatory activities.”

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”

Synthetic cannabinoid receptor agonists and antagonists: implication in CNS disorders.

“Since the discovery of the cannabinoid receptors, numerous studies associate the endocannabinoid system with several physiological and pathological processes including cancer, appetite, fertility, memory, neuropathic and inflammatory pain, obesity, and neurodegenerative diseases.

Over the last two decades, several researches have been dedicated extensively on the cannabinoid receptors ligands since the direct activation of cannabinoid receptors results in several beneficial effects, in the brain and in the periphery.

During past years, cannabinoid CB1 and CB2 receptor ligands from plants or lab were rapidly developed and then various new structures were reported to be cannabinoids.

The CB1 and CB2 receptor ligands offer several therapeutic opportunities for several CNS-related diseases.

Based on the scientific literature, this review provides an overview of CB1 and CB2 receptor synthetic ligands obtained from drug research and in particular those synthesized for therapeutic purposes and potential clinical applications for central nervous system disorders.”

Beyond Cannabis: Plants and the Endocannabinoid System.

“Plants have been the predominant source of medicines throughout the vast majority of human history, and remain so today outside of industrialized societies.

One of the most versatile in terms of its phytochemistry is cannabis, whose investigation has led directly to the discovery of a unique and widespread homeostatic physiological regulator, the endocannabinoid system.

While it had been the conventional wisdom until recently that only cannabis harbored active agents affecting the endocannabinoid system, in recent decades the search has widened and identified numerous additional plants whose components stimulate, antagonize, or modulate different aspects of this system.

These include common foodstuffs, herbs, spices, and more exotic ingredients: kava, chocolate, black pepper, and many others that are examined in this review.”

Harvesting the biosynthetic machineries that cultivate a variety of indispensable plant natural products.

“Plants are a sustainable resource for valuable natural chemicals best illustrated by large-scale farming centered on specific products. Here, we review recent discoveries of plant metabolic pathways producing natural products with unconventional biomolecular structures.

Prenylation of polyketides by aromatic prenyltransferases (aPTases) ties together two of the major groups of plant specialized chemicals, terpenoids and polyketides, providing a core modification leading to new bioactivities and downstream metabolic processing. Moreover, PTases that biosynthesize Z-terpenoid precursors for small molecules such as lycosantalene have recently been found in the tomato family.

Gaps in our understanding of how economically important compounds such as cannabinoids are produced are being identified using next-generation ‘omics’ to rapidly advance biochemical breakthroughs at an unprecedented rate. For instance, olivetolic acid cyclase, a polyketide synthase (PKS) co-factor from Cannabis sativa, directs the proper cyclization of a polyketide intermediate.

Elucidations of spatial and temporal arrangements of biosynthetic enzymes into metabolons, such as those used to control the efficient production of natural polymers such as rubber and defensive small molecules such as linamarin and lotaustralin, provide blueprints for engineering streamlined production of plant products.”

A pharmacological basis of herbal medicines for epilepsy.

“Epilepsy is the most common chronic neurological disease, affecting about 1% of the world’s population during their lifetime. Most people with epilepsy can attain a seizure-free life upon treatment with antiepileptic drugs (AEDs).

Unfortunately, seizures in up to 30% do not respond to treatment. It is estimated that 90% of people with epilepsy live in developing countries, and most of them receive no drug treatment for the disease. This treatment gap has motivated investigations into the effects of plants that have been used by traditional healers all over the world to treat seizures.

Extracts of hundreds of plants have been shown to exhibit anticonvulsant activity in phenotypic screens performed in experimental animals.

Some of those extracts appear to exhibit anticonvulsant efficacy similar to that of synthetic AEDs.

Dozens of plant-derived chemical compounds have similarly been shown to act as anticonvulsants in various in vivo and in vitro assays.

To a significant degree, anticonvulsant effects of plant extracts can be attributed to widely distributed flavonoids, (furano)coumarins, phenylpropanoids, and terpenoids.

Flavonoids and coumarins have been shown to interact with the benzodiazepine site of the GABAA receptor and various voltage-gated ion channels, which are targets of synthetic AEDs.

Modulation of the activity of ligand-gated and voltage-gated ion channels provides an explanatory basis of the anticonvulsant effects of plant secondary metabolites.

Many complex extracts and single plant-derived compounds exhibit antiinflammatory, neuroprotective, and cognition-enhancing activities that may be beneficial in the treatment of epilepsy.

Thus, botanicals provide a base for target-oriented antiepileptic drug discovery and development.

In the future, preclinical work should focus on the characterization of the effects of plant extracts and plant-derived compounds on well-defined targets rather than on phenotypic screening using in vivo animal models of acute seizures. At the same time, available data provide ample justification for clinical studies with selected standardized botanical extracts and plant-derived compounds.”

Phytocannabinoids for Cancer Therapeutics: Recent Updates and Future Prospects.

“Phytocannabinoids (pCBs) are lipid-soluble phytochemicals present in the plant, Cannabis sativa L. and non-cannabis plants which have a long history in traditional and recreational medicine.

The plant and constituents were central in the discovery of the endocannabinoid system, the most new target for drug discovery.

The endocannabinoid system includes two G protein-coupled receptors; the cannabinoid receptors-1 and -2 (CB1 and CB2) for marijuana’s psychoactive principle ∆(9)-tetrahydrocannabinol (∆9-THC), their endogenous small lipid ligands; namely anandamide (AEA) and 2-arachidonoylglycerol (2-AG), also known as endocannabinoids and the proteins for endocannabinoid biosynthesis and degradation such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL).

The endocannabinoid system has been suggested as a pro-homeostatic and pleiotropic signaling system activated in a time- and tissue-specific way during pathological conditions including cancer.

Targeting the CB1 receptors become a concern because of adverse psychotropic reactions. Hence, targeting the CB2 receptors or the endocannabinoid metabolizing enzyme by phytocannabinoids obtained from non-cannabis plant lacking psychotropic adverse reactions has garnered interest in drug discovery.

These pCBs derived from plants beyond cannabis appear safe and effective with a wider access and availability.

In recent years, several pCBs derived other than non-cannabinoid plants have been reported to bind to and functionally interact with cannabinoid receptors and appear promising candidate for drug development in cancer therapeutics.

Several of them also target the endocannabinoid metabolizing enzymes that control endocannabinoid levels. In this article, we summarize, critically discuss the updates and future prospects of the pCBs as novel and promising candidates for cancer therapeutics.”