cbd oil dosage for pancreatitis

Does CBD Oil Help With Chronic Pancreatitis Attacks?

The pancreas is an abdominal gland located in front of the first and second lumbar vertebrae, right behind the stomach. It is responsible for digestion and metabolizing active ingredients in food and medications with external enzymes. The pancreas is made of lobules, small ducts that come from each lobe into a bigger duct. The pancreatic duct and the common bile duct connect with each other, entering the duodenum.

A healthy pancreas guarantees that metabolic functions and digestion are optimized. Any disturbance in the organ’s health may compromise these functions and lead to an array of health conditions, including pancreatitis.

Acute pancreatitis is a disease triggered by the sudden inflammation of the pancreas or the presence of gallstones trapped in the pancreatic ducts. Either of these two causes results in an obstruction of the common duct, making it impossible for the digestive enzymes to go through the intestines.

Pancreatitis can also be chronic, which is the underlying cause of Type 1 diabetes.

CBD has remarkable anti-inflammatory properties, but is it enough to relieve the symptoms of pancreatic diseases? Or should you only use it as an adjunctive treatment?

What does science say?

Does CBD Help with Pancreatitis? (Highlights)

  • Research shows that CBD has anti-inflammatory effects on animals with acute pancreatitis (1).
  • A 2016 study reported that CBD reduced inflammation markers in the pancreas of non-obese and diabetic rats (2).
  • Another study from 2016 found that transdermal application of CBD reduced pain and inflammation in arthritic mice. Abdominal pain is one of the tell-tale symptoms of pancreatitis (3).
  • In a 2020 review, CBD was found to have anti-inflammatory and antioxidant properties. Pancreatitis patients suffer from an inflamed pancreas (4).
  • More human studies should be conducted on CBD’s potential therapeutic properties on pancreatitis.

CBD and Pancreatitis: What You Need to Know

Pancreatitis treatment aims at managing pain, especially in the upper abdomen. Doctors typically prescribe painkillers for this condition.

However, conventional pain medications may cause dangerous side effects, such as brain fog, constipation, nausea, sedation, slowed breathing, and further liver damage. Prescription painkillers are also highly addictive as the user builds a tolerance to them. This, in turn, increases the risk of an overdose.

A study published in the journal Pancreas highlighted CBD’s anti-inflammatory effects in the treatment of acute pancreatitis induced in mice with cerulein. Cerulein is a decapeptide (amino acid) involved in gastrointestinal smooth muscle movements as well as in pancreatic and gastric secretions. The authors of the study also discovered that CBD improved the pathological changes in the mice and lowered the activity of the pancreatic enzymes (5).

Acute pancreatitis occurs as a result of the sudden inflammation of the pancreas. The condition may range from mild to life-threatening. However, it is typically treatable with supportive management.

A study performed on non-obese diabetic mice in 2016 found that CBD curbed inflammation markers in the pancreas of the subjects. The research team also suggested that CBD may lower the incidence of type 1 diabetes.

The pancreas plays an important role in the management of insulin. Its inability to produce sufficient amounts of insulin may lead to type 1 diabetes. Insulin is a hormone that allows the cells to process energy-producing sugar.

In a 2019 review published in the Journal of Pancreatic Cancer, the researchers investigated CBD and THC in terms of their effects on pancreatic cancer. The authors concluded that CBD and THC had antiproliferative and proapoptotic effects in pancreatic cancer models.

In other words, these cannabinoids may inhibit the growth of cancer cells and trigger their natural mechanism for programmed death. The loss of apoptotic control is one of the reasons why cancer cells can survive for long periods.

According to the review, cannabinoids may be useful as complementary therapies for pancreatic cancer. However, it recommends further research on the anti-cancer benefits of several cannabinoids, their formulations, and dosing under clinical conditions.

CBD Oil Benefits for Pancreatitis

CBD and other cannabinoids in CBD oil are derived from cannabis plants. This is the most common type of cannabinoids that can be used to treat pancreatitis. Other types include endocannabinoids (the ones produced in the body) and synthetic cannabinoids from laboratories.

Unlike THC, the other major cannabinoid, CBD doesn’t have mind-altering effects on people who take it.

Here are the most noteworthy benefits of CBD for pancreatitis.

CBD for Pancreatitis Pain

According to the current scientific literature on CBD’s potential benefits on pain-related conditions, the cannabinoid has remarkable analgesic properties.

A 2016 study reported that a topical CBD formulation reduced inflammation and pain in mice with arthritis. The mice that took 6.2 mg and 62 mg of topical CBD gels per day demonstrated reduced swelling of the joints and improved spontaneous pain markers.

The authors also mentioned that CBD didn’t have any side effects on the subjects.

In a 2020 randomized study published in the journal Current Pharmaceutical Biotechnology, the researchers analyzed CBD oil’s effects on patients suffering from peripheral neuropathy, which causes damage to nerves outside the brain and spinal cord (9).

The study found that severe neuropathic pain was reduced in the subjects that were administered CBD. Neuropathic pain is one of the side effects of chronic pancreatitis. The authors also noted that CBD was well-tolerated and might be an effective alternative to conventional painkillers prescribed for peripheral neuropathy.

A 2018 study from the journal Transplantation Proceedings evaluated CBD’s benefits for chronic pain patients who have had a kidney transplant (10).

Seven patients took 50 mg of CBD twice daily for three weeks. They slowly increased the dosage to 150 mg of CBD twice a day.

Four patients reported a positive partial response to CBD, while two patients experienced pain improvement. One patient didn’t notice any difference in pain levels.

CBD for Liver Inflammation

Inflammation is the key player in acute and chronic pancreatitis.

A 2020 review published in the journal Antioxidants pointed to CBD as a potent antioxidant and anti-inflammatory.

A 2018 study that analyzed CBD’s effects on an in vitro (outside of living organism) model of allergic contact dermatitis showed that CBD and other phytocannabinoids changed inflammatory responses by modulating cytokine production in several experimental models of inflammation. The authors noted that CBD has potent anti-inflammatory properties (12).

Cytokines are molecules that help maintain communication between the cells of the immune system. They play an essential role during immune responses, as they signal cells towards trauma sites, infection, and inflammation.

Current research suggests that oral administration of CBD might produce anti-inflammatory effects in animal models. CBD is known to help with two symptoms of inflammation — edema, and hyperalgesia.

Edema refers to swelling caused by the excessive fluid contained in the body tissues. Hyperalgesia means the increased sensitivity to pain sensations and exaggerated response to pain.

CBD for Pancreatitis-induced Nausea

Pancreatitis is often accompanied by nausea and vomiting. As reported by a study shared in the British Journal of Pharmacology, CBD may be clinically relevant in reducing these symptoms. However, the study was referring to post-chemotherapy nausea.

A 2020 study assessed the potential benefits of continuous CBD administration on rat and shrew models. The authors found that CBD reduced vomiting in the shrews (14).

The research team mentioned that CBD’s effects against nausea were similar in male and female rodents. They suggested that CBD may be effectively used in reducing nausea and preventing vomiting in patients with chronic conditions. The subjects didn’t develop tolerance to the compound.

How CBD Works to Relieve the Symptoms of Pancreatitis?

The activation of digestive enzymes, while they’re still in the pancreas, is one of the main causes of pancreatitis. This occurrence triggers inflammation as it irritates the organ’s cells.

According to a study published in the journal Proceedings of the National Academy of Sciences of the United States of America, CBD’s anti-inflammatory benefits may stem from its ability to enhance signaling of the adenosine receptor A2A (15).

The authors of the study stated that CBD blocked the uptake of adenosine and decreased serum tumor necrosis factor — the substance that causes inflammation.

As an antagonist of the A2A adenosine receptor, CBD reverses this inflammatory response, suggesting that CBD’s mechanism of improving adenosine signaling by blocking its uptake results in lowered inflammation.

CBD delays the breakdown of adenosine from the extracellular space. Adenosine is a potent anti-inflammatory molecule that regulates immune function.

CBD’s effects on the symptoms of pancreatitis are also related to its interaction with the CB2 receptors in the immune system. On top of producing anti-inflammatory effects, CBD is also able to modulate the activity of the immune system, reducing hyperactivity without shutting it down like commonly prescribed immunosuppressants.

Pros and Cons of Using CBD for Pancreatitis

The Pros:

  • Studies show that CBD is a promising treatment for pancreatitis.
  • CBD has an excellent safety profile. It only has a few mild side effects when consumed in large doses, including dry mouth, appetite changes, dizziness, and diarrhea.
  • There is no evidence of CBD dependence on animals and humans. Therefore, the potential for substance abuse is extremely low.

The Cons:

  • There are no clinical human studies that would investigate CBD’s efficacy and safety specifically for pancreatitis.
  • CBD is not supported by the US Food and Drug Administration (FDA). CBD products are also unregulated, so there’s a risk of buying a mislabeled or contaminated product.

How to Use CBD for Pancreatitis?

To begin with, consider the method of administration. It should suit your lifestyle and dosage preferences aside from providing high bioavailability.

CBD is available in many different forms. The most common type of product is CBD oil. This liquid extract is suspended in an inert oil — MCT oil, hemp seed oil, or olive oil — for better absorption and easier dosing. The oil is taken under the tongue with a glass dropper. Holding it there for about 60 seconds allows for direct absorption into the bloodstream. The effects are usually felt within 15–30 minutes after administration.

If you dislike the taste of CBD oil, capsules are a good alternative. CBD capsules provide a fixed amount of cannabidiol per serving, which makes dosing easier and more convenient. Capsules are portable and easy-to-take; you just swallow them down with water. However, since they need to pass through the digestive system, the effects are delayed by 30–90 minutes.

CBD edibles, such as honey sticks and gummies are another decent option for on-the-go users. They are available in plenty of flavors and are considered the most enjoyable form of CBD. Similar to capsules, edibles need more time to kick in than oils.

If you’re looking for fast relief from your pancreatitis symptoms, CBD vape pens will be your best bet. A vape pen contains CBD E-liquid that you inhale whenever you need your dose. Inhalation delivers CBD to the bloodstream through the lung tissue. The effects usually come within minutes after puffing the liquid.

Last but not least, CBD topicals can be used to address localized discomfort, such as abdominal pain during pancreatitis. You can combine a topical formulation with one of the above formats for a multifaceted approach to treating your condition.

Choosing the Right Product

Studies show that cannabis extracts produce the best results when administered as a combination of CBD and THC. However, medical-grade CBD from marijuana isn’t federally legal, so people are turning to hemp-derived CBD oil.

Hemp-based products are categorized as health supplements, and as such, they are not regulated by any government agency. This, in turn, creates opportunities for fly-by-night companies to churn out mediocre to low-quality products at premium prices.

Here are a few steps to follow if you want to ensure the high-quality of your CBD oil:

  • Check the hemp source — as dynamic bio accumulators, hemp plants absorb every substance from their environment. The best CBD oils are made from hemp that has been grown organically, in clean soil, and without pesticides. They yield CBD-rich flowers, which are the perfect source material for full-spectrum extracts.
  • Opt for full-spectrum CBD — full-spectrum extracts are made from the whole plant. They contain all naturally occurring compounds in hemp, including CBD, the supportive cannabinoids, terpenes, and traces of THC. These substances help the body process CBD more efficiently due to their synergistic effects. Full-spectrum CBD is more desired than CBD isolate among users due to that mechanism.
  • Look for third-party lab reports — reputable CBD companies send samples of their products to independent laboratories for testing. These laboratories analyze the potency of CBD and check for common contaminants, such as pesticides, heavy metals, mycotoxins, and solvent residue. The results should be proven with the Certificate of Analysis (CoA) displayed on the company’s site or shared on request.

CBD Dosage: How Much to Take for Pancreatitis?

When using CBD for pancreatitis, you should check with a holistic doctor experienced in cannabis use. Doing so will help you figure out the potentially effective dosage range for your situation.

The rule of thumb is to start with a low dosage and gradually increase the amount of CBD until you achieve the desired effects. Severe cases of pancreatitis may require higher-than-average doses.

Although studies haven’t yet looked at dosing for CBD in pancreatitis patients, one clinical study has found that CBD’s effects are dose-dependent. 57 participants took different doses of CBD — 150 mg, 300 mg, and 600 mg) before taking part in a simulated public speaking test.

The subjects who took 300 mg of CBD reported a significant reduction in their anxiety levels before their test. The other groups didn’t notice considerable improvements.

The research team concluded that CBD’s efficacy follows a bell-shaped dose-response pattern. However, an Israeli study from 2015 found that the pattern doesn’t apply to full-spectrum extracts, meaning that whole-plant products may be more consistent and predictable when it comes to dosage.

Summarizing the use of CBD for Pancreatitis

Pancreatitis is a debilitating condition that can affect both humans and animals. Commonly prescribed medications for this disease may have dangerous effects in pancreatitis patients, hence the popularity of CBD as a potentially effective alternative treatment.

Studies have demonstrated that CBD might not only help with the condition itself, but also with the associated symptoms. Researchers also found that CBD may alleviate pain, inflammation, and nausea — problems experienced by people with pancreatitis.

The painkilling effects of CBD appear to be bolstered when a certain amount of THC is introduced in a formulation. For this reason, you should look for products with the full spectrum of cannabinoids and terpenes.

Before taking CBD oil for pancreatitis, we encourage you to seek medical advice among professionals. The condition can be life-threatening, and a consultation with an experienced specialist will help you find the right dosage and avoid potential CBD-induced drug interactions.

Literature:

  1. Li, Kun et al. “Anti-inflammatory role of cannabidiol and O-1602 in cerulein-induced acute pancreatitis in mice.” Pancreas vol. 42,1 (2013): 123-9. doi:10.1097/MPA.0b013e318259f6f0
  2. Lehmann, Christian et al. “Experimental cannabidiol treatment reduces early pancreatic inflammation in type 1 diabetes.” Clinical hemorheology and microcirculation vol. 64,4 (2016): 655-662. doi:10.3233/CH-168021
  3. Hammell, D C et al. “Transdermal cannabidiol reduces inflammation and pain-related behaviors in a rat model of arthritis.” European journal of pain (London, England)vol. 20,6 (2016): 936-48. doi:10.1002/ejp.818
  4. Atalay, Sinemyiz et al. “Antioxidative and Anti-Inflammatory Properties of Cannabidiol.” Antioxidants (Basel, Switzerland) vol. 9,1 21. 25 Dec. 2019, doi:10.3390/antiox9010021
  5. Sharafi, Golnaz et al. “Potential Use of Cannabinoids for the Treatment of Pancreatic Cancer.” Journal of pancreatic cancer vol. 5,1 1-7. 25 Jan. 2019, doi:10.1089/pan can.2018.0019
  6. Lehmann, C. op. cit.
  7. Sharafi, Golnaz et al. “Potential Use of Cannabinoids for the Treatment of Pancreatic Cancer.” Journal of pancreatic cancer vol. 5,1 1-7. 25 Jan. 2019, doi:10.1089/pan can.2018.0019
  8. Hammell, D C. op. cit.
  9. Sharafi, Golnaz et al. “Potential Use of Cannabinoids for the Treatment of Pancreatic Cancer.” Journal of pancreatic cancer vol. 5,1 1-7. 25 Jan. 2019, doi:10.1089/pan can.2018.0019
  10. Xu, Dixon H et al. “The Effectiveness of Topical Cannabidiol Oil in Symptomatic Relief of Peripheral Neuropathy of the Lower Extremities.” Current pharmaceutical biotechnology vol. 21,5 (2020): 390-402. doi:10.2174/1389201020666191202111534
  11. Shafari, G. op. Cit.
  12. Cuñetti, L et al. “Chronic Pain Treatment With Cannabidiol in Kidney Transplant Patients in Uruguay.” Transplantation proceedings vol. 50,2 (2018): 461-464. doi:10.1016/j.transproceed.2017.12.042
  13. Petrosino, Stefania et al. “Anti-inflammatory Properties of Cannabidiol, a Nonpsychotropic Cannabinoid, in Experimental Allergic Contact Dermatitis.” The Journal of pharmacology and experimental therapeutics vol. 365,3 (2018): 652-663. doi:10.1124/jpet.117.244368
  14. Rock, Erin M et al. “Evaluation of repeated or acute treatment with cannabidiol (CBD), cannabidiol acid (CBDA) or CBDA methyl ester (HU-580) on nausea and/or vomiting in rats and shrews.” Psychopharmacology vol. 237,9 (2020): 2621-2631. doi:10.1007/s00213-020-05559-z
  15. Carrier, Erica J et al. “Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression.” Proceedings of the National Academy of Sciences of the United States of America vol. 103,20 (2006): 7895-900. doi:10.1073/pnas.0511232103
Livvy Ashton

Livvy is a registered nurse (RN) and board-certified nurse midwife (CNM) in the state of New Jersey. After giving birth to her newborn daughter, Livvy stepped down from her full-time position at the Children’s Hospital of New Jersey. This gave her the opportunity to spend more time writing articles on all topics related to pregnancy and prenatal care.

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Can CBD Help Pancreatitis in Dogs?

Pancreatitis in dogs is common, in fact, nearly 50 percent of dogs and cats with pancreatic issues will develop pancreatitis in their lifetime. When left untreated, this can lead to serious illness, pain, and can even be fatal. However, recognizing the signs of pancreatitis early and starting with a holistic regimen can better your pet’s chances of living a long, healthy life.

The pancreas is part of both the digestive and endocrine systems and is needed for the digestion of food, production of enzymes, and creation of insulin. Needless to say, this organ is vital for a fully balanced body. But, dangerous side effects of prescription medications for pancreatitis may throw the body even further out of balance, which is why so many pet parents are turning to holistic treatments to ease their pup’s pancreatic problems.

Table of Contents

What is Pancreatitis?

The pancreas is the organ responsible for producing important enzymes that allow the body to absorb fats and other nutrients from food, and the pancreas is important in the process of digestion. Pancreatitis is inflammation of the pancreas.

Normally, pancreatic enzymes are in an interactive state and travel to the small intestine, where they are activated to begin the digestion process. But, in cases of pancreatitis, the enzymes are released and activated prematurely and don’t reach their target. This results in the pancreas effectively digesting itself and surrounding organs. When the pancreas in inflamed, digestive enzymes can also escape into the abdominal cavity which causes damage to the pancreas, intestines, and other surrounding organs and tissue.

There are two types of pancreatitis in dogs: acute and chronic. Acute means that the symptoms present quickly, with no prior warning or build-up. Chronic means that the condition builds and worsens over a longer period of time. Both types can be extremely painful for your dog, but acute may be more noticeably painful because of the sudden onset. Within these two types, there are also two degrees of pancreatitis: mild and severe. Both acute and chronic pancreatitis can be mild or severe.

What Causes Pancreatitis in Dogs?

There are several causes of pancreatitis in dogs, including obesity, diabetes, hypothyroidism, hypocalcemia, bacterial or viral infections, gastric tract diseases, abdominal trauma, genetic disposition, toxins, prescription medications, scorpion stings, and ingestion of too many high-fat meals. Dogs who have epilepsy may also be at higher risk of pancreatitis. Small breeds like the miniature schnauzer, miniature poodle, and cocker spaniel are at higher risk of pancreatitis.

What are the Symptoms of Pancreatitis in Dogs?

The severity of symptoms depends on whether the case is mild or severe. These symptoms do not all have to be present, but may include:

  • Fever
  • Vomiting
  • Diarrhea
  • Loss of appetite
  • Weight loss
  • Dehydration
  • Fatigue and sluggishness
  • Mild to severe abdominal pain
  • Depression
  • Increased heart rate
  • Difficulty breathing

What Should I Do if My Dog Has Pancreatitis?

If you suspect that your dog has pancreatitis, you should take them to your holistic veterinarian right away. Because it is a very serious condition that can often be mistaken for a different issue, you should be sure to ask your veterinarian to test for pancreatitis.

Your veterinarian may run a variety of tests and may first check for gallstones and reflux. An x-ray, radiograph, ultrasound, and blood work will be able to test for elevated enzymes and trauma to the pancreas and surrounding organs. The vet may also test insulin levels because the pancreas can impact the production of insulin in the body.

Often a veterinarian will prescribe pain management options since there is no fast, easy way to fix the issue. They may want to do IV fluid therapy, medication to help prevent vomiting and dehydration, monitoring of fat intake, and anti-inflammatory medications. It should be noted that, as with any medication, there may be dangerous side-effects.

Can My Dog Die From Pancreatitis?

When left untreated, pancreatitis can be fatal. It can also cause severe organ damage and brain damage. However, pancreatitis can be prevented and with proper treatment, permanent organ damage can be avoided.

Does CBD Oil Help with Pancreatitis in Dogs?

Full spectrum hemp extract – known commonly as “CBD oil” – is a safe and effective way to treat inflammation and manage pain associated with pancreatitis. It is also effective in preventing inflammation from building up in healthy dogs.

A study published in 2006 in Current Neuropharmacology also states that CBD has therapeutic benefits for both people and pets suffering from chronic pain and acute chronic pain episodes. They concluded that compounds found in cannabis reduce inflammation. In fact, the most abundant phytocannabinoid in cannabis, CBD, has strong anti-inflammatory properties, while CBC, CBG, and THCV have also demonstrated anti-inflammatory properties. Cannabinoids act as anti-inflammatory agents by inducing apoptosis, inhibiting of cell proliferation, suppressing cytokine production, and inducing T regulatory cells.

What does that mean for your dog? Less inflammation and less pain.

Full spectrum hemp extract can also help treat nausea and GI pain associated with pancreatitis. CBD is also helpful in regaining a pet’s appetite. Research published in Nutraceuticals in Veterinary Medicine states that CBD interacts with the endocannabinoid system in dogs to treat cancer, improve sleep, prevent obesity and metabolic diseases, resolve anxiety and stress, treat inflammatory conditions, improve pulmonary and cardiac conditions, and acts as a neuro-protectant.

Dosing CBD for Pancreatitis in Dogs

Our EASE tincture is a 500 mg Full Spectrum Hemp Extract, formulated with turmeric and frankincense to specifically help with inflammatory issues. Based on research and our experience, we recommend starting with 9-18 mg (equal to 1-2 mL of our EASE tincture) daily. Because every dog reacts differently, you may find that your dog responds better to a higher or lower dosage. You should note that dogs cannot overdose on CBD, as it is safe even in extremely high doses.

For the fastest and most thorough absorption, lift the lip and apply dose directly onto the gums. If added to food, the medicine may not be as effective. It can take significantly longer (30-45 min.) to reach the bloodstream as it works its way through the gastrointestinal system.

Split the recommended daily dosage into smaller doses throughout the day (micro-dosing) for best absorption and to keep it in the bloodstream. It will stay in the bloodstream for about 6-8 hours, and peaks at 2 hours. Make sure to shake the bottle before each use and always keep away from heat.

Preventing Pancreatitis in Dogs

One of the most important things that can help prevent or treat pancreatitis is a pet’s gut health. Inflammation of the pancreas disrupts normal functions, such as blood sugar levels and producing the digestive enzymes that are necessary for nutrient digestion and absorption. Poor quality diets, processed food high in carbohydrates, cooked fats, and drugs (especially steroids) contribute to the epidemic of chronic, recurring pancreatitis. Carbohydrates contribute to inflammation and a low-fat diet contributes to pancreatic and kidney stress.

We recommend changing your pet’s diet to raw or freeze-dried, to get their gut health in check. A species-appropriate, nutritionally balanced, raw food diet is preferred for treatment of pancreatic disease in pets. However, a raw diet does not have to be pre-packaged. You can feed your dog many of the foods that you already buy for yourself. You can learn more about how to feed raw by listening to my podcast, It’s a Dog’s Life.

About Angela Ardolino

Angela Ardolino is a holistic pet expert who has been caring for animals for over 20 years and operates a rescue farm, Fire Flake Farm, in Florida. She is also the owner of Beautify the Beast, a natural pet salon and shop. After getting her certificate in Medical Cannabis Biology and Therapeutic use from the University of Vermont School of Medicine, she founded CBD Dog Health to provide high quality, all-natural medical cannabis products designed specifically for pets.

Potential Use of Cannabinoids for the Treatment of Pancreatic Cancer

Department of Surgery, University of Melbourne, Austin Health, Melbourne, Australia.

Hong He

Department of Surgery, University of Melbourne, Austin Health, Melbourne, Australia.

Mehrdad Nikfarjam

Department of Surgery, University of Melbourne, Austin Health, Melbourne, Australia.

Abstract

Background: Cannabinoid extracts may have anticancer properties, which can improve cancer treatment outcomes. The aim of this review is to determine the potentially utility of cannabinoids in the treatment of pancreatic cancer.

Methods: A literature review focused on the biological effects of cannabinoids in cancer treatment, with a focus on pancreatic cancer, was conducted. In vitro and in vivo studies that investigated the effects of cannabinoids in pancreatic cancer were identified and potential mechanisms of action were assessed.

Results: Cannabinol receptors have been identified in pancreatic cancer with several studies showing in vitro antiproliferative and proapoptotic effects. The main active substances found in cannabis plants are cannabidiol (CBD) and tetrahydrocannabinol (THC). There effects are predominately mediated through, but not limited to cannabinoid receptor-1, cannabinoid receptor-2, and G-protein-coupled receptor 55 pathways. In vitro studies consistently demonstrated tumor growth-inhibiting effects with CBD, THC, and synthetic derivatives. Synergistic treatment effects have been shown in two studies with the combination of CBD/synthetic cannabinoid receptor ligands and chemotherapy in xenograft and genetically modified spontaneous pancreatic cancer models. There are, however, no clinical studies to date showing treatment benefits in patients with pancreatic cancer.

Conclusions: Cannabinoids may be an effective adjunct for the treatment of pancreatic cancer. Data on the anticancer effectiveness of various cannabinoid formulations, treatment dosing, precise mode of action, and clinical studies are lacking.

Introduction

Pancreatic cancer is the fourth major cause of cancer death and is likely to become the second major cause of cancer death after lung cancer by 2030, with an urgent need to improve treatment outcomes. 1,2 There has been interest in the use of cannabinoids for the treatment of chemotherapy-related side effects such as cachexia, lethargy, and nausea, but their potential use as an anticancer agent is not well supported. 3,4 Cannabinoids can be classified into plant-derived, endocannabinoids and synthetic groups. 5

Plant-derived cannabinoids are largely the product of Cannabis sativa and Cannabis indica plant species. 6 There are more than 60 phytocannabinoid entities found in cannabis plant extracts, among which there are currently two of main clinical interest: cannabidiol (CBD) and tetrahydrocannabinol (THC). 7,8 Endocannabinoids are endogenous cannabinoids that include anandamide (AEA) and 2-arachidonoylglycerol (2-AG), involved in a variety of physiological and cognitive processes. Several synthetic cannabinoid compounds have been produced such as the aminoalkyl indole derivative WIN-55 that mimics THC and JWH-133, a potent CB2 receptor agonist that has anti-inflammatory effects. Pre-clinical studies have shown that certain synthetic cannabinoids also have antiangiogenic and antitumor effects. 5,9,10

Methods

A literature review of studies reporting on the cannabinoids in cancer treatment was undertaken with a focus on pancreatic cancer. An electronic search was conducted in PubMed, MEDLINE, EMBASE, and Web of Science for articles published from November 1961 until September 2018. References of relevant literature were reviewed to identify additional studies. In vitro and in vivo studies that have investigated the effects of cannabinoids in pancreatic cancer, including potential mechanisms of action and signaling pathways, were assessed.

Results and Discussion

Cannabis plants

Cannabinoids are compounds extracted from two types of plants, C. sativa and C. indica. Cannabis plants contain more than 400 chemical compounds, over 60 of them are phytocannabinoid entities, including delta-8-THC (d8-THC), cannabinol (CBN), cannabicyclol (CBL), cannabichromene (CBC), and cannabigerol (CBG);although THC and CBD are recognized as the two main substances, THC, CBD, and CBN have mostly been used in different studies. 8,11–13 These plants can be differentiated by their physical characteristics, C. indica has a short and dense plant structure with dark green leaves, while C. sativa is a tall and skinny plant with pale green appearance. 14,15

The C. sativa plants are also categorized into industrial hemp plants and medicinal plants. Hemp plants are grown for fiber and seed oil production, animal feed, and for their high nutritional value. 6 Both plants contain the THC, but medicinal plants generally have a higher content of THC that is concentrated in the plant resin glands. 16–18 Hemp plants are known to contain low resin levels, while medical plants are high in resin levels that cover the female’s flowering tops and leaves. The THC concentration in flowering tops is significantly more than other parts of the plant. 16,17,19 In addition, studies reveal that the THC:CBD ratio in C. sativa is generally higher than C. indica. Therefore, the euphoric and relaxing effects, after using C. sativa, are likely to be greater than with C. indica. 15,16

Cannabinoid receptors

The bodies’ endogenous opioid and cannabinoid systems have remained unchanged for more than 500 million years of human evaluation. 17 The endogenous cannabinoid system contains endocannabinoids, cannabinoid receptors, second messengers, and anabolic and catabolic enzymes such as the fatty acid amide hydrolase (FAAH) system. 17,20,21 Cannabinoid receptors located on cell membranes are members of the G-protein-coupled receptor (GPCR) family. 22,23 Cannabinoid receptor-1 (CB1) is found in moderate levels mainly in the brain and neural tissues and in lower levels in respiratory, digestive, and reproductive systems and urinary tracts. 22,24 It is mainly responsible for the psychological impacts of THC. 18,25

Cannabinoid receptor-2 (CB2) is mainly found in peripheral organs, specifically rich in thymus, tonsils, and spleen of immune system. 9,26,27 CB2 sequence appears more preserved between species than CB1 receptor. Furthermore, there is a third putative human cannabinoid receptor, G-protein-coupled receptor 55 (GPR55). 21 Studies have shown that malignant cells can alter the physiologic function of GPR55 and other GPCRs to enhance tumor growth and metastasis. 28,29 The endocannabinoids, 2-AG and AEA, are among the main endogenous cannabinoids that stimulate CB1, CB2, and GPR55, and also act on transient receptor potential ion channels, including transient receptor potential vanilloid (TRPV). 20,21,24

There are emerging data on other potential cannabinoid receptors, but to date, CB1, CB2, and GPR55 are considered the main cannabinoid targets. 30

THC and CBD and their effects on cancer

THC is responsible for most of the psychological effects of cannabis. 31 THC was first discovered to inhibit the growth of lung adenocarcinoma cells in vitro and in vivo. 5 THC binds to activate cannabinoid receptors, predominantly CB1 contained at high concentrations in specific brain regions associated with emotions, thinking, perception, memory, and coordination. 32 THC works like the AEA neurotransmitter that is produced in the body to regulate perception of pain, eating, and sleeping habits. Except for the initial relaxed state, it can bring about anxiety, delusions, hallucinations, and emotions of happiness. Its effects begin immediately or 30 min after consumption, depending on the route of administration. 33

CBD refers to that main cannabis compound with desirable medical characteristics, without the stoning effects. 31 The discovery of CBD was in 1940, which is more than 20 years earlier than THC. 34 It simulates cannabinoid (CB1 and CB2) receptors indirectly, 35 and also involves several other receptor pathways that include but are not limited to TRPV1, GPR55, and peroxisome proliferator-activated receptors. 21,36 CBD in particular increases the susceptibility of tumor cells to the lymphokine-activated killer cells, which can result in cell lysis. 37

Cannabis rich in CBD is less psychoactive than those rich in THC. Dominant CBD strains are more suitable for applications in relieving spasms and pain, psychosis, anxiety, inflammation, and some other conditions, with lesser effects on lethargy and lower likelihood of causing dysphoria. 38 It can be of value in treating depression and some side effects that result from cancer treatment. 39 Overall, CBD is preferred for medical applications and has fewer health risks compared with THC and is useful in negating some of the adverse effects of THC. 36,40

Mechanism of action

In vitro models for different cancer types have been utilized to elucidate mechanisms by which these cannabinoids and endocannabinoids influence the proliferation, migration, and apoptosis of cancer cells. 5 The mechanisms to affect cancer cell proliferation, migration, and apoptosis by cannabinoids are complex and can differ between cancer types. 41–43 They can also inhibit tumor vascularization by altering the morphology of blood vessels and reducing blood vessel proangiogenic factors, including vascular endothelial growth factor. 42,43

Cannabinoids stimulate the production of ceramides by activation of ceramide synthase enzyme, 44 which causes a downstream activation of a cascade that signals through the extracellular regulated kinase (ERK) system leading to cell cycle arrest and apoptosis. When CB1 and CB2 receptors are activated, the stress-regulated protein p8 controls the activating transcription factor 4 (ATF-4), C/EBP-homologous protein (CHOP), and tribbles homologue3 (TRB3) expression. The ceramide-ERK signaling pathway is triggered to promote mitochondrial intrinsic apoptosis via mechanisms that have not yet been recognized. 45 An increase in ceramide can also activate the p38 mitogen-activated protein kinase pathway leading to apoptosis through several mechanisms. 10,42,46

Activation of CB1 or CB2 receptors can also inhibit the activity of adenylyl cyclase and decreases the levels of cyclic adenosine monophosphate 47 and the activation of protein kinase A. As a result, there is a decrease in gene transcription causing apoptosis. 41 Activation of cannabinoid receptors can also promote cancer cell survival and inhibit apoptosis through PI3K/PKB pathways, implicated in cell survival. 48

Effects of cannabinoids on pancreatic cancer

Effects of cannabis receptors

Studies showed that CB1 and CB2 receptors are expressed in pancreatic cancer cells and have very low or nondetectable mRNA levels in normal pancreatic cells. 49 In a study by Michalski et al., 49 the effects of cannabinoids in pancreatic cells were investigated, with identification of cannabinoid receptor expression in several human pancreatic cancer cell lines and human pancreatic cancer biopsies. These results indicated that activation of cannabinoid receptors, particularly CB2, may induce pancreatic cancer cell apoptosis without affecting the normal pancreas cells.

Michalski et al. also evaluated cannabinoid receptors together with the endocannabinoid metabolizing FAAH and monoacylglycerol lipase (MGLL) enzymes in both normal (n:10) and pancreatic cancer cells from patients with resected pancreatic ductal adenocarcinoma (n:40). Immunohistochemistry staining showed that immunoreactivity for FAAH and MGLL was low in healthy human pancreatic cells, as well as islets and nerves when compared with the immunoactivity for FAAH and MGLL in pancreatic cancer tissues, although low levels of these enzymes in pancreatic cancer cells were correlated with shorter survival.

Wide intrapancreatic nerves were found to be immunoreactive for FAAH and MGLL. In addition, there was a correlation between low CB1 receptor expression and prolonged survival for patients with pancreatic cancer. CB2 receptor expression did not correlate with survival. The levels of endocannabinoids AEA and 2-AG in serum of patients with pancreatic cancer cells in comparison with normal controls were similar. 49

In vitro studies

Cytotoxic effects of cannabis in vitro occur through cannabinoid receptor-dependent and cannabinoid receptor-independent mechanisms. 50,51 A study by Fogli et al. showed that cannabis receptor binding by synthetic receptor agonists, WIN-55,212-2 (CB1 and CB2), ACEA (CB1), and JWH-015 (CB2), caused a substantial cell death of MiaPaCa-2 cell. 52 The authors also demonstrated that the CB1 inverse agonist (AM251) induced apoptosis and affected transcriptional genes via the JAK/STAT and MAPK signaling network in MiaPaCa2 pancreatic cancer cells, acting through CB1 receptor-independent pathways. 52 In addition, AM251 synergically increased the anticancer effect of pyrimidine analog chemotherapy agent, 5-fluorouracil. 52

It is possible, however, that these agents have CB1 agonistic effects at higher concentrations, in keeping with findings reported for a structurally similar ligand, SR141716A. 53,54

The CB1 and CB2 selective agonists, arachidonylcyclopropylamide (ACPA) and GW, inhibited proliferation and invasion of Panc1 cells, respectively. 55 ACPA and GW through activating the CB1 and CB2 receptors stimulated 5′ adenosine monophosphate-activated protein kinase activation via a reactive oxygen species (ROS)-dependent escalate of AMP/ATP ratio, causing cell autophagy and cell growth inhibition. 55,56

Ceramide synthesized by de novo synthesis was found to be involved in the apoptosis of pancreatic cancer cells induced by THC. 57 THC has been shown to cause a dose-dependent reduction in cell viability by inducing apoptotic cell death. 58 The stress-regulated protein p8 was involved in the apoptosis of pancreatic cancer cells caused by THC. This protein has been shown to increase with ceramide treatment and has powerful antitumor effects. 59 There was an increase in p8 mRNA levels in MiaPaca2 pancreatic cancer cells treated with THC, which was blocked by a potent antagonist of CB2 (SR144528). Knockdown of p8 mRNA prevented apoptosis induced by THC in MiaPaCa2 cells. 59

Furthermore, several p8-dependent genes, including the endoplasmic reticulum (ER) stress-related gene TRB3 (a novel ER stress-inducible gene), CHOP, and ATF-4, were identified and associated with apoptotic signaling. The mRNAs of TRB3, CHOP, and ATF-4 were increased to a similar degree as p8 by THC treatment. 45 Moreover, removing the p8 mRNA prevented upregulation of TRB3, CHOP, and ATF-4. THC induced a p8- and ceramide-mediated apoptotic response in pancreatic cancer cells through upregulation of these genes. 45

The combination of gemcitabine and cannabinoid receptor agonists in the treatment of pancreatic cancer enhanced intracellular production of ROS, resulting in antiproliferative effects. Gemcitabine stimulated the mRNAs of both CB1 and CB2 via an NF-κB-mediated mechanism. 60 Nuclear factor-kappaB (NF-κB) inhibitors, MG12 and BAY, blocked gemcitabine-stimulated increase of either CB1 or CB2 mRNAs, while interleukin (IL)-1, an inducer of NF-κB, increased the expression of CB1 and CB2. 60 Gemcitabine also plays a part in cannabinoid-induced ER stress and antiproliferation. 60 Cannabinoid-induced autophagy was enhanced by gemcitabine through ROS-mediated mechanism. 60 In addition, cannabinoids substantially increase the apoptotic effect of gemcitabine. 60

A recent study showed that the GPR55 receptor, regulated by tumor suppressor p53, may have a crucial role in pancreatic cancer development, via cell cycle regulation and MAPK signaling pathways. 61 CBD binds to the GPR55 receptor and blocks its activity. Cell growth, cell cycle progression, and MAPK signaling in ASPC1, HPAFII, BXPC3, and PANC1 pancreatic cancer cell lines were inhibited by treatment with the GPR55 antagonist CID16020046 (CID) and CBD. Moreover, HPAFII and PANC1 cell growth was reduced to a greater extent with the combination of CBD and gemcitabine, compared with either treatment alone. 61 This study demonstrated that the gemcitabine effects on pancreatic cancer cells might be potentiated by inhibition of GPR55.

In vivo studies

Pre-clinical studies on various cancers have shown that synthetic exogenous, endo-, and phytocannabinoids decrease angiogenesis, growth, and tumor cell migration and induction of apoptosis in cancer cells. 9,62 The antitumor effects of cannabinoids were also investigated in in vivo models of pancreatic cancer. Xenografted MiaPaca2 pancreatic tumor growth was inhibited by THC (15 mg/kg/day) treatment. 58 The pancreatic tumor growth in an orthotropic model was also inhibited by the synthetic cannabinoid receptor agonist WIN55212,2. 49 WIN55212,2 also induced apoptosis in pancreatic cancer cells through possibly the activation of TRB3, which is a proapoptotic protein responsible for the apoptosis induced by ER stress.

WIN55212,2 increased the expression of downstream ER stress-related targets involved with apoptosis in pancreatic cancer but not in healthy pancreatic cells, indicating that cannabinoid stimulates apoptosis selectively in pancreatic cancer cells. 58

The route of cannabinoid administration has significant effects on pharmacokinetics, bioactivity, bioavailability, and effectiveness of drugs. Cannabinoids are water insoluble and cannot be administered intravenously. In addition, cannabinoids are partially degraded by the stomach acids; as a result, oral administration may not be the most effective route for cancer treatment. 63 The inhalation route of cannabinoids combined with nanomaterials may be useful for targeting lung cancer, but the effectiveness in treating other sites is less certain. 64 Intratumor (IT) administration of low doses of cannabinoids enhances the effectiveness of drug. 4,65,66

A study by Yasmin-Karim et al. revealed that a superior pancreatic cancer treatment outcome could be achieved using the combination of cannabinoids and radiotherapy. 7 Similar findings have been demonstrated in a brain glioma cancer model. 67 Improved survival was also demonstrated with IT administration of cannabinoids into subcutaneously implanted murine PANC-02 pancreatic cancers measuring 6 mm in maximum dimension. 7 Furthermore, treating Kras, P53, and Cre mice with a combination of CBD (100 mg/kg) by daily intraperitoneal (IP) administration and gemcitabine (100 mg/kg) by IP administration every 3 days, IP after 80 days of age prolonged the animal survival three times more than vehicle or gemcitabine treatment alone. 61

Similar findings were shown in a study by Donadelli et al., in which a CB1 binding ligand SR141716 (SR1) combined with gemcitabine reduced tumor growth greater than either agent alone. 60 Based on their in vitro finding, the authors found that an increase in ROS and autophagy pathways may explain the observed synergistic effects in vivo. 60 SR1 has been utilized as an antiobesity agent and is considered a reverse agonist that possessed agonist activity at higher concentrations. 53 The use of SR1 as an anticancer agent in the clinical situation is, however, unknown, as the drug has been withdrawn from the worldwide market due to unacceptable psychiatric side effects.

Effects of cannabis on pancreatic stellate cells

Pancreatic stroma contains pancreatic stellate cells (PSCs), immune cells, neural elements, extracellular matrix, and blood vessels. 68 Interaction of PSCs and cancer cells enhances tumor invasion, growth, chemoresistance, and immunosuppression. 69 PSCs migrate to damaged sites and induce differentiation and tissue repair promoting fibrosis. 70 Activation of cannabinoid receptors using WIN55212,2 reduces the migration of PSCs derived from chronic pancreatitis. 70 This reduction in migration could be related to a reduction production of extracellular matrix and inflammatory cytokines, including IL-6, MCP-1, fibronectin, collagen 1, and α-smooth muscle actin. 70,71

The reduction of PSC migration by activation of cannabinoid receptors was followed by a reduction in matrix metalloproteinase-2 (MMP-2) levels. 70,72 Increased MMP-2 level enables deposition of pathogenic fibrillar collagens. Therefore, suppression of MMP-2 by cannabinoids could contribute to reducing collagen synthesis and reducing the inflammation and fibrosis leading to chronic pancreatitis. 70 Previous studies have demonstrated the positive association between chronic pancreatitis and pancreatic cancer, 73 and it is possible that administration of cannabinoids may prevent progression from chronic pancreatitis to pancreatic cancer.

Conclusion

Endogenous cannabinoids, synthetic or cannabis extracted from plants, can reduce tumor invasion and growth, induce tumor cell death, and inhibit tumor angiogenesis via cannabinoid receptor or receptor-independent pathways. Cannabinoid receptors appear to be highly expressed in pancreatic cancer compared with normal pancreatic tissue. CBD and THC appear to have antiproliferative and proapoptotic effects. CBD in a clinically relevant pancreatic cancer model improved survival outcomes when combined with gemcitabine. Clinical studies on the utility of cannabinoids in the treatment of pancreatic cancer are lacking and urgently needed.

Acknowledgment

We acknowledge Pancare Foundation (www.pancare.org.au) for supporting pancreatic cancer research in the Department of Surgery.

Abbreviations Used

2-AG 2-arachidonoylglycerol
AEA anandamide
ATF-4 activating transcription factor 4
CB1 cannabinoid receptor-1
CB2 cannabinoid receptor-2
CBD cannabidiol
CBN cannabinol
CHOP C/EBP-homologous protein
ER endoplasmic reticulum
ERK extracellular regulated kinase
FAAH fatty acid amide hydrolase
GPCR G-protein-coupled receptor
GPR55 G-protein-coupled receptor 55
IT intratumor
MGLL monoacylglycerol lipase
MMP-2 matrix metalloproteinase-2
NF-κB nuclear factor-kappaB
PSC pancreatic stellate cell
ROS reactive oxygen species
THC tetrahydrocannabinol
TRB3 tribbles homologue3
TRPV transient receptor potential vanilloid

Author Disclosure Statement

No competing financial interests exist.

Cite this article as: Sharafi G, He H, Nikfarjam M (2019) Potential use of cannabinoids for the treatment of pancreatic cancer, Journal of Pancreatic Cancer 5:1, 1–7, DOI: 10.1089/pancan.2018.0019.