Best CBD Oil for Lymphoma in Dogs
Are you looking for alternatives that may help manage canine lymphoma ? This article discusses CBD oil and how this product may assist your furry friend by helping alleviate its symptoms of lymphoma.
Spruce Dog CBD Oil 750mg
- Has coconut oil as carrier which is generally easier on dogs
- Has milder taste and no flavorings
- Easy to use just sprinkle on dog’s food twice daily
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Best CBD OIl For Dogs
Honest Paws Wellness Oil for Dogs
- Full Spectrum
- Contains other natural ingredients to boost immunity
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Best High Potency
Nuleaf Naturals Pet CBD Oil
- Concentrated to approximately 50mg CBD per ml of oil
- Great for cats, dogs and other four-legged friends
- Can also be used by humans
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Best High Potency
4 Corners Cannabis Pet Tincture
- Generous on their options
- Different sizes and strengths available for your needs
- The flavor peanut butter is available perfect for pets who are picky when it comes to eating
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cbdMD Pet CBD Oil Tincture for Dogs
- Uses hemp grown through organic farming methods.
- Contains CBD Oil and MCT Oil only
- With two yummy flavors
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Best CBD Oil for Lymphoma in Dogs 2022
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Compare the Best CBD for Lymphoma in Dogs for 2022
1. Spruce Dog CBD Oil 750mg
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Spruce’s dog-friendly CBD has been specially formulated for dogs. Instead of hemp seed oil for the carrier oil, the product contains coconut oil, which is generally easier on the digestion for dogs. The taste is also milder with no flavorings, making it more likely that dogs will eat it with their food.
Using Spruce CBD for dogs is simple. All owners have to do is sprinkle the desired dose on the dog’s food at mealtime once or twice a day. Each dose should consist of about two to three drops per 20 pounds of dog weight.
2. Honest Paws Wellness Oil for Dogs
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A calming full-spectrum hemp oil that combines naturally occurring CBD with other ingredients for healthy immunity, calm moods, and a healthy brain.
3. Nuleaf Naturals Pet CBD Oil
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CBD for dogs, cats and other four-legged friends! Our product is concentrated to approximately 50mg cannabinoids per milliliter of oil. While this product is designed for pets, it’s great for humans, too.
4. 4 Corners Cannabis Pet Tincture
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4 Corners Cannabis Pet Tinctures are generous on their options since there are different sizes and strengths available for you exact needs. The flavor peanut butter is available perfect for pets who are picky when it comes to eating.
5. cbdMD Pet CBD Oil Tincture for Dogs
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With nothing but MCT oil combined with CBD oil sourced from U.S. hemp that is grown using organic farming methods, these CBD Oil Tinctures for Dogs can be added to their favorite foods while still providing the same effects that you enjoy. We have two flavors to choose from: Natural and Peanut Butter.
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How CBD Helps With Lymphoma in Dogs
Cannabidiol (CBD) is a non-psychoactive drug extracted from the cannabis plant. CBD possesses anti-cancer properties (1) . These benefits may help manage lymphoma in dogs .
A review published in 2016 mentioned that cannabinoids may potentially prevent the growth and spread of cancer cells and stimulate the immune system ’s response against the disease (2) .
CBD is a cannabinoid that comes from the Cannabis sativa plant.
Some trials in the review were conducted on mice. However, one study suggested that CBD may work similarly in other animals, except insects, because the animals’ endocannabinoid system (ECS) functions similarly across all species (3) .
The ECS is located in the animal’s central nervous syste m and is responsible for regulating the body’s balance and maintaining the dog’s quality of life (4) .
The interaction of CBD with the ECS receptors in the nervous and immune systems may have various benefits . These benefits include anti-anxiety effects, anti-inflammatory properties, and potential anti-cancer effects on canines (5) .
There are different types of cancer among dogs, and lymphoma is the most common. Scientists have little understanding of what causes canine lymphoma . However, dogs are exposed to similar environmental factors that cause cancer among humans (6) .
Lymphoma is an umbrella term for any type of cancer that emerges from lymphocytes .
Lymphocytes refer to a group of white blood cells that help fight infection. Lymphocytes are located in the lymphatic system composed of the lymph nodes , bone marrow , and spleen.
Veterinarians diagnose canine cancer by taking a sample of the dog’s lymph nodes or affected organ.
Some vets may also perform staging tests to determine how much the disease has progressed. These tests include blood tests, X -rays, urinalysis, bone marrow aspiration, and abdominal sonograms.
- Multicentric lymphoma – This type of lymphoma is the most common among dogs and is characterized by the rapid enlargement of lymph nodes.
The swelling lymph nodes may grow 3 to 10 times the average size. However, they are not painful and only feel like a firm, rubbery lump under the skin.
- Alimentary lymphoma – This form of canine cancer is the second most common and usually targets the dog’s intestinal organ.
- Extranodal lymphoma – This form of lymphoma affects a specific organ like the eyes, skin, kidneys, or lungs.
Cutaneous lymphoma targets the skin and is one of the common forms of extranodal lymphoma.
Symptoms vary on the area where extranodal lymphoma occurs. For example, cutaneous lymphoma appears as raised nodules or scaly lesions on the skin, lips, or the roof of the mouth.
Extranodal lymphoma occurring in the central nervous system may cause seizures.
- Mediastinal lymphoma – This type of cancer in dogs is one of the rare forms of lymphoma. Mediastinal lymphoma affects the mediastinal lymph nodes and the thymus located between the lungs.
Dogs with mediastinal lymphoma may have difficulty breathing because of the tumor growth or fluid accumulation within the chest. Other signs include swelling of the front legs or face, extreme thirst, or urination.
Currently, the most effective cancer treatment for dogs is chemotherapy (8) . The veterinarian’s chemotherapy recommendation may vary depending on the diagnosis or type of lymphoma .
For example, dogs with multicentric lymphoma may be given the UW-25 chemotherapy protocol.
This protocol is a 25-week chemotherapy session using four chemotherapy drugs known as CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine sulfate (Oncovin), and prednisone).
Typical side effects of chemotherapy in dogs are diarrhea, mild vomiting, reduced appetite, and decreased activity levels (9) .
Benefits and Use of CBD for Lymphoma in Dogs
A study published in The Young Researcher in 2018 mentioned that CBD may be effective in inducing apoptosis (cell death) in many types of cancers , including diffuse large B-cell lymphoma (DLBCL) (10) .
The in vitro study indicated that CBD may have a strong potential to help reduce DLBCL and minimize cancer relapse. However, additional studies in vivo are needed to determine if the results are similar for dogs with lymphoma .
DLBCL is known to be the most common aggressive B-cell lymphoma affecting dogs worldwide (11) .
CBD i s known for its anti-inflammatory properties (12) . These effects may help manage multicentric, extranodal, and mediastinal lymphoma by reducing symptoms such as swelling and inflammation.
CBD also provides analgesic (anti-pain) effects (13) . Such properties may help alleviate pain associated with alimentary or extranodal lymphoma .
CBD Oil Dosage for Dogs With Lymphoma
Currently, there is no Food and Drug Administration-approved dosage guide for CBD products for the management or treatment of canine lymphoma .
However, a 2019 study performed on healthy dogs and cats stated that 2 milligrams of CBD per kilogram of body weight may be a viable dosage with no harmful side effects (14) .
A study in the American Journal of Veterinary Research examined the efficacy of repeated oral administration of CBD among healthy adult beagles (15) .
The study mentioned that doses of 1 to 12mg/kg of CBD administered once daily over 28 days are well tolerated among dogs.
Caution is advised when attempting to administer high doses of CBD in dogs. Higher CBD dosage side effects include dry mouth, drowsiness, or low blood pressure (16) .
You may start with lower doses of CBD for your dog, especially when you are still starting to use CBD for your pet.
Various factors like the dog’s size and weight may influence the CBD dose amount.
Tetrahydrocannabinol ( THC ), another cannabinoid present in some CBD products , has potentially toxic effects on canines at specific doses (17) .
Inform your veterinarian about your dog’s condition before deciding if CBD is suitable for your pet.
However, most states have laws prohibiting veterinarians from prescribing or administering cannabis -based products (18) .
How to Administer CBD for Dog Lymphoma
There are various ways for pet owners to administer CBD products to dogs with lymphoma . Here are some ways dogs may take CBD.
- CBD oil tinctures are administered sublingually or under the tongue. These tinctures usually come with a dropper or spray for easy administration of CBD to your dogs.
Sublingual administration enables the CBD oil to enter the bloodstream faster, allowing for faster absorption.
- CBD capsules are administered orally, allowing the CBD to pass through the digestive tract before being absorbed by the body.
- CBD edibles such as soft chews, biscuits, or dog treats are also administered orally. These products come in different servings, flavors, and doses.
- CBD topicals are applied to the dog’s skin. Some topicals for dogs include creams, massage oils, and balms.
How Long Does CBD Take to Help Lymphoma in Dogs ?
Onset times of CBD oil on dogs may vary based on the dosage and route administration.
Sublingual administration using an oromucosal spray or dropper allows CBD to directly enter the bloodstream under the tongue and bypass the digestive tract, leading to faster onset times.
Oral administration by ingesting edibles or capsules allows CBD to pass through the dog’s digestive tract then break down in the liver. This administration method has a slower onset time.
CBD applied topically, such as creams or lotions, may start to take effect depending on the skin thickness. Topicals usually work for skin problems or joint pains and do not get absorbed into the bloodstream.
One study stated that the thickness of the dog’s skin or absorptivity of the CBD-infused topicals may limit transdermal absorption (19) .
Transdermal delivery involves applying CBD topical through the skin so that it is slowly absorbed by the body.
Aside from dosage and administration methods, onset times of CBD products may also vary depending on the dog’s size and weight.
How Long Will CBD Help With Lymphoma in Dogs ?
A 2018 animal study showed that the elimination half-life of a 75mg dose of CBD-infused oil is 199.7 ± 55.9 minutes, while a 75mg dose of CBD micro-encapsulated capsule was at 95.4 ± 29.2 minutes (20) .
Half-life is the duration for the drug’s quantity to be decreased to 50%.
In the same study, the researchers could not ascertain the elimination half-life of 75mg of CBD transdermal creams. This result was due to the lack of an elimination phase in the concentration -time profiles.
Thus, the researchers suggest that additional trials with a more extended period of CBD administration for at least several months be conducted.
Extending the trial duration may provide a better assessment of CBD concentrations and time of effectiveness.
Side Effects and Risks of Using CBD for Lymphoma in Dogs
Some dogs taking CBD may experience diarrhea, vomiting, loss of appetite , or lethargy. Ataxia may also affect the dog’s coordination and balance, especially when CBD is ingested in large doses (21) .
Other side effects of CBD in dogs include dry mouth, drowsiness, and low blood pressure (22) . While these effects may be well tolerated among humans, the pets’ tolerance to these side effects may vary.
One study regarding the safety of increasing CBD doses conducted on beagles mentioned that dogs may tolerate CBD dose volumes of up to 640.5mg or around 64.7mg of CBD per kilogram of the dog’s body weight (23) .
The study also stated that CBD oil formulations with higher CBD content are safer and well tolerated than those with higher THC content.
CBD may inhibit the cytochrome P450 enzyme in the body. If your dog is taking other medication, CBD’s effect may limit or interfere with the drug’s metabolization.
Consider seeking advice from your veterinarian regarding your dog’s condition and medication before purchasing CBD products for your pet.
How to Shop for the Best CBD Oil for Dogs With Cancer
- Extraction method – CBD is extracted from the cannabis plant using CO 2 , ethanol, or hydrocarbon extraction.
CO 2 extraction uses liquefied CO 2 to extract CBD and other components. This method does not use combustible solvents and poses no threat of catching fire (24) .
Ethanol extraction uses ethanol to pull the CBD oil from the hemp plant .
- Cannabinoidcontent – Full-spectrum CBD oil contains all the naturally occurring cannabinoids and compounds in the cannabis plant.
These compounds include THC , terpenes , flavonoids, and fatty acids . Combining these compounds produces an entourage effect that enhances the benefits of CBD oil than when the compounds are taken individually (25) .
However, THC may cause intoxication on canines resulting in stumbling, vomiting, lethargy, agitation, or shaking (26) . Consider broad-spectrum products or isolates as alternatives for your pet.
Broad-spectrum CBD oil has the same cannabinoid content as full-spectrum without the THC .
- Certificate of analysis (COA) – B rands selling CBD products must have updated COAs accessible on their websites.
The COA shows the CBD product ’s actual cannabinoid content and the presence of pesticides and contaminants, if any.
- CBD producttype – Dog owners may choose from various CBD products depending on their preferred dosage or route of administration.
CBD oil tinctures are administered sublingually or under the tongue. Edibles like dog treats or chews are taken orally. Capsules are also administered orally. CBD topicals like creams or lotions are applied to the skin.
Legality of CBD
To date, the FDA has not provided approval for cannabis use on dogs. The agency is unable to guarantee the safety and efficacy of these products on animals (27) .
Review your local and state laws regarding the legal consumption of CBD for your dogs before purchasing pet CBD products .
Most states have legislation prohibiting veterinarians from prescribing or administering CBD for dogs (28) .
However, Nevada-based veterinarians may recommend and administer CBD products that contain less than 0.3% THC (29) .
CBD has anti-inflammatory properties (30) . These benefits may help manage the symptoms of multicentric, extranodal, and mediastinal lymphoma .
CBD also has pain relief effects (31) . Such properties may help reduce pain associated with alimentary and extranodal lymphoma .
CBD’s anti-cancer properties may help reduce diffuse large B-cell lymphoma (DLBCL) and minimize cancer relapse (32) . However, additional studies must be performed to determine if CBD may help dogs with lymphoma .
DLBCL is known to be the most common aggressive B-cell lymphoma affecting dogs worldwide (33) .
To date, there is no evidence of CBD causing canine lymphoma to worsen. However, CBD may have side effects on dogs, such as dry mouth, drowsiness, or low blood pressure (34) .
CBD products containing high levels of THC may be toxic for dogs (35) . Talk to a veterinarian about your dog’s condition and research the THC levels on CBD products before purchasing one for your pet.
CBD may interact with other medications by inhibiting the cytochrome P450 enzyme in your dog’s body . This effect may interfere with the metabolization of drugs.
Ask your veterinarian about your dog’s condition and medication before purchasing CBD products for your pet.
Currently, the most effective cancer treatment option for lymphoma in dogs is chemotherapy (36) . The type of chemo usually depends on the vet’s diagnosis and cancer type.
Currently, there are no FDA-approved doses for CBD products for managing or treating canine lymphoma .
One study mentioned that 2 milligrams per kilogram (mg/kg) of CBD may be a viable dosage for dogs with no harmful side effects (37) .
Most states have laws prohibiting veterinarians from recommending, prescribing, or administering cannabis -based products for dogs (38) .
In Nevada, veterinarians may recommend and administer CBD products that contain less than 0.3% THC (39) .
Cannabis, CBD oil and cancer
Cannabis is a plant and a class B drug. It affects people differently. It can make you feel relaxed and chilled but it can also make you feel sick, affect your memory and make you feel lethargic. CBD oil is a chemical found in cannabis.
- Cannabis has been used for centuries recreationally and as a medicine.
- It is illegal to possess or supply cannabis as it is a class B drug.
- Research is looking at the substances in cannabis to see if it might help treat cancer.
- There are anti sickness medicines that contain man-made substances of cannabis.
What are cannabis and cannabinoids?
Cannabis is a plant. It is known by many names including marijuana, weed, hemp, grass, pot, dope, ganja and hash.
The plant produces a resin that contains a number of substances or chemicals. These are called cannabinoids. Cannabinoids can have medicinal effects on the body.
The main cannabinoids are:
- Delta-9-tetrahydrocannabinol (THC)
- Cannabidiol (CBD)
THC is a psychoactive substance that can create a ‘high’ feeling. It can affect how your brain works, changing your mood and how you feel.
CBD is a cannabinoid that may relieve pain, lower inflammation and decrease anxiety without the psychoactive ‘high’ effect of THC.
Different types of cannabis have differing amounts of these and other chemicals in them. This means they can have different effects on the body.
Cannabis is a class B drug in the UK. This means that it is illegal to have it, sell it or buy it.
CBD oil, cannabis oil and hemp oil
There are different types of oil made from parts of the cannabis plant. Some are sold legally in health food stores as a food supplement. Other types of oil are illegal.
CBD oil comes from the flowers of the cannabis plant and does not contain the psychoactive substance THC. It can be sold in the UK as a food supplement but not as a medicine. There is no evidence to support its use as a medicine.
Cannabis oil comes from the flowers, leaves and stalks of the cannabis plant. Cannabis oil often contains high levels of the psychoactive ingredient THC. Cannabis oil is illegal in the UK.
Hemp oil comes from the seeds of a type of cannabis plant that doesn’t contain the main psychoactive ingredient THC. Hemp seed oil is used for various purposes including as a protein supplement for food, a wood varnish and an ingredient in soaps.
Why people with cancer use it
Cannabis has been used medicinally and recreationally for hundreds of years.
There has been a lot of interest into whether cannabinoids might be useful as a cancer treatment. The scientific research done so far has been laboratory research, with mixed results, so we do not know if cannabinoids can treat cancer in people.
Results have shown that different cannabinoids can:
- cause cell death
- block cell growth
- stop the development of blood vessels – needed for tumours to grow
- reduce inflammation
- reduce the ability of cancers to spread
Scientists also discovered that cannabinoids can:
- sometimes encourage cancer cells to grow
- cause damage to blood vessels
Cannabinoids have helped with sickness and pain in some people.
This means a cannabis based product used to relieve symptoms.
Some cannabis based products are available on prescription as medicinal cannabis. The following medicines are sometimes prescribed to help relieve symptoms.
Nabilone is a drug developed from cannabis. It is licensed for treating severe sickness from chemotherapy that is not controlled by other anti sickness drugs. It is a capsule that you swallow whole.
Sativex is a cannabis-based medicine. It is licensed in the UK for people with Multiple Sclerosis muscle spasticity that hasn’t improved with other treatments. Sativex is a liquid that you spray into your mouth.
Researchers are looking into Sativex as a treatment for cancer related symptoms and for certain types of cancer.
How you have it
Cannabis products can be smoked, vaporized, ingested (eating or drinking), absorbed through the skin (in a patch) or as a cream or spray.
CBD oil comes as a liquid or in capsules.
Prescription drugs such as Nabilone can cause side effects. This can include:
- increased heart rate
- blood pressure problems
- mood changes
- memory problems
Cannabis that contains high levels of THC can cause panic attacks, hallucinations and paranoia.
There are also many cannabis based products available online without a prescription. The quality of these products can vary. It is impossible to know what substances they might contain. They could potentially be harmful to your health and may be illegal.
Research into cannabinoids and cancer
We need more research to know if cannabis or the chemicals in it can treat cancer.
Clinical trials need to be done in large numbers where some patients have the drug and some don’t. Then you can compare how well the treatment works.
Many of the studies done so far have been small and in the laboratory. There have been a few studies involving people with cancer.
Sativex and temozolomide for a brain tumour (glioblastoma) that has come back
In 2021, scientists reported the final results of a phase 1 study to treat people with recurrent glioblastoma (a type of brain tumour that has come back). The study looked at Sativex in combination with the chemotherapy drug temozolomide.
Researchers found that adding Sativex caused side effects, which included, vomiting, dizziness, fatigue, nausea and headache but patients found the side effects manageable.
They also observed that 83 out of 100 people (83%) were alive after one year using Sativex, compared to 44 out of 100 people (44%) taking the placebo.
However, this phase 1 study only involved 27 patients, which was too small to learn about any potential benefits of Sativex. The study wanted to find out if Sativex and temozolomide was safe to take by patients.
Researchers have now started a larger phase 2 trial called ARISTOCRAT, to find out if this treatment is effective and who might benefit from it. Speak to your specialist if you want to take part in a clinical trial.
Sativex and cancer pain
There are trials looking at whether Sativex can help with cancer pain that has not responded to other painkillers.
The results of one trial showed that Sativex did not improve pain levels. You can read the results of the trial on our clinical trials website.
Cancer and nausea and vomiting
A cannabis based medicine, Nabilone, is a treatment for nausea and vomiting.
A Cochrane review in 2015 looked at all the research available looking into cannabis based medicine as a treatment for nausea and sickness in people having chemotherapy for cancer. It reported that many of the studies were too small or not well run to be able to say how well these medicines work. They say that they may be useful if all other medicines are not working.
A drug called dexanabinol which is a man made form of a chemical similar to that found in cannabis has been trialled in a phase 1 trial. This is an early trial that tries to work out whether or not the drug works in humans, what the correct dose is and what the side effects might be. The results are not available yet. You can read about the trial on our clinical trials database.
Word of caution
Cannabis is a class B drug and illegal in the UK.
There are internet scams where people offer to sell cannabis preparations to people with cancer. There is no knowing what the ingredients are in these products and they could harm your health.
Some of these scammers trick cancer patients into buying ‘cannabis oil’ which they then never receive.
You could talk with your cancer specialist about the possibility of joining a clinical trial. Trials can give access to new drugs in a safe and monitored environment.
The science blog on our website has more information about cannabis and cancer.
Cannabidiol as potential anticancer drug
Professor Daniela Parolaro, Department of Theoretical and Applied Sciences, Biomedical Division, Center of Neuroscience, University of Insubria, Via A. da Giussano 10, 21052 Busto Arsizio (VA), Italy. Tel.: +39 03 3133 9417, Fax: +39 03 3133 9459, E-mail: [email protected]
Over the past years, several lines of evidence support an antitumourigenic effect of cannabinoids including Δ 9 -tetrahydrocannabinol (Δ 9 -THC), synthetic agonists, endocannabinoids and endocannabinoid transport or degradation inhibitors. Indeed, cannabinoids possess anti-proliferative and pro-apoptotic effects and they are known to interfere with tumour neovascularization, cancer cell migration, adhesion, invasion and metastasization. However, the clinical use of Δ 9 -THC and additional cannabinoid agonists is often limited by their unwanted psychoactive side effects, and for this reason interest in non-psychoactive cannabinoid compounds with structural affinity for Δ 9 -THC, such as cannabidiol (CBD), has substantially increased in recent years. The present review will focus on the efficacy of CBD in the modulation of different steps of tumourigenesis in several types of cancer and highlights the importance of exploring CBD/CBD analogues as alternative therapeutic agents.
The endocannabinoid system: a brief overview
The endocannabinoid system (eCB) is a recently discovered signalling system comprising the cannabinoid CB1 and CB2 receptors, their intrinsic lipid ligands, endocannabinoids (eCBs), such as the N-arachidonoylethanolamide (anandamide, AEA) and the 2-arachidonoylglycerol (2-AG), and the associated enzymatic machinery (transporters, biosynthetic and degradative enzymes).
The cannabinoid CB1 and CB2 receptors are both G protein-coupled receptors: CB1 receptors are highly distributed in the central nervous system (CNS), with low to moderate expression in periphery, whereas CB2 receptors are high in the immune system, with much lower and more restricted distribution in the CNS [1, 2].
Endogenous ligands for the cannabinoid receptors were discovered soon after their characterization. The two major known endogenous ligands are anandamide (AEA) and 2-AG [3–6]. Both are arachidonic acid derivatives produced from phospholipid precursors through activity-dependent activation of specific phospholipase enzymes . Later on, a number of other eCB ligands have been discovered, including N-arachidonoyldopamine, N-arachidonoylglycerolether and O-arachidonoylethanolamine .
AEA and 2-AG do not share the same biosynthetic or metabolic pathways. Different pathways can produce AEA from the phospholipid precursor N-arachidonoyl-phosphatidylethanolamine, the most important being a direct conversion catalyzed by an N-acyl-phosphatidylethanolamine-selective phosphodiesterase. 2-AG is mainly synthesized through activation of phospholipase C and subsequent production of diacylglycerol, which is converted to 2-AG by diacylglycerol lipase. After its re-uptake, AEA is hydrolyzed by the enzyme fatty acid amide hydrolase (FAAH), producing arachidonic acid and ethanolamine, while 2-AG is primarily metabolized by monoacylglycerol lipase, leading to the formation of arachidonic acid and glycerol . Apart from their binding to CB1 and CB2 receptors, eCBs may bind to other receptors. For example, AEA may intracellularly activate the potential vanilloid receptor type 1 (TRPV1) . Moreover, other putative cannabinoid receptors are the ‘orphan’ G protein-coupled receptor, GPR55 , and the peroxisome proliferator-activated receptor, PPAR [12, 13]. However, CB1 and CB2 receptors are certainly the most known targets for AEA and 2-AG, which activate them with different affinity. AEA has the highest affinity in both cases, whereas 2-AG has the highest efficacy in both cases .
Physiological or pathological stimuli induce synthesis and release of endocannabinoids, which can subsequently activate cannabinoid receptors. Therefore eCBs are synthesized and released ‘on demand’ through the cleavage of membrane phospholipid precursors.
Multiple sclerosis and spinal cord injury, neuropathic pain, cancer, atherosclerosis, stroke, myocardial infarction, hypertension, glaucoma, obesity/metabolic syndrome and osteoporosis are some of the diseases in which alterations in the eCB system have been demonstrated, thus paving the way for new therapeutic strategies aimed at restoring normal eCB system functionality .
Currently, the term ‘cannabinoid’ refers to more than 100 terpenophenols derived from Cannabis sativa, as well as to synthetic compounds that directly or indirectly interact with cannabinoid receptors. Δ 9 -THC is the most psychoactive component of the plant Cannabis sativa, and its biological actions as well as the ones of synthetic cannabinoid compounds (synthetic compounds active on cannabinoid receptors) are primarily mediated by CB1 and CB2 receptors. Cannabinoids are further classified into phytocannabinoids (subclassified in different categories according to their chemical structures, such as Δ 9 -THC, Δ 8 -THC, cannabinol, CBD and cannabicyclol), synthetic compounds active on cannabinoid receptors (i.e. JWH133, WIN55212-2, SR141716) and endocannabinoids (i.e. AEA and 2-AG) which are produced endogenously ( Figure 1 ).
Chemical structures of Δ 9 -tetrahydrocannabinol (Δ 9 -THC), cannabidiol (CBD), anandamide (AEA) and WIN55212-2
Cannabinoids in the treatment of cancer
Cannabinoids are currently used in cancer patients to palliate wasting, emesis and pain that often accompany cancer. A significant advancement in cannabinoid use in cancer treatment came from the discovery of a potential utility of these compounds for targeting and killing cancer cells. In 1975 Munson et al.  demonstrated that the administration of Δ 9 -THC, Δ 8 -THC and cannabinol inhibited the growth of Lewis lung adenocarcinoma cells in vitro as well as in vivo after oral administration in mice. The interest in anticarcinogenic properties of cannabinoids was even renewed after the discovery of the eCB system and the cloning of the specific cannabinoid receptors. Since then, several cannabinoids have been shown to exert anti-proliferative and pro-apoptotic effects in various cancer types (lung, glioma, thyroid, lymphoma, skin, pancreas, uterus, breast, prostate and colorectal carcinoma) both in vitro and in vivo[18–26]. Moreover, other antitumourigenic mechanisms of cannabinoids are currently emerging, showing their ability to interfere with tumour neovascularization, cancer cell migration, adhesion, invasion and metastasization .
However, the clinical use of Δ 9 -THC and additional synthetic agonists is often limited by their unwanted psychoactive side effects, and for this reason interest in non-psychoactive phytocannabinoids, such as CBD, has substantially increased in recent years. Interestingly CBD has no psychotropic activity and, although it has very low affinity for both CB1 and CB2 receptors, it has been recently reported to act with unexpectedly high potency in vitro as antagonist of CB1 receptors in the mouse vas deferens  and brain  tissues. Additionally, CBD displays inverse agonism at human CB2 receptors . Moreover, other putative molecular targets of CBD are TRPV, 5-HT1A, GPR55 and PPARγ receptors (see Figure 2 ). Besides its beneficial effects in the treatment of pain and spasticity and other CNS pathologies, several reports demonstrated that CBD possesses antiproliferative, pro-apoptotic effects and inhibits cancer cell migration, adhesion and invasion.
Some of the potential biological targets of CBD
This review will focus on the most recent evidence regarding the efficacy of CBD in the modulation of tumourigenesis in several types of cancer. The data available so far are summarized in Table 1 and are discussed in detail in the following paragraphs.
Effects of cannabidiol on different types of cancer
|Cancer||In vitro effect||Receptor involvement||ROS production||Molecular cell signalling||Autophagy||Apoptosis||In vivo effect||Reference|
|Breast||↓ proliferation||CB2;||↑||NC||NC||+||↓ xenografts growth|||
|TRPV1||↓ lung metastases|
|↓ viability||non-CB1;||↑||↓ pAkt; ↑ cytochrome C||+||+||NC|||
|↓ invasion||NC||↑||↓ Id-1; ↑ pERK||NC||NC||↓ tumour growth||[27, 28]|
|↓ size and number of metastases|
|Glioma||↓ proliferation||non-CB1;||↑||↓ pERK; ↓ pAkt; ↓ HIF-1α||NC||+||↓ tumour growth||[32, 33, 36, 37]|
|partial-CB2;||↑ cytochrome C|
|↓ proliferation and invasiveness||NC||NC||NC||NC||NC||NC|||
|↓ migration||non-CB1;||NC||Ptx insensitive||NC||NC||NC|||
|Leukaemia||↓ viability||NC||NC||caspase-3 activation||NC||+||NC|||
|↓ viability||CB2||↑||↓ p-p38||NC||+||↓ tumour burden|||
|caspase activation; ↓ Bid||↑ tumour cell apoptosis|
|↑ cytochrome C|
|Lung||↓ invasion||CB1;||NC||↑ p-p38; ↑ p-ERK; ↑ TIMP-1||NC||NC||↓ lung metastases||[46, 47]|
|TRPV1||↓ PAI-1||↓ PAI-1 in xenografts|
|Thyroid thymoma||cytostatic effect||NC||NC||NC||NC||+||NC|||
|Colon||↓ proliferation||CB1;||NC||↓ Akt; ↑ 2-AG||NC||+||↓ ACF, polyps and tumours|||
NC = not checked. ↑ increase; ↓ decrease.
CBD and breast cancer
In 2006 Ligresti et al.  demonstrated for the first time that CBD potently and selectively inhibited the growth of different breast tumour cell lines (MCF7, MDA-MB-231), with an IC50 of about 6 µ m , and exhibited significantly lower potency in non-cancer cells. CBD and CBD-rich extracts (containing approximately 70% CBD together with lesser amounts of other cannabinoids) also inhibited the growth of xenografts, obtained by s.c. injection into athymic mice of human MDA-MB-231 cells, and reduced infiltration of lung metastases derived from intrapaw injection of breast carcinoma cells. Among the possible cellular and molecular mechanisms underlying these effects, CBD seemed to involve direct TRPV1 activation and/or CB2 indirect activation (via FAAH), as well as induction of oxidative stress. Later on, McAllister’s group  demonstrated that, besides proliferation, CBD also interfered with two other crucial steps of breast cancer cell progression, invasion and metastasization. Among the three different groups of cannabinoid compounds tested (phytocannabinoids with affinity for CB1 and CB2 receptors, phytocannabinoids with no appreciable affinity for CB1 and CB2 receptors and synthetic compounds with affinity for CB1 and CB2 receptors), CBD was shown to be one of the most effective inhibitors of human breast cancer cell proliferation, being equipotent to Δ 9 -THC and CP55940 in inhibiting, respectively, MDA-MB-231 and MDA-MB-436 cell growth, and being the most potent inhibitor of the MDA-MB-231 cell migration. Interestingly, CBD regulated the expression of key genes involved in the control of cell proliferation and invasion through the downregulation of Id-1 expression, an inhibitor of basic helix-loop-helix transcription factors, whose overexpression in breast cancer cells is responsible for proliferation, migration and invasion. Therefore, the ability of CBD to decrease significantly Id-1 expression in breast cancer cells was associated with its efficacy in reducing tumour aggressiveness.
Four years later, the same group  demonstrated that the observed effect of CBD on Id-1 expression was mediated by the upregulation of the extracellular signal-regulated kinase phosphorylation (pERK). Indeed, the ERK inhibitor, U0126, partially reverted CBD-induced inhibition of proliferation and invasion as well as its effect on Id-1 expression. Besides ERK upregulation, also the production of reactive oxygen species (ROS) was shown to mediate CBD-induced effects on cell proliferation and Id-1 expression, since the use of a ROS scavenger (tocopherol) reversed the aforementioned CBD effects. Moreover, these authors demonstrated that CBD was effective in reducing the primary tumour mass and the size and number of metastatic foci in vivo.
Finally, the excellent paper of Shrivastava et al.  adds fresh light on the cellular mechanism through which CBD induces cell death in breast cancer cells. These authors showed that CBD induced a concentration-dependent cell death of both oestrogen receptor-positive and oestrogen receptor-negative breast cancer cells with a mechanism independent of CB1, CB2 and TRPV1 receptor activation. Interestingly, the effective concentrations of CBD in tumour cells have little effect on non tumourigenic, mammary cells. Moreover, electron microscopy revealed morphologies consistent with the coexistence of autophagy and apoptosis, these events being promoted by the induction of endoplasmic reticulum (ER) stress and the inhibition of Akt/mTOR/4EBP1 signalling. In addition, CBD-driven increase in ROS production is fundamental to induce both apoptosis and autophagy. Examining further the cellular mechanism involved in CBD-induced cell death, they found that CBD reduced mitochondrial membrane potential, triggered the translocation of the Beclin2 interacting protein (Bid) to the mitochondria and the release of cytochrome C to the cytosol and, ultimately, the activation of the intrinsic apoptotic pathway.
Finally, the relationship between CBD-induced apoptosis and autophagic cell death was explored by blocking each form of cell death with specific inhibitors. Caspase inhibition reduced CBD-induced apoptosis and the expression of protein markers in breast cancer cells, whereas the inhibition of autophagy enhanced apoptosis as a compensatory/alternative mechanism of cell death. The apoptosis : autophagy ratio in CBD-induced cell death seemed to be mediated via Beclin1, a key signalling molecule in the autophagic process. CBD treatment induced the cleavage of Beclin1 and the subsequent translocation of the cleavage product to the mitochondria where it may induce apoptosis through the enhancement of cytochrome C release [34, 35].
As a whole this work highlights the presence of a complex balance between autophagy and mitochondria-mediated apoptosis in CBD-induced breast cancer cell death and strengthens the idea that CBD can be considered as an alternative agent for breast cancer therapy. Figure 3 shows a schematic representation of the signalling pathways associated with the effect of CBD in breast cancer cell proliferation and invasion.
Schematic representation of the signalling pathways associated with CBD effects on breast cancer
CBD and glioma
CBD also possesses anti-tumoural properties in gliomas, tumours of glial origin characterized by a high morphological and genetic heterogeneity and considered one of the most devastating neoplasms, showing high proliferative rate, aggressive invasiveness and insensitivity to radio- and chemotherapy.
After the seminal paper of Jacobsson et al.  demonstrating a serum-dependent effect of CBD upon C6 murine glioma cell proliferation, Massi et al. in 2004  reported that CBD was effective in inhibiting U87-MG and U373 human glioma cell proliferation in vitro through the induction of apoptosis. Interestingly, CBD did not affect viability of non-transformed primary glial cells . When tumour xenografts were generated in immune-deficient mice, in vivo intratumoural treatment with CBD significantly reduced tumour growth .
The anti-proliferative effect of CBD was cannabinoid and vanilloid receptors independent. The CB2 receptor antagonist SR144528 reverted the effect of CBD, but in a weak and transient manner . More importantly, this paper demonstrated for the first time that the anti-tumour effect of CBD involved the induction of oxidative stress, through increased early production of ROS, depletion of intracellular glutathione and increased GSH-associated enzymatic activity. Accordingly, the CBD anti-proliferative effect was reversed by the anti-oxidant, tocopherol. Importantly, CBD did not induce ROS production in non-transformed primary glial cells .
Among the cellular events involved in glioma cell death, CBD produced a time-dependent release of cytochrome C and activation of caspase-8, −9 and −3, suggesting the involvement of both the intrinsic and extrinsic apoptotic pathways . Marcu et al.  later confirmed the efficacy of CBD in inhibiting the growth of multiple glioblastoma cell lines in a more potent way than Δ 9 -THC. Interestingly, combined treatment of Δ 9 -THC with CBD demonstrated that CBD enhanced the Δ 9 -THC inhibitory effect on glioblastoma cell growth, but not on invasiveness . In line with this, more recently Torres et al.  confirmed that combined treatment with CBD and Δ 9 -THC greatly reduced human glioma cell viability enhancing both autophagy and apoptosis and triggering caspase-3 activation. Moreover, combined administration of submaximal doses of CBD and Δ 9 -THC reduced the growth of U87-MG cell-derived tumour xenografts in nude mice to a greater extent than treatment with the individual compounds, suggesting the potential use of combination therapy which would reduce the amount of the psychoactive Δ 9 -THC.
The synergistic effect of combined therapy implied in vitro cell cycle arrest, ROS induction and apoptosis through sustained activation of caspases-3, −7 and −9, as well as specific modulation of the extracellular signal-regulated kinase, ERK . These effects were not observed with either compound individually, indicating them as a prerogative of combination treatment. Differently from Marcu’s data , our recent results (Dr. Valenti, University of Insubria, Varese, pers. comm.)  showed that, both in U87-MG and in Δ 9 -THC-resistant T98G human glioma cell lines, CBD per se strongly down-regulates two signalling molecules crucial in tumour cell proliferation, ERK and PI3K/Akt. In addition it inhibited the hypoxia-inducible transcription factor HIF-1α, one of the most critical stimuli for cell survival, motility and tumour angiogenesis. Thus, inhibition of these three molecules appears as part of the multiple molecular targets for CBD anti-neoplastic activity .
Further biochemical analysis of glioma tumour tissues excised from nude mice treated in vivo with CBD indicated a significant decrease of activity and content of 5-LOX, as well as a marked stimulation of FAAH and a decrease of AEA content .
Besides cell growth, CBD reduced glioma cell migration  and invasiveness in a Boyden chamber test , at concentrations lower than those required to inhibit cell proliferation. The CBD anti-migratory effect was not antagonized by the selective cannabinoid receptor antagonists or by pretreatment with pertussis toxin, indicating no involvement of classical cannabinoid receptors and/or Gi/o protein-coupled receptors.
CBD seems to counteract glioma cell proliferation and invasion through multiple mechanisms, as summarized in Figure 4 .
Schematic representation of the signalling pathways associated with CBD effects on glioma
CBD and leukaemia/lymphoma
Gallily et al.  provided first evidence of a possible exploitation of CBD in the treatment of lymphoblastic diseases. They demonstrated that CBD treatment induced apoptosis, through caspase-3 activation in human acute myeloid leukaemia HL-60 cell line, whereas it had no effect on human monocytes from normal individuals.
Later on, McKallip et al. , using the murine EL-4 lymphoma cell line and the human Jurkat and Molt-4 leukaemia cell lines, demonstrated that CBD exposure led to a significant CB2 receptor-mediated decrease in the number of viable cells as well as to the induction of apoptosis, both in vitro and in vivo.
In Jurkat cells, CBD exposure resulted in the activation of caspase-8, -9, and -3, the cleavage of poly(ADPribose) polymerase and the decrease in full-length Bid, suggesting a possible cross-talk between the intrinsic and extrinsic apoptotic pathways. Moreover, exposure to CBD led to the loss of mitochondrial membrane potential and subsequent release of cytochrome C. As in other tumour cells, CBD-induced apoptosis required an increase of ROS production. Finally, CBD decreased the levels of phospho-p38 mitogen-activated protein kinase , and this effect was blocked by treatment with a CB2-selective antagonist or ROS scavenger. In addition, CBD treatment caused a significant reduction in tumour burden and increased the level of apoptotic tumours in EL-4-bearing mice .
Together, the results suggest that CBD, acting through CB2 receptors and ROS production, may represent a novel and highly selective treatment for leukaemia. Moreover, previous evidence indicated that human leukaemias and lymphomas expressed significantly higher levels of CB2 receptors compared with other tumour cell lines, suggesting that tumours of immune origin may be highly sensitive to the CB2-mediated effects of CBD .
CBD and lung cancer
Given the poor response of lung cancer to available therapy and its aggressive biological nature, a series of targets and new therapeutic strategies for their treatment are currently being investigated [47–50].
Recently, Ramer et al. [51–53] investigated the effect of CBD on the invasive properties of A549 cells, a line of human lung carcinoma cells expressing both CB1 and CB2, as well as TRPV1 receptors. Using Matrigel invasion assays, they found a CBD-driven impaired invasion of A549 cells that was reversed by CB1 and CB2 receptors as well as TRPV1 antagonists.
CBD treatment concomitantly upregulated the tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) and the CBD-elicited decrease in tumour cell invasiveness was reversed by knocking down TIMP-1 expression through a siRNA approach. These results suggest a causal link between TIMP-1 upregulation and CBD anti-invasive action. CBD was also shown to induce p38 and ERK phosphorylation as upstream mechanisms for TIMP-1 induction and subsequent decreased invasiveness. Interestingly all these cellular events were blocked by cannabinoids or TRPV1 receptor antagonists.
The significant inhibition of A549 cell invasion following CBD treatment was also accompanied by the downregulation of another important factor involved in the regulation of cell spreading, the plasminogen activator inhibitor PAI-1 . CB1 and CB2 as well as TRPV1 receptor antagonists suppressed the observed effect of CBD on PAI-1 secretion and cell invasion. Recombinant human PAI-1 and PAI-1 siRNA led to a concentration-dependent up- and down-regulation of invasiveness, respectively, suggesting a crucial role of PAI-1 in A549 invasiveness.
Additionally,in vivo studies in thymic aplastic nude mice revealed a significant inhibition of A549 lung metastases following CBD treatment  and a significant downregulation of PAI-1 protein was demonstrated in A549 xenografts of CBD-treated rats .
It is worth noting that CBD decreased invasiveness in a range of therapeutically relevant concentrations (0.01 to 0.05 µ m ), since the peak plasma concentrations of CBD in healthy volunteers following administration of Sativex™ (1:1 ratio of Δ 9 -THC and CBD) was reported to be between 0.01 µ m to 0.05 µ m .
Together, these findings provide a novel mechanism underlying the anti-invasive action of CBD on human lung cancer cells and imply its use as a therapeutic option for the treatment of highly invasive cancers.
CBD and endocrine tumours
Thyroid cancer is the most common endocrine malignancy and Ligresti et al.  demonstrated that CBD exerted anti-proliferative effects on rat thyroid KiMol cells, transformed with the v-K-ras oncogene. This effect of CBD was associated with a cell cycle block at the G1/S phase transition, as well as the induction of apoptosis.
Later on, Lee et al.  demonstrated that CBD markedly induced apoptosis in both murine thymocytes and EL-4 thymoma cells, with CBD-mediated apoptosis occurring earlier in EL-4 cells than in thymocytes. The cellular events triggered by CBD were similar in both T cells, ROS generation playing a pivotal role. The presence of N-acetyl-L-cysteine (NAC), a precursor of glutathione, markedly attenuated the induction of apoptosis and restored the diminished levels of cellular thiols.
The observation that CBD induced oxidative stress in thymocytes, EL-4 cells and splenocytes  substantiates the notion that, unlike monocytes, T cells both primary and immortalized, are all sensitive and respond similarly to CBD, with a central role of ROS generation.
CBD and colon cancer
Colon cancer is a major cause of morbidity and mortality in Western countries. A recent paper from Izzo’s group  demonstrated the chemopreventive effect of CBD in a preclinical animal model of colon cancer based on azoxymethane (AOM) administration in mice. AOM treatment was associated with aberrant crypt foci (ACF), polyps and tumour formation, as well as with the upregulation of phospho-Akt, iNOS and COX-2 and the downregulation of caspase-3. CBD was effective in reducting ACF, polyps and tumours and counteracted AOM-induced phospho-Akt and caspase-3 changes. In vitro studies, supported the beneficial effect of CBD. Indeed, in colorectal carcinoma cell lines, CBD protected DNA from oxidative damage, increased endocannabinoid concentrations and reduced cell proliferation in a CB1-, TRPV1- and PPARγ-antagonist sensitive manner.
In the light of its safety records, these results suggest that CBD might be worthy of clinical consideration in colon cancer prevention.
CBD and angiogenesis
Angiogenesis consists of the formation of new blood vessels from pre-existing ones and represents another promising therapeutic target for cancer therapy. Collectively, cannabinoids have been demonstrated to act as anti-angiogenic factors by disposing tumour cells to decrease the production of pro-angiogenic factors and/or by direct modulation of endothelial cells .
Surprisingly, so far no study has investigated the effect of CBD on angiogenesis. Our data currently awaiting publication  demonstrated that CBD potently inhibited HUVE cells proliferation, migration and invasion through the induction of endothelial cell cytostasis without triggering apoptosis. Interestingly, CBD also affected endothelial cell differentiation into tubular capillaries as well as the outgrowth of capillary-like structures from HUVEC spheroids in vitro. In addition, the anti-angiogenic properties of CBD were demonstrated also in vivo, using a matrigel sponge model. These effects were associated with down-modulation of several molecules associated with angiogenesis, including MMP2, MMP9, uPA, endothelin-1, PDGF-AA and CXCL16.
Collectively, these preliminary data demonstrate that, besides its well known pro-apoptotic anti-proliferative and anti-invasive actions, CBD may also exert anti-angiogenic effects, thus further strengthening its potential application in cancer therapy.
Conclusion and future directions
Collectively, the non-psychoactive plant-derived cannabinoid CBD exhibits pro-apoptotic and anti-proliferative actions in different types of tumours and may also exert anti-migratory, anti-invasive, anti-metastatic and perhaps anti-angiogenic properties. On the basis of these results, evidence is emerging to suggest that CBD is a potent inhibitor of both cancer growth and spread.
Interestingly, the anticancer effect of this compound seems to be selective for cancer cells, at least in vitro, since it does not affect normal cell lines. The efficacy of CBD is linked to its ability to target multiple cellular pathways that control tumourigenesis through the modulation of different intracellular signalling depending on the cancer type considered. The most common effect of CBD is the increase in ROS production that seems to be determinant for triggering its beneficial action in all the considered cancer cell types. The role of cannabinoid/vanilloid receptors in mediating CBD effects is more controversial. In some cases (lung, leukaemia, colon) a clear contribution of these receptors has been demonstrated through the use of specific antagonists, but in other cancer types (glioma and breast) their relevance appears only marginal or absent. Besides the in vitro data, the efficacy of CBD in reducing tumour growth and, in some cases, metastasization was confirmed in experimental animal models. However, the potential clinical application of CBD for cancer therapy needs some consideration. Its low toxicity is certainly a good starting point. CBD behaves as a non toxic compound; indeed oral administration of CBD 700 mg day −1 for 6 weeks did not show any overt toxicity in humans  suggesting its possible exploitation for prolonged treatment. The route of administration appears more problematic since CBD oral absorption is slow and unpredictable. However, 6 weeks of oral CBD treatment 10 mg kg −1 day −1 provoked a mean plasma concentration of CBD between 6 and 11ng ml −1 (about 0.036 µ m )  that did not differ significantly over the 6 weeks of administration. Interestingly, this range of concentration was demonstrated to be active in inhibiting lung cancer cell invasion [52, 53], thus suggesting that in some cases the oral route could be the appropriate choice. Additionally, experimental data showed that combined treatment with CBD and Δ 9 -THC could be more effective in reducing cancer cell proliferation, suggesting that the co-administration may represent a better choice for cancer therapy. Accordingly, oromucosal treatment with Sativex™ 10 mg (a formulation with a 1:1 ratio of CBD and Δ 9 -THC, recently approved for multiple sclerosis) resulted in a CBD plasma concentration of effective in reducing lung cell invasion in vitro. Thus, the results obtained with Sativex™ suggest that the use of different associations of phytocannabinoids in a variable proportion might lead to a better outcome without pharmacokinetic interaction . Moreover, oromucosal administration may represent a first choice in the presence of nausea and vomiting. Finally, the use of CBD/Sativex can be suggested in combination with classical chemotherapeutic agents to check for the presence of a synergistic effect that might potentially allow clinical chemotherapeutic dose reduction, thereby reducing toxicity while maintaining efficacy. In the light of its safety record and considering that CBD is already currently used in patients with multiple sclerosis, the findings here summarized suggest that CBD might be worthy of clinical consideration for cancer therapy.
The drug/molecular target nomenclature conforms to the BJP’s Guide to Receptors and Channels .