CBD Oil For Leukemia

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Leukemia Did you know that cannabis can alleviate some symptoms of cancer and the painful side effects of certain cancer treatments? Since cannabinoid treatments are growing in availability, Studies show that CBD may be beneficial for patients with leukemia. People are using cannabis to treat different types of cancer as an adjunctive therapy; is CBD a viable option to force the disease into remission? Clinical effects of a single dose of cannabinoids to patients with chronic lymphocytic leukemia Christopher M. Melén a Department of Medicine at Huddinge, Division of Hematology, Karolinska

Leukemia

Did you know that cannabis can alleviate some symptoms of cancer and the painful side effects of certain cancer treatments? Since cannabinoid treatments are growing in availability, cancer patients are increasingly beginning to look to medical marijuana to help fight their cancer.

Medical marijuana is becoming more popular as a treatment for leukemia due to its cancer cell fighting properties and therapeutic effects. You may find that knowing more about the benefits of medical marijuana and leukemia may help you better cope with the condition and its treatment.

How Marijuana Can Be an Effective Treatment for Leukemia

New research has revealed that cannabinoids increase the effectiveness of chemotherapy treatments in leukemia patients. UK researchers found that THC and CBD, the two major cannabinoids, were both effective when combined with chemo. However, the effect dramatically improved when used simultaneously. Pot’s overall medical effects also increase when you pair marijuana with coconut oil or other substances.

To relieve nausea associated with chemo and cancer-related pain, many patients often turn to cannabis and leukemia treatment. But weed has recently been growing in popularity as a treatment for leukemia and other types of cancer.

Evidence shows that medical cannabis is a viable treatment option for leukemia. Researchers found that the THC cannabinoids in medical marijuana can kill leukemia cells. Research also shows that, unlike chemo that targets cancer cells and healthy cells alike, medical pot only targets the cancer cells, not the healthy cells.

Researchers credit the widespread medical applications of marijuana to the endocannabinoid system (the natural cannabinoid system of your body.) What they found is that cannabinoid receptors are in many parts of your body, even your white blood cells. Because of this, researchers are continuing their promising investigation of marijuana for leukemia.

Leukemia & Medical Marijuana Research

A study from 2005 looked into the role of mitogen-activated protein kinases (MAPKs) in cannabinoid-induced leukemia cell death. Some types of MAPKs take part in apoptosis and autophagy, or cell death and turnover. Understanding how cannabis causes cancer cell death can help us learn how to make better treatments, so the researchers behind this study specifically examined the CB2 receptor.

Before observing the cell death process, the team reaffirmed that their leukemia cells had CB2 receptors. After confirming their presence, they administered THC and another CB2-related cannabinoid. A type of MAPK called p38 MAPK activated in response to CB2 receptor stimulation, showing a link. Blocking p38 MAPK lessened the CB2 receptor’s ability to kill leukemia cells.

Another study supported the possibility of using cannabis as a supplement to radiation therapy. When a team from Israel observed the effects of CBD and a synthetic counterpart on leukemia cells, they recorded the effects that occurred in cells with and without prior gamma radiation exposure.

While the compounds killed plenty of leukemia cells on their own, they worked even better when used after radiation therapy. Without radiation, CBD killed about 61% of cells, while the synthetic counterpart killed around 43% of leukemia cells. But, those numbers respectively rose to 93% and 95% for cells with previous radiation exposure.

What Symptoms of Leukemia Can Medical Marijuana Treat?

Medical marijuana helps ease the following cancer symptoms in patients:

  • Nausea
  • Vomiting
  • Pain
  • Lack of appetite

Best Strains of Marijuana to Use for Leukemia

Pain is a common and dreaded chemotherapy side effect. While marijuana might not be something you’re interested in, it can help relieve chronic pain. Many patients prefer it over opioid painkillers.

Painkilling strains of marijuana include:

  • Chemo (Indica)
  • Blackberry Kush (Indica)
  • Death Star (Indica)

Depression fighting strains include:

  • Harlequin (Sativa)
  • Trainwreck (Hybrid)
  • CBD Critical Cure (Indica)
  • White Widow (Hybrid)

Fatigue and Insomnia fighting strains include:

  • White Widow (Hybrid)
  • Granddaddy Purple (Indica)

Nausea and Vomiting strains include:

  • Lavender (Indica)
  • Chernobyl (Hybrid)

Stress fighting strains include:

  • Moby Dick (Sativa)
  • Blue Dream (Hybrid)

Lack of Appetite strains include:

  • Granddaddy Purple (Indica)

Best Methods of Marijuana Treatment to Treat Leukemia Symptoms

With medical cannabis growing in popularity, there are many new methods of consuming marijuana. These newer methods allow you to benefit from the plant’s therapeutic potential for leukemia and other medical conditions.

When you think about medical weed, your first thought is probably an image of someone lighting up a joint. Although this is a popular way to consume this miracle drug, it’s not the healthiest. By inhaling cannabis, most of the cannabinoids are entering your body through your lungs and passed to your bloodstream. Because of this direct exchange, you’re shortening its effect.

Some better methods of consuming your medical weed include:

  • Vaporizing
  • Edibles
  • Juicing
  • Transdermal patches
  • Sublingual uptake
  • Oils
  • Tinctures
  • Topicals

Even though medical marijuana is presently federally illegal in the U.S., it’s legal in many states for valid medical use. To qualify for medical cannabis, you must first receive a diagnosis of a qualifying condition and obtain a local doctor’s recommendation for a medical marijuana card.

To find out if your state has legalized the use of medical cannabis, you can check our list. Then just search for a medical marijuana doctor to receive your cannabis for leukemia.

What Is Leukemia?

Leukemia is blood cell cancer. It begins in your bone marrow, which creates your blood cells. With leukemia, immature blood cells turn into cancer. Blood cells have different functions:

  • Red blood cells transport oxygen to all areas of your body.
  • White blood cells assist your body in fighting infection.
  • Platelets help with blood clotting.

With leukemia, abnormal white blood cells known as leukemia cells form from your bone marrow. These abnormal cells don’t do the work that your normal white blood cells do. They grow faster than normal cells, and they continue to grow when they shouldn’t.

As time passes, leukemia cells begin crowding out your healthy blood cells. Serious problems can arise from this such as bleeding, infections and anemia. Leukemia cells may also begin spreading to your lymph nodes or other organs, resulting in pain or swelling.

Leukemia may come on quickly or gradually. Slow growing leukemia is chronic. With acute leukemia, abnormal cells increase in number quickly.

Patients who have slow-growing leukemia may not have symptoms. Patients who have quick-growing types of leukemias may experience symptoms, including:

  • Frequent infections
  • Weight loss
  • Fatigue
  • Physical weakness
  • Easy bruising
  • Bleeding easily
  • Slow-healing wounds
  • Anemia
  • Bone pain
  • Petechiae
  • Shortness of breath
  • Swollen or enlarged gums
  • Feeling full or bloated
  • Enlarged spleen
  • Fever and chills
  • Night sweats
  • Headaches
  • Unusual pallor
  • Swollen lymph nodes

These symptoms may start off mildly but can become more pronounced as leukemia advances.

Children often develop acute leukemia while adults may have either acute or chronic. Doctors can cure some types of leukemia. Other types of leukemia can’t be cured and can only be controlled.

Treatments might include radiation, chemotherapy or stem cell transplantation. These are the most common treatments although there are several others described below. You may require therapy even if your symptoms go away, to prevent a relapse.

Types of Leukemia

There are several types of leukemia, categorized by the type of white blood cells affected and the rate in which it worsens.

The four primary types of leukemia are:

  • Acute myelogenous leukemia (AML)
  • Acute lymphoblastic leukemia (ALL)
  • Chronic myelogenous leukemia (CML)
  • Chronic lymphocytic leukemia (CLL)

Acute Myelogenous Leukemia (AML)

AML causes your body to generate too many white blood cells, known in this case as myelocytes. Leukemia cells begin building up in your bone marrow and blood, leaving less room for your healthier blood cells. The symptoms of AML include easy bleeding, infections and anemia. AML affects men more than women. It also affects kids. As you age, the incidence of AML can increase.

Acute Lymphoblastic Leukemia (ALL)

ALL also causes your body to generate too many white blood cells known as lymphocytes. These leukemia cells can’t fight infection effectively. The cells build up in your bone marrow and blood and don’t leave much room for your healthy blood cells. Easy bleeding, infections and anemia can result. ALL typically develops and worsens in a very short span of time.

Chronic Myelogenous Leukemia (CML)

CML causes the same reaction as AML and ALL. It worsens slowly and is more common in men than it is in women. CML is most common in adults in their 50s, and rarely affects children.

Chronic Lymphocytic Leukemia (CLL)

The same reaction happens with CLL as the other leukemia types. It’s most common in adults who are in their 60s, and more common in men than women. Children don’t often develop CLL. Patients with CLL tend to get more infections since it compromises the immune system.

There are other types of leukemia that aren’t as common, such as hairy cell leukemia. Leukemia also has subtypes, like the subtype of AML known as acute promyelocytic leukemia.

History of Leukemia

In 1845, John Hughes Benett officially identified leukemia as a diagnosis in Edinburgh. In the 19th century, other European physicians recognized abnormally high white blood cell levels in their patients, calling it “weisses blut” that meant “white blood.” Today, “leukemia” comes from the Greek terms “leukos” and “heima” that also means “white blood.”

The formation of four types of leukemia occurred in 1913. They were:

  • Chronic myelogenous leukemia
  • Chronic lymphocytic leukemia
  • Erythroleukemia
  • Acute lymphocytic leukemia

In 1970, doctors confirmed that some patients could be cured of leukemia. By the 1980s, leukemia survival rates were approximately 70 percent.

Effects of Leukemia

The symptoms you experience with leukemia depend on what type of the disease you have. Common signs and symptoms of leukemia may include:

  • Weakness, persistent fatigue
  • Chills or fever
  • Weight loss without trying
  • Severe or frequent infections
  • Recurrent nosebleeds
  • Enlarged spleen or liver, swollen lymph nodes
  • Easy bruising or bleeding
  • Excessive sweating, particularly at night
  • Bone tenderness or pain
  • Petechiae (small red spots on the skin)

Besides the physical effects of leukemia, this disease can also affect your mental well-being. A cancer diagnosis can change your life. It may overwhelm you, and the side effects of treatment can make it difficult to handle everyday life stresses.

Your mood can change at any time once you receive your diagnosis. Some people struggle with anxiety or depression immediately following their diagnosis. Other people’s mood may change during treatment. Your body may have both mental and physical reactions to cancer treatment.

Although it’s harder to recognize mental changes, they can be just as hard to deal with as physical changes. However, it’s important to recognize and manage changes in mood. Some mood change symptoms may include:

  • Depression or feeling down
  • Irritability
  • Difficulty remembering and concentrating
  • Changing emotions like anger or crying
  • Problems with sexual performance or loss of sexual interest
  • Loss of motivation and energy
  • Excessive sleeping, insomnia or other changes in sleep
  • Fatigue
  • Loss of interest in socializing, activities and social events
  • Changes in appetite (loss of appetite or overeating)
  • Suicidal thoughts or feeling life isn’t worth living
  • Feelings of worthlessness or hopelessness
  • Anxiety
  • Excessive or frequent fear, worry, or uneasiness
  • Increasing interest in alcohol
  • Panic attacks

Leukemia Statistics

  • Around every three minutes, in the U.S., one person receives a blood cancer diagnosis
  • In the U.S. in 2017, around 172,910 individuals are expected to get a diagnosis of leukemia
  • New leukemia cases in 2017 in the U.S. are projected to comprise around 10.2 percent of the 1,688,780 new cancer diagnosis case estimate
  • Leukemia accounts for nearly one out of three cancers and is the most common cancer in teens and children
  • Acute lymphocytic leukemia makes up around three out of four leukemia cases among teens and children
  • Acute lymphocytic leukemia is the most common cancer in early childhood and peaks between two and four-year olds

Current Treatments Available for Leukemia and Their Side Effects

To recommend a treatment protocol for leukemia, doctors perform several tests to diagnose the condition. These include conducting a complete blood count and performing a tissue biopsy from your bone marrow and possibly other organs such as your spleen and liver.

Treatments for cancer, such as chemotherapy medications, may impact how you feel physically and emotionally. They may disrupt your sleep and cause nausea, depression, loss of appetite, fatigue and anxiety.

Your leukemia treatment plan depends on several factors. Your physician recommends the treatment best for your leukemia case based on your overall health, age, the type you have and if the cancer is spreading to other body parts.

Common treatments doctors typically prescribe for leukemia include:

Chemotherapy

Chemo is a major type of leukemia treatment. It consists of chemicals that kill leukemia cells. Your doctor may give you one dose or a mixture of drugs depending on your type of leukemia. It may come as an injection or a pill.

Side effects of chemotherapy include:

  • Pain
  • Fatigue
  • Nausea and vomiting
  • Throat and mouth sores
  • Constipation
  • Diarrhea
  • Nervous system effects
  • Blood disorders

Biological Therapy

Biological therapy helps your immune system identify leukemia cells and attack them.

Side effects of biological therapy include:

  • Weakness
  • Fever
  • Chills
  • Joint or muscle aches
  • Nausea or vomiting
  • Headache
  • Dizziness
  • Fatigue
  • Heightened or lowered blood pressure
  • Occasional breathing difficulties
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Targeted Therapy

Targeted therapy attacks specific cancer cell vulnerabilities. For instance, Gleevec (imatinib) stops protein action in leukemia cells when you have chronic myelogenous leukemia helping to control leukemia.

Side effects of targeted therapy include:

  • High blood pressure
  • Skin problems such as dry skin, hair depigmentation, acneiform rash, nail changes
  • Gastrointestinal perforation
  • Problems with wound healing and blood clotting

Radiation Therapy

Radiation therapy consists of high-energy beams like X-rays that damage leukemia cells, stopping them from growing. Your doctor may apply radiation over your entire body or just a certain area of your body if there’s a concentrated group of leukemia cells. The doctor may give you radiation therapy before a stem cell transplant to prepare you for the procedure.

Side effects of radiation therapy include:

  • Fatigue
  • Skin problems such as itching, dryness, peeling
  • Dry mouth
  • Nausea
  • Shortness of breath
  • Diarrhea

Stem Cell Transplant

A stem cell transplant replaces unhealthy bone marrow with bone marrow that’s healthy. You’ll receive a high dose of radiation therapy or chemotherapy before your stem cell transplant procedure to destroy your unhealthy bone marrow. Your doctor will then give you an infusion that contains stem cells that form blood to help rebuild your bone marrow. Your doctor may use your stem cells or stem cells from a donor.

CBD Oil for Leukemia: Benefits, Effects & How to Use

Did you know that cannabis compounds like THC and CBD may alleviate the symptoms of cancer — and even kill the malignant cells while protecting the healthy ones?

The anti-cancer benefits of cannabis have been regularly demonstrated in laboratory conditions, on animal models, and in preclinical human trials. Not only do cannabinoids produce therapeutic effects on tumors, but they also help mitigate certain side effects of conventional treatments (e.g. chemotherapy and radiation).

It’s no wonder why so many people are turning to CBD for different types of cancer, including leukemia, the so-called silent killer. How exactly does CBD help leukemia patients? Can you use it on its own or only as an adjunctive treatment?

In this article, we explain the mechanism of action and cover the recent studies regarding CBD and leukemia.

Benefits of CBD for Leukemia

CBD oil has a dense nutritional content that may help ease the symptoms of leukemia among other health conditions. Full-spectrum hemp extracts contain particularly high levels of antioxidants, vitamins, proteins, and essential fatty acids on top of terpenes, terpenoids, and minerals. All these compounds may promote optimal health.

CBD might also have anti-cancer effects that have the potential to stop the growth of malignant cells. However, it’s important to remember that there’s a lack of clinical trials in this area, and the majority of the research comes from animal models and human case reports.

That being said, below we outline some of the ways in which CBD might be useful for leukemia.

CBD Triggers Apoptosis in Cancer Cells

Apoptosis is a process where the body naturally destroys harmful cells to help maintain homeostasis. As mentioned in the previous sections, leukemia results from the abnormal production of immature white blood cells that stuff the lymphatic system and the blood, making it difficult for other types of essential blood cells to grow.

Studies have found that CBD oil packs potent anti-cancer properties that may help reduce the rate at which the malignant cells spread. Moreover, CBD signals the body’s endocannabinoid system (ECS) to produce more of its therapeutic messengers (endocannabinoids) to restore the state of homeostasis. Through apoptosis, CBD is able to eliminate cancer cells in human leukemia (1).

Cannabinoids also interact with the CB2 receptors that are widely present in the immune system. This interaction helps the body distinguish between useful and detrimental cells. It also triggers ceramide and sphingolipid synthesis, triggering the death of unhealthy cells (2).

CBD’s affinity with CB2 receptors may also help produce immunomodulatory effects, optimizing the activity of the immune system. Researchers have highlighted CBD as an antitumorigenic agent that inhibits the reproduction of cancer cells (3). Doing so enables it to control the number of leukemia-affected cells and makes space for the growth of healthy white blood cells, red blood cells, and platelets.

CBD Helps Nourish Healthy Cells

As mentioned above, CBD may be a good source of essential nutrients required for healthy cell development (4). These include terpenoids, flavonoids, vitamins, essential fatty acids, and proteins. Consuming a full-spectrum CBD extract suspended in a carrier fat like MCT oil may increase your intake of many of these compounds.

Nutrients, especially amino acids and vitamins, are paramount for the formation of healthy blood cells. According to various health experts and medical researchers, increasing the bioavailability of these high-quality nutrients may decrease the chance of cell mutation while keeping the healthy cells protected against damage.

Considering the above, CBD oil may be able to lay the ground for healthy white cell production by creating the right environment for them to thrive.

Studies have also found that CBD may be useful in relieving the side effects of chemotherapy and radiation, including:

  • Inflammation and pain
  • Insomnia and sleep deprivation
  • Depression

What to Know About Leukemia?

Leukemia is a type of cancer that affects white blood cells. It starts to develop in the bone marrow, where it causes abnormal growth of these cells, mutating and multiplying in number. White blood cells regulate the performance of the immune system by fighting disease-causing bacteria.

Leukemia causes kind of a chain reaction in the body. The excess white cells are under-developed and thus serve no purpose in the body. However, abnormal production disrupts the growth of other important blood cells, such as platelets, red blood cells, etc. A lower red blood count (RBC) can further put a person’s health at risk since red blood cells are responsible for transporting oxygen, food nutrients, and other vital components to various parts of the body.

Researchers haven’t yet identified the cause of leukemia, but there are several factors that can spur its development, including:

  • Poor diet
  • Unhealthy lifestyle
  • Genetic burden

According to statistics, more than 75% of reported leukemia cases refer to children.

Types of Leukemia

There are several types of leukemia depending on the type of white blood cells affected and the rate at which it deteriorates.

The four major types of leukemia are:

  • Acute myelogenous leukemia (AML)
  • Acute lymphoblastic leukemia (ALL)
  • Chronic myelogenous leukemia (CML)
  • Chronic lymphocytic leukemia (CLL)

Below we share a brief overview of each.

Acute Myelogenous Leukemia (AML)

AML triggers the body to produce too many white blood cells known as myelocytes. Leukemia starts building up in your bone marrow and blood, leaving less space for the healthy blood cells. The symptoms of AML include infections, anemia, and easy bleeding. AML is more common in men than in women. It also affects kids, but the prevalence of AML increases with age.

Acute Lymphoblastic Leukemia (ALL)

ALL stimulates the excess production of lymphocytes. These white blood cells can’t fight infection effectively, building up in your bone marrow and blood, reducing the room for your healthy blood cells. Similar to AML, this type of leukemia may cause easy bleeding, anemia, and infections. ALL typically shows up and worsens in a very short time span.

Chronic Myelogenous Leukemia (CML)

CML causes the same symptoms as AML and ALL. It deteriorates slowly and affects more men than women. CML is most common in adults over 50s; it rarely affects children.

Chronic Lymphocytic Leukemia (CLL)

This is the chronic form of ALL and involves the same reaction as the other leukemia types. It commonly affects adults in their 60s and over. Women are less likely to develop CLL than men. Patients with CLL are more exposed to infections due to a poorly functioning immune system.

Symptoms of Leukemia

  • Anemia
  • Bone pain
  • Easy bruising
  • Easy bleeding
  • Enlarged spleen
  • Fatigue
  • Feeling full or bloated
  • Fever and chills
  • Frequent infections
  • Night sweats
  • Physical weakness
  • Petechiae
  • Shortness of breath
  • Swollen or enlarged gums
  • Swollen lymph nodes
  • Unusual pallor
  • Weight loss

Current Treatments & Their Side Effects

Before recommending a treatment protocol for leukemia, doctors run several examinations to diagnose the condition. Usually, a complete blood count and tissue biopsy from your bone marrow are performed.

Treatments for leukemia vary from radiation to chemotherapy and bone marrow transplant; each of them is effective to some extent, but it also has side effects that can cause the patient to feel more miserable than cancer itself. They may cause severe pain, nausea, depression, loss of appetite, disrupt your sleep, and trigger anxiety.

Common leukemia treatments include:

  • Chemotherapy – chemo is the go-to treatment for many types of cancer, including leukemia. It uses chemicals that kill leukemia cells and can be administered in one dose or as a mixture of drugs depending on what type of leukemia you’re struggling with. Chemotherapy may come as an injection or a pill.
  • Biological Therapy – this form of treatment helps your immune system identify leukemia cells and eliminate them. Side effects of biological therapy include fever, chills, fatigue, changes in blood pressure, and overall weakness.
  • Targeted Therapy – targeted therapies are aimed to attack specific cancer cell cultures. For instance, Gleevec, a commonly used targeted therapy, inhibits protein action in leukemia cells when you suffer from chronic myelogenous leukemia. There’s a risk of side effects such as high blood pressure, skin problems, and gastrointestinal perforation.
  • Radiation Therapy – radiation uses high-energy beams like X-rays that destroy leukemia cells and prevent further proliferation of cancer. Your doctor may recommend radiation over your entire body or just a specific area if there’s a higher concentration of leukemia cells. The doctor may apply radiation therapy before a stem cell transplant to prepare you for the surgery.
  • Stem Cell Transplant – this procedure replaces unhealthy bone marrow with a healthy one. Patients receive a high dose of radiation therapy or chemotherapy before their stem cell transplant to remove unhealthy bone marrow. An infusion with stem cells is then applied to form blood that rebuilds the bone marrow.

Are There Any Risks & Side Effects of Using CBD for Leukemia?

CBD is an acknowledged adaptogenic compound with minimal side effects. Many international health agencies, such as the World Health Organization (WHO), have reported that CBD is well tolerable in humans, even in doses as high as 1,500 daily over the course of several weeks. When taken in regular doses, CBD oil doesn’t have adverse reactions. However, large doses may cause the following side effects:

  • Dry mouth
  • Appetite fluctuation
  • Dizziness
  • Fatigue
  • Diarrhea

CBD-induced drug interaction is another concern for patients with leukemia. CBD inhibits the activity of the cytochrome p450, a system of enzymes that metabolize active ingredients in medications. If you take any medication that has a grapefruit warning on it, you probably shouldn’t take it along with CBD oil. Consult a doctor to reduce the likelihood of such events.

How to Use CBD for Leukemia?

CBD comes in many different forms. Its potential to reduce the symptoms of various health conditions can make it challenging to find the right delivery method. Here we highlight some of the most common methods of consuming CBD for leukemia:

  • CBD Oil – CBD oil is a sublingual product that involves putting the CBD extract under the tongue and allowing it to stay for up to 60 seconds before swallowing. The sublingual route of administration allows the CBD to be absorbed directly into the bloodstream. It is considered the most effective way of delivering CBD into the system of all methods that avoid inhalation. Sublingual CBD comes in three types of products: oil drops, tinctures, and sprays.
  • CBD Capsules – oral products like capsules are the most popular form of CBD among on-the-go users. If you live a busy lifestyle and don’t have the time to measure out your doses with a dropper — but instead prefer a fixed dose of CBD per serving — capsules are a decent alternative to oils. CBD capsules are also odorless and tasteless, so you don’t have to deal with the botanical aftertaste. However, since capsules need to pass through the digestive system, they act slower than oils, usually within 40–90 minutes after application.
  • CBD Edibles – CBD is infused into a lot of foods and drinks nowadays. You can choose between gummies, honey sticks, protein bars, chocolates, and beverages like tea or coffee. Edibles offer the most enjoyable way to consume CBD, but similar to capsules, they have a delayed onset and may lose some of their potency on their way to the bloodstream due to the first-pass metabolism in the liver.
  • CBD Vapes – vaporized CBD reaches your system through inhalation. Once you pull the CBD vapor into your lungs, it will absorb into the bloodstream through the lung tissue, ensuring fast-acting effects and high availability for the body. The vape pen heats the CBD liquid to the point where it releases cannabinoid-rich vapor, avoiding combustion. The effects of vaporized CBD are usually felt within minutes, but they have the shortest duration, up to 3–4 hours.
  • CBD Topicals – when you apply CBD topically, it interacts with the cannabinoid receptors that are located in the skin’s epidermis layer. From there, it produces its anti-inflammatory and analgesic effects, contributing to less pain in leukemia patients. Topicals are available as creams, balms, gels, lotions, and salves; their absorption rate and duration of effects vary depending on the formulation. People commonly use them for skincare, but some people also claim to find relief from painful flare-ups during leukemia.
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CBD Dosage for Leukemia

Dosing CBD is a tricky job for several reasons.

First, everybody is different; your age, gender, weight, metabolism, eating habits, and severity of your leukemia symptoms will all influence your effective dosage range. According to some researchers, a low dose of CBD ranges from less than 1 mg to 50 mg/kg/day.

The good news is that you can’t fatally overdose on CBD, so experimenting with different doses isn’t a risky business. Nevertheless, if you want to make sure you’re not wasting too much CBD, we recommend that you start low and slow. Start with 10 mg of CBD twice daily and observe the effects for one week. If you don’t feel any difference in your symptoms, increase the dosage, and continue for the next few days. Adjust the dose until you find the one that works for you.

If you’re thinking of adding CBD oil to your anti-leukemia regime, consult this idea with a holistic doctor experienced in cannabis use. Doing so will help you determine the effective dose and avoid the aforementioned CBD-drug interactions.

Summarizing the use of CBD for Leukemia

CBD may be an effective treatment for the symptoms and side-effects of leukemia and its conventional treatments as it also gives an anti-nausea effect. CBD and other cannabinoids are also useful in many other types of cancer. However, the subject is still under-researched when it comes to human trials, so doctors don’t recommend using CBD as a replacement for leukemia therapy.

When browsing through different CBD products, make sure to choose a high-quality CBD oil from a reputable brand. Despite the boom in CBD and cannabis in general, the market remains unregulated due to the particular classification of hemp-derived CBD as health supplements. Be sure to talk to your physician for professional advice regarding the consumption method, CBD dosage, and potential contraindications.

Literature:

  1. McKallip, Robert J et al. “Cannabidiol-induced apoptosis in human leukemia cells: A novel role of cannabidiol in the regulation of p22phox and Nox4 expression.” Molecular pharmacology vol. 70,3 (2006): 897-908. doi:10.1124/mol.106.023937
  2. Nichols, James M, and Barbara L F Kaplan. “Immune Responses Regulated by Cannabidiol.” Cannabis and cannabinoid research vol. 5,1 12-31. 27 Feb. 2020, doi:10.1089/can.2018.0073
  3. Scott, Katherine A et al. “Anticancer effects of phytocannabinoids used with chemotherapy in leukemia cells can be improved by altering the sequence of their administration.” International journal of oncology vol. 51,1 (2017): 369-377. doi:10.3892/ijo.2017.4022
  4. Pagano, Stefano et al. “Biological effects of Cannabidiol on normal human healthy cell populations: Systematic review of the literature.” Biomedicine & pharmacotherapy = Biomedicine & pharmacotherapies vol. 132 (2020): 110728. doi:10.1016/j.biopha.2020.110728
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.

Clinical effects of a single dose of cannabinoids to patients with chronic lymphocytic leukemia

Christopher M. Melén a Department of Medicine at Huddinge, Division of Hematology, Karolinska Institutet, Stockholm, Sweden;b Medical Unit Hematology, Karolinska University Hospital, Stockholm, Sweden Correspondence [email protected]
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Magali Merrien c Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, SwedenView further author information

Agata M. Wasik c Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, SwedenView further author information

Georgios Panagiotidis d Department of Laboratory Medicine, Division of Pharmacology, Karolinska Institutet, Stockholm, Sweden;e Unit of Clinical Pharmacology, University Hospital, Stockholm, SwedenView further author information

Olof Beck d Department of Laboratory Medicine, Division of Pharmacology, Karolinska Institutet, Stockholm, Sweden;e Unit of Clinical Pharmacology, University Hospital, Stockholm, Sweden https://orcid.org/0000-0002-3546-8872View further author information

Kristina Sonnevi a Department of Medicine at Huddinge, Division of Hematology, Karolinska Institutet, Stockholm, Sweden;b Medical Unit Hematology, Karolinska University Hospital, Stockholm, SwedenView further author information

Henna-Riikka Junlén a Department of Medicine at Huddinge, Division of Hematology, Karolinska Institutet, Stockholm, Sweden;b Medical Unit Hematology, Karolinska University Hospital, Stockholm, Sweden https://orcid.org/0000-0003-4749-0601View further author information

Birger Christensson c Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden;f Department of Clinical Pathology and Cytology, Karolinska University Hospital, Stockholm, SwedenView further author information

Birgitta Sander c Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden;f Department of Clinical Pathology and Cytology, Karolinska University Hospital, Stockholm, SwedenView further author information

Björn Engelbrekt Wahlin a Department of Medicine at Huddinge, Division of Hematology, Karolinska Institutet, Stockholm, Sweden;b Medical Unit Hematology, Karolinska University Hospital, Stockholm, Sweden https://orcid.org/0000-0003-3566-8847View further author information

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Original Articles

Clinical effects of a single dose of cannabinoids to patients with chronic lymphocytic leukemia

Abstract

This phase II clinical trial investigates a one-time oromucosal dose of tetrahydrocannabinol/cannabidiol (THC/CBD) in 23 patients with indolent leukemic B cell lymphomas. Primary endpoint was a significant reduction in leukemic B cells. Grade 1 − 2 adverse events were seen in 91% of the patients; most common were dry mouth (78%), vertigo (70%), and somnolence (43%). After THC/CBD a significant reduction in leukemic B cells (median, 11%) occurred within two hours (p = .014), and remained for 6 h without induction of apoptosis or proliferation. Normal B cells and T cells were also reduced. CXCR4 expression increased on leukemic cells and T cells. All effects were gone by 24 h. Our results show that a single dose of THC/CBD affects a wide variety of leukocytes and only transiently reduce malignant cells in blood. Based on this study, THC/CBD shows no therapeutic potential for indolent B cell lymphomas (EudraCT trial no. 2014-005553-39).

Introduction

Indolent B cell leukemias are malignant diseases with several available treatment options [ 1 , 2 ]. However, some patients do not respond to or do not tolerate these interventions, particularly the elderly. For these patients, the treatment contributes to a reduced quality of life and survival. Therefore, novel treatments and identification of factors influencing outcome are needed. Previous experimental studies have indicated that cannabinoids may induce cell death in lymphoma [ 3–5 ].

Two G-protein coupled receptors (CB1 and CB2) mediate most of the effects seen by cannabinoids [ 6–9 ]. CB1 is highly expressed in synapses within the central nervous system and to a lesser degree in the peripheral nerves and the enteric nervous system of the gastro-intestinal tract. CB1 regulates synaptic signaling and it is through this receptor that delta-9-tetrahydrocannabinol (THC) produces the psychoactive effects associated with Cannabis sativa [ 8 , 10 ]. While THC is an agonist to CB1, the other major component of Cannabis sativa, cannabidiol (CBD), acts as a CB1 antagonist [ 11 ], counteracting the psychotropic effects of THC [ 12 ]. CB2 is expressed in the immune system including B cells, T cells, monocytes/macrophages, and dendritic cells [ 7 , 13 ]. In mice, CB2 signaling is important for retention of immature B cells in bone marrow sinusoids [ 14 ] and for the positioning and retention of marginal zone B cells in splenic marginal zones [ 15 , 16 ].

A key mechanism for lymphocyte migration and tissue localization is the chemokine receptor CXCR4 and its ligand CXCL12 [ 14 ]. Specifically, CXCR4 expression is high on lymphocytes in blood and these lymphocytes migrate toward CXCL12 which is produced by stroma cells in lymph nodes and bone marrow. CXCR4 is a G-protein coupled receptor, known to interact with other G-protein coupled receptors, such as CB2, to modulate the CXCL12-induced effects on cell migration and homing [ 17 , 18 ].

THC and CBD have shown various effects on the immune system, such as inhibition of mitogen-stimulated lymphocyte cell replication [ 19 ] and T-cell proliferation and cytokine production by signaling via CB2 [ 20 , 21 ].

Many B-cell lymphomas express CB1 and CB2. Extensive screening for CB1 mRNA expression across different B-cell leukemias/lymphomas demonstrated increased CB1 expression in most cases of mantle cell lymphoma, follicular lymphoma, and in approximately half of CLL cases compared to normal B cells [ 22 , 23 ]. Low CB1 expression levels have been associated with lymphocytosis in mantle cell lymphoma [ 24 ] and longer survival in CLL [ 25 ]. Micromolar concentrations of synthetic agonists to both CB1 and CB2 have been demonstrated to induce cell death of CB1- or CB2-expressing lymphoid cell-lines in vitro and in xenografts [ 3 , 5 , 26 ].

In view of these findings, we conducted a clinical trial to investigate the therapeutic potential of THC/CBD in indolent B cell leukemia/lymphoma. In this phase II clinical trial, patients received a single administration of an oromucosal spray approved for treating pain and spasticity in multiple sclerosis, Sativex ® (THC/CBD, in a molecular ratio 1/1) [ 27 ], to investigate 1) whether THC/CBD would reduce leukemia/lymphoma cells in blood and 2) how an elderly population would tolerate THC/CBD.

Methods

Study design

Asymptomatic patients with CLL or leukemic (lymphocytes > 5 × 10 9 /L) mantle, follicular or marginal zone lymphomas received a single dose of THC/CBD. The primary endpoint was a reduction of malignant (clonal) B cells in blood. Blood samples were collected at four timepoints (9 am, 11 am, 1 pm, and 3 pm) on a day prior to THC/CBD and at the same timepoints on a day with THC/CBD (administered at 9 am) and 24 and 168 h after THC/CBD. The maximum tolerated dose was established by stepwise increasing the dose of THC/CBD in every third patient until two adverse events grade 2 were seen in two or more consecutive patients (using common terminology criteria for adverse events, version 4.0), starting from 2.7 mg THC and 2.5 mg CBD (one actuation of Sativex) to 18.9 mg THC and 17.5 mg CBD (seven actuations). At the scheduled interim analysis when the seven actuation-dose was identified, 10 patients had been treated and we saw an early decrease of leukemic and normal lymphocytes already 2 h (11 am) after THC/CBD, which continued to 1 pm (4 h) and started to resolve by 3 pm. To ascertain that the changes were not due to a hitherto unknown diurnal rhythm of normal lymphocytes or leukemic cells, we sampled all subsequent 13 patients (12 with CLL) also on a date prior to THC/CBD (median 6 d before [range, 1–26]), and we included an additional measurement at 10 am on the THC/CBD day (Supplementary Figure S1).

The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee in Stockholm (2015/281-31/2 with amendments 2016/210-32 and 2017/556-32) and by the Swedish Medical Products agency and registered as EudraCT trial no. 2014-005553-39. Patients were included, after providing informed consent, between April 2016 and February 2019. The date of last follow-up was 25 June 2020.

Adverse events and peak plasma concentrations of THC and CBD will also be reported in a parallel pharmacologic manuscript describing the evaluation of measuring THC and CBD in other fluids than plasma (Melén et al., manuscript submitted).

Chemistry, pharmacology assays, and flow cytometry

Complete blood counts and other routine chemistry analyses were conducted using the facilities of the Karolinska University Laboratory. Assays of THC and CBD concentration measurement were conducted at the Department of Pharmacology using liquid chromatography–mass spectrometry method as described previously [ 28 ]. Multiparameter flow cytometry on peripheral blood samples for characterizing lymphoid and myeloid cell populations, as well as for assessing caspase-3 activation (by cleavage of active caspase substrate – PhiPhiLux) for apoptosis in CD19 + CD5+ cells, was done in the routine flow cytometry unit at the Dept. of Clinical Pathology and Cytology (Supplementary Tables S1 and S2; Supplementary Methods). Surface expression of the homing chemokine receptor CXCR4 was analyzed using flow cytometry (Supplementary Figure S2) and CXCR4high/CXCR4low ratios were calculated.

Enrichment of malignant B cells and analysis of cell proliferation

Blood samples were enriched for B cells by negative selection using RosetteSep ™ , collected using Ficoll-Paque PLUS (GE Healthcare Life Science, Marlborough, MA). The flow cytometer BD FACSCanto II (BD Biosciences, San Diego, CA) was used to determine the purity of B cells (Supplementary Methods) and data analysis was performed using the FlowJo software version 10 (Ashland, USA). Cell proliferation of enriched malignant B cells was assessed by incorporation of 3 H-Thymidine (Supplementary Methods).

RNA isolation and real-time PCR

mRNA expression levels of genes encoding for CB1 (CNR1) and CB2 (CNR2) were assessed by real-time PCR [ 24 ] after RNA isolation and complementary DNA synthesis from enriched B cells (Supplementary Methods). Custom-made primers were purchased from Invitrogen, sequences for respective genes are provided in Supplementary Methods.

Statistics

Comparisons between repeated measurements in the same individuals were done, using the Wilcoxon matched-pairs signed-ranks test. The 9 am results from the day prior to, and the day of, THC/CBD were used as separate baselines. Survival was analyzed with Kaplan–Meier curves. Assessments of other associations were conducted using Spearman, Fisher’s exact, or Mann–Whitney–Wilcoxon tests, according to the nature of the variables. p values are two-tailed and calculated using Stata version 14.2 (StataCorp LLC, College Station, TX). Apoptosis and proliferation data were analyzed using GraphPad Prism version 8 (GraphPad software Inc., La Jolla, CA). p .05 was considered significant.

Results

Twenty-three (20 with CLL) elderly patients with indolent B cell malignancy received a one-time administration of THC/CBD. The patients are described in Table 1 .

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Table 1. Clinical characteristics at inclusion.

Adverse events

The maximum tolerated dose was seven actuations (18.9 mg THC/17.5 mg CBD); this dose was given to 15 patients. Transient adverse events were seen in 21/23 patients, all grade 1 or 2; most common were dry mouth (78%), vertigo (70%), and somnolence (43%; Table 2 ). The adverse events occurred within the first 6 h, did not require hospitalization and all patients returned home at 4 pm.

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Table 2. Adverse events.

THC/CBD concentrations in plasma

The peak plasma concentrations of THC and CBD were reached at different time points for different patients. For THC, the peak concentration in plasma (median 8.8 ng/mL) was seen at 1 h (n = 5), 2 h (n = 12), and 4 h (n = 6) and ranged from 0.7 to 24.7 ng/mL. The peaks of CBD (median 4.9 ng/mL) were at 1 h (n = 7), 2 h (n = 8), 4 h (n = 7), and 6 h (n = 1), with a range of 0.2–17.3 ng/mL. The relation between the plasma concentrations of THC and CBD was linear (R 2 = 0.90; p < .00005; Figure 1 (A)). THC and CBD levels correlated with the number of actuations (p < .00005) and with the severity of adverse events (p = .043; Figure 1(B)).

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Figure 1. Peak plasma levels of THC and CBD, number of actuations and adverse events. (A) Peak plasma levels of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), each dot representing a patient. (B) Peak plasma levels of THC and the number of actuations of THC/CBD and the worst adverse event per patient (gray dot, no adverse event; dark gray triangle, adverse event grade 1; black diamond, adverse event grade 2).

Figure 1. Peak plasma levels of THC and CBD, number of actuations and adverse events. (A) Peak plasma levels of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), each dot representing a patient. (B) Peak plasma levels of THC and the number of actuations of THC/CBD and the worst adverse event per patient (gray dot, no adverse event; dark gray triangle, adverse event grade 1; black diamond, adverse event grade 2).

Effects of THC/CBD on blood cells

Baseline cell counts and relevant fold changes are presented in Table 3 , and representative graphs of the median values are shown in Figure 2. As expected, there was an increase of neutrophils, 4 h after THC/CBD, climaxing at 126% by 6 h (Figure 2; Table 3 ). Serum cortisol levels also increased 4 h after THC/CBD (Figure 2, Table 3 ). After THC/CBD, leukemic B cells decreased already by 10 am, reaching equal nadir at 11 am and 1 pm (11% decrease), and remained reduced at 3PM (8%; Figure 2(A); Table 3 ). There was a similar but larger reduction in normal B cells after THC/CBD, from 10 am with a nadir at 3 pm (37%; Figure 2(B); Table 3 ). There was also a decrease in CD3+ cells (nadir 35% at 3 pm; Figure 2(C); Table 3 ) but there was no change in CD4/CD8 ratio (Figure 2(D)). Decreases in CD56+ cells and in platelets were also observed (Figure 2(E,F)). Twenty-four hours after THC/CBD, no effects remained on any leukocyte subset ( Table 3 ).

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Figure 2. Changes in median levels of blood leukocyte subsets and serum cortisol levels during the days without and with THC/CBD. For simplicity, only median values are shown here, detailed data are represented in Table 3 . (A) Leukemic B cells. (B) Normal B cells. (C) CD3+ T cells. (D) CD4/CD8 ratio. (E) CD56+ NK cells. (F) Platelets. (G) Neutrophils. (H) Serum cortisol. Dashed black lines are from the day without treatment (n = 13) and solid gray lines are from the day with treatment (n = 23). All results are presented in relation to sampling at baseline (9 am) for each day. All cell-subset analyses were calculated from absolute blood counts, except CD4/CD8 (ratio). One circumflex (^) indicates significant changes at the day without treatment, with respect to baseline with p < .05. One asterisk (*) and two asterisks (**) indicate significant changes at the day with treatment, with respect to baseline with p < .05 and p < .005, respectively.

Figure 2. Changes in median levels of blood leukocyte subsets and serum cortisol levels during the days without and with THC/CBD. For simplicity, only median values are shown here, detailed data are represented in Table 3 . (A) Leukemic B cells. (B) Normal B cells. (C) CD3+ T cells. (D) CD4/CD8 ratio. (E) CD56+ NK cells. (F) Platelets. (G) Neutrophils. (H) Serum cortisol. Dashed black lines are from the day without treatment (n = 13) and solid gray lines are from the day with treatment (n = 23). All results are presented in relation to sampling at baseline (9 am) for each day. All cell-subset analyses were calculated from absolute blood counts, except CD4/CD8 (ratio). One circumflex (^) indicates significant changes at the day without treatment, with respect to baseline with p < .05. One asterisk (*) and two asterisks (**) indicate significant changes at the day with treatment, with respect to baseline with p < .05 and p < .005, respectively.

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Table 3. Changes with and without THC/CBD.

Influence of cannabinoid receptor expression

The leukemic B cells in all 23 patients expressed CB2 while 17/23 expressed CB1 ( Table 1 ). Neither CB1 nor CB2 mRNA levels changed after the administration of THC/CBD at any timepoint (p > .05 for every comparison). The six CB1-negative cases, all CLL, showed a deeper reduction after THC/CBD (15% decrease at 1 pm; p = .028) than in the CB1-positive cases (10% decrease; p = .013; Figure 3(A)).

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Figure 3. Reduction of CB1-expressing and non-expressing malignant B cells and CXCR4 surface expression. For simplicity, only median values are shown here, detailed data are represented in Table 3 . (A) Reduction of leukemic B cells after THC/CBD in CB1 positive (dashed gray line; n = 17) and CB1 negative (dotted gray line; n = 6) cases. Changes in CXCR4+/CXCR4- ratio in (B) leukemic B cells and (C) T cells.

Figure 3. Reduction of CB1-expressing and non-expressing malignant B cells and CXCR4 surface expression. For simplicity, only median values are shown here, detailed data are represented in Table 3 . (A) Reduction of leukemic B cells after THC/CBD in CB1 positive (dashed gray line; n = 17) and CB1 negative (dotted gray line; n = 6) cases. Changes in CXCR4+/CXCR4- ratio in (B) leukemic B cells and (C) T cells.

Effects on CXCR4 expression, apoptosis, and proliferation

Ratios of CXCR4high/CXCR4low were similar in CB1-negative and CB1-positive cases (median 9.4 and 9.5, respectively; p = .54) and were stable in leukemic cells and T cells when no drug had been given. However, after THC/CBD administration CXCR4high/CXCR4low ratios increased in leukemic B cells (Figure 3(B)) and T cells (Figure 3(C)) at 1 and 3 pm ( Table 3 ). Apoptosis and cell proliferation did not change at any timepoint (Supplementary Figure S3).

Existence of a diurnal rhythm in patients with CLL

Thirteen patients (12 with CLL) were sampled on a date prior to THC/CBD (median 6 d before [range, 1–26]), to ascertain any hitherto unknown diurnal rhythm of normal lymphocytes or leukemic cells. Without THC/CBD, there was a late significant reduction in leukemic cells at 1 pm only (11%; Table 3 ); other leukocyte subsets including T cells did not change (Figure 2; Table 3 ).

Long-term follow-up

Leukemic cell counts moderately increased between the non-THC/CBD day (approximately one week before therapy), the THC/CBD day, and one week after THC/CBD. The 9 am leukocyte counts went from 23.2 (day without THC/CBD) to 24.7 (immediately before THC/CBD) to 26.0 (a week after THC/CBD) x 10 9 /L (Supplementary Figure S4(A)). Thus, the increase in leukemic cells that was observed one week after THC/CBD was considered a natural, gradual increase caused by the disease.

Median follow-up was 2.8 years (range, 1.4–4.2). Seven patients required treatment after the trial, six with rituximab-bendamustine and one with ibrutinib. One patient died from a cerebral stroke and one from kidney cancer, both >2 years after the trial and without any evidence of leukemia progression. Overall survival and time to next treatment are shown in Supplementary Figure S4(B).

Discussion

Cannabinoids are increasingly prescribed for treatment of spasticity, pain, and epilepsy [ 29 ]. Some patients use cannabinoids during chemotherapy, to alleviate adverse events, such as nausea and fatigue [ 30 , 31 ]. A recent study showed that almost one-fifth of cancer patients use cannabinoids as self-treatment [ 32 ]. The effects these cannabinoids have on benign and malignant cells in vivo are not fully known, since most knowledge comes from descriptive studies and animal models.

In this trial, repeated sampling after a single dose of THC/CBD showed a quick decrease in circulating leukemic and normal B and T cells in patients with indolent B cell leukemia. To investigate whether this was due to diurnal rhythms, the same repeated samplings were conducted on a day prior to THC/CBD administration on subsequent patients. We then found that CLL cells in untreated patients display a diurnal fluctuation, with similarities to circadian rhythms. Circadian rhythms are 24-h variations in physiological processes and are generated by the expression of circadian clock genes in humans. In the CLL cells, the significant diurnal change in untreated patients might be due to an aberrant expression of clock genes. The transcription factor BMAL1 and the gene CRY1, both part of the circadian system, are described as being epigenetically inactivated in CLL [ 33 ]. We did not detect any diurnal changes in normal B or T cells within the time frame of 9–3 pm.

It was safe to administrate a single dose of THC/CBD to these elderly patients. Still, psychotropic adverse events were frequent, being the main dose-limiting toxicity. For most patients, the side effects were unpleasant, but they all could return home at the end of the day. After the first 24 h, there were neither beneficial nor adverse effects of this single THC/CBD dose, and the natural course of the disease remained unperturbed.

Sativex, containing a mixture of THC/CBD, was the only approved cannabinoid compound available to us, therefore we could not separate the effects of THC and CBD. This is a limitation of the study. Our trial did not reproduce in vitro findings of induced cell death caused by high concentrations of synthetic [ 3 , 5 , 26 ] and natural [ 4 , 34 ] cannabinoids. Indeed, the psychotropic side effects prohibited the attainment of tumoricidal plasma concentrations of cannabinoids. We cannot, however, exclude that THC/CBD acts differently than other cannabinoids previously used for in vitro studies.

Patients with CB1-negative leukemia showed a faster and deeper reduction of leukemic cell counts compared to CB1-positive cases. Normal B cells, which also have very low CB1 expression [ 7 ], behaved similarly, with a more profound decrease than leukemic B cells. We cannot in this study mechanistically explain the slower reduction of the leukemic cells in blood when both cannabinoid receptors are expressed, but it has been shown that CB1 and CB2 can form heterodimers in neurons and when such heterodimers were formed, stimulation of one receptor led to negative modulation of its partner [ 35 ]. If this also would occur in leukemic cells, CB1 stimulation would impair the stimulation of CB2. Since CB2 is involved in homing of leukocytes to secondary lymphoid tissues, this could partly explain why CB1-negative cases and normal B cells, which have very low CB1 expression, had a more profound decrease after exposure to the study drug [ 14–16 ].

We detected an increased expression of CXCR4 on the cell surface of leukemic cells and T cells from blood, at 6 h after THC/CBD. CXCR4, together with other chemokine receptors and integrins, plays an important role in the interaction between lymphoma cells and the microenvironment, increasing cell survival and drug resistance [ 36 , 37 ]. We also found that the administration of THC/CBD increased cortisol levels. Cortisol is known to affect circadian rhythms in T cells [ 38 ], and to increase CXCR4 expression in T lymphocytes [ 39 ]. It is likely that the increase of cortisol was secondary to stress from adverse events rather than directly induced by the THC/CBD [ 40 ]. Based on our findings we believe that the increase of CXCR4high expressing cells (both leukemic B cells and T cells) seen 6 h after THC/CBD is a secondary effect due to elevated cortisol levels and that this increased expression of CXCR4 is associated to a redistribution of lymphocytes from blood at 6 h. The increase of neutrophils after THC/CBD is probably also a secondary effect of cortisol and has also been observed in a study investigating the chronic use of synthetic cannabinoids [ 41 ].

However, our main finding, the fast decrease of circulating leukemic cells 1–2 h after a single dose of THC/CBD, cannot be explained by the later changes in CXCR4 expression or cortisol levels. Furthermore, THC/CBD did not affect cell proliferation or apoptosis on leukemic cells in blood. Therefore, we propose that cannabinoids induce a redistribution of malignant B cells away from blood. However, we do not know where the cells relocate to. It is possible that the cells adhere to the endothelium of blood vessels, or migrate from blood to spleen, lymph nodes, and/or bone marrow. Nevertheless, our data point toward the involvement of the cannabinoid receptors in regulation of the tissue localization of lymphocytes, as previously suggested in experimental studies in mice [ 14–16 ]. Whether chronic use of cannabinoids might result in a sustained redistribution of lymphocyte subsets is not known. In a small study of 20 multiple sclerosis patients, Sativex intake for up to six weeks did not significantly affect the levels of different blood cells populations [ 42 ].

Cannabinoids may also impact immune checkpoint control: a recent study of cancer patients with solid tumors given immune checkpoint inhibitors showed that concomitant cannabinoid use correlated with inferior time to progression and overall survival [ 43 ]. Our study demonstrates that THC/CBD affects a wide variety of immune cells in vivo, and this should be taken into consideration when cannabinoids are used to treat, for example, nausea from chemotherapy, because cannabinoid-induced immune modulation could have unforeseen effects.

We conclude that a single dose of THC/CBD causes considerable adverse events in elderly, cannabis-naïve patients but did not affect apoptosis or proliferation of the malignant cells. Instead, THC/CBD probably induced an early redistribution of malignant and benign blood cells away from blood. If the malignant cells home to lymphoid tissues and bone marrow, such a redistribution would be opposite of that induced by successful anti-tumoral therapies such as inhibitors of Bruton’s tyrosine kinase and phosphoinositide 3-kinase, where malignant cells egress from the bone marrow to the peripheral blood [ 44 , 45 ]. It is important to consider that cannabinoids might negatively interfere with anti-leukemia/lymphoma treatment. Based on our findings, this mixture of cannabinoids should not be considered as treatment for indolent lymphomas.

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