The potential for cannabinoids, the isolated components of cannabis, to treat cancer has been known for quite some time. In 1974, researchers with the University of Virginia showed that tetrahydrocannabinol (THC), the psychotropic component of cannabis, slowed lung tumor growth in mice. Since then, dozens of preclinical studies (using cultured cells or animal models, not people) have revealed how THC and cannabidiol (CBD), the most well-known nonpsychotropic cannabinoid, kill numerous types of cancer cells or shrink tumors in animals. A review article published in July 2020 by researchers with Dalhousie University in Canada summarized the evidence for CBD – “Treatment with CBD exhibited a multitude of beneficial anti-cancer effects in lung, breast, colon, prostate, melanoma, leukemia, cervical, brain, neuroblastoma and multiple myeloma cancer cells.” Studies showing how THC inhibits breast, brain, lung, skin, liver, pancreatic, prostate, colon, cervical, and oral cancer cells were also analyzed. Given the strength and depth of this evidence, it is not surprising that pharmaceutical companies are looking into using cannabinoids to treat cancer in humans.

Just because something works in test tubes and animals does not mean it will work in humans. Thankfully, emerging evidence suggests cannabis can indeed exert some level of anticancer effect in real patients. GW Pharmaceuticals, a UK-based pharmaceutical company that was recently acquired in May 2021 by Jazz Pharmaceuticals, has been studying the potential of cannabinoids to treat glioblastoma for many years. Glioblastoma is an especially severe form of brain cancer that even with standard treatment (chemotherapy and radiation) has a median survival time of only about 15 months. This aggressiveness makes the results of GW’s double-blind, placebo-controlled trial testing a cannabis-derived THC/CBD product in concert with chemotherapy (temozolomide [TMZ]) against glioblastoma even more impressive. The trial, published February 2021, found that 83.3% of patients who received THC/CBD along with the TMZ chemotherapy were still alive after 1 year, compared to 44.4% who received TMZ and a placebo. Moreover, after two years, the median overall survival was estimated to be 21.8 months in the cannabis group and 12.1 months in the placebo group.

These stark improvements can most reasonably be explained by the cannabinoids working alongside the chemotherapy to inhibit progression of the cancer. Indeed, preclinical evidence clearly shows that both THC and CBD synergize with TMZ. For example, a 2011 study by researchers with Complutense University in Spain stated that, “Treatment with TMZ and submaximal doses of THC and CBD produced a strong antitumoral action in both TMZ-sensitive and TMZ-resistant tumors.

While GW Pharmaceuticals is the only company to have completed human trials, many other companies have completed preclinical studies and are preparing for human research. Interestingly, although THC and CBD have attracted most of the attention as anticancer compounds derived from cannabis, a company called Flavocure Biotech, located in Maryland, is looking at an entirely different type of molecule. In addition to cannabinoids, cannabis also contains flavonoids, which are found in a wide variety of plants and impart color to flowers, in addition to serving a wide variety of protective biological functions. In a 2019 study, funded by Flavocure Biotech and the National Institutes of Health, and conducted by researchers with Dana-Farber Cancer Institute at Harvard Medical School, a specific cannabis-derived flavonoid called FBL-03G was shown to kill pancreatic cancer cells and delay tumor progression in mice. This study was apparently used to support the Food and Drug Administration’s designation of FBL-03G (also known as Caflanone) as an orphan drug to treat pancreatic cancer. While such designation is not formal marketing approval or an endorsement of effectiveness, it incentivizes drug development for rare diseases, and is only granted if there is legitimate scientific rationale for a therapy’s potential effectiveness. The fact the FDA has granted orphan drug designation (ODD) to Caflanone is a testament to the real potential of this compound to treat pancreatic cancer.

Several other companies have received ODD for using cannabis-derived products to treat cancer. Not surprisingly, GW Pharmaceuticals has ODD for treating glioma (glioblastoma is an advanced form of glioma). Benuvia Therapeutics, located in Arizona, also has an ODD listing for CBD to treat glioblastoma specifically. The status of their work on this application is unclear, and the company seems more focused on other non-cannabinoid products.

Axium Pharmaceuticals is a small pharmaceutical company in North Carolina, which also received an ODD for CBD and THC to treat glioblastoma in January 2018. Their current work is unclear and they do not appear to have a website, but the fact they obtained an ODD suggests they have some concrete work underway.

Diverse Biotech in Pennsylvania was granted an ODD for the use of CBD to treat glioblastoma in April 2020. A post on their website dated March 2020 stated they had signed a partnership with Duke University Medical Center to further explore CBD for this purpose. Professor Steve Keir of Duke University commented, “We are excited to be collaborating with Diverse Biotech and to evaluate their cannabidiol compounds in our [glioblastoma] models. One of the main goals of our lab is to find new therapies that might improve the outcomes for patients living with this disease. Preclinical testing of novel agents is the first step in this process.”

The above examples primarily concerned glioblastoma, but a Canadian pharmaceutical company called Tetra Bio-Pharma is interested in the use of THC to treat hepatocellular carcinoma, the most common form of liver cancer. They received their ODD for this purpose in November 2019. According to their pipeline page, the company has apparently not made much progress on further testing. However, a May 2021 article reported that the first patient had entered their clinical trial for testing THC and CBD against breakthrough cancer pain, indicating they are moving forward with using cannabinoids for other cancer applications.

Can-Fite BioPharma is an Israeli firm primarily working with single-target synthetic drugs. They are also pursuing the use of CBD and THC to treat liver cancer, and their initial preclinical experiments demonstrated inhibition of liver cancer cell growth with a 5:1 CBD:THC ratio. While the timeline of future research is unclear, the company has filed patent applications related to this discovery.

Cannabics Pharmaceuticals is a Maryland-based pharmaceutical company that conducts research and development activities in Israel. They have an especially strong focus on using cannabinoids to treat cancer, as their homepage immediately links to more information about their goals to develop a cannabinoid-based drug for treating colorectal cancer. A March 2021 press release described how their drug candidate RCC-33 resulted in 35% prolonged survival in mice inoculated with human colorectal cancer cells. While the composition of RCC-33 is unclear, it is described as nonpsychoactive, and thus is either CBD-rich or contains other cannabis constituents aside from THC.

Apollon Formularies is a UK-based pharmaceutical company with most of its operations apparently being carried out by its affiliate in Jamaica known as Apollon Formularies Jamaica Limited. They are federally licensed in Jamaica to cultivate, manufacture, and sell medical cannabis products. A May 2021 press release announced they had worked with a company called Aion Therapeutics to demonstrate that combining medical cannabis formulations and medicinal mushroom formulations (non-psychedelic) resulted in nearly 100% destruction of HER2+ breast cancer cells in preclinical studies. The CEO of Apollon Jamaica, Paul Burke, stated that he wants to “bring these formulations to market as quickly as possible” to help women in Jamaica who cannot afford conventional treatments. A further press release on June 14, 2021 announced that Apollon had signed a long-term lease for its first International Cancer Institute in Jamaica and is moving forward on getting it ready to begin treating patients.

Enveric Biosciences, located in Florida, is focused on exploring the therapeutic utility of cannabinoids for radiation dermatitis and chemotherapy-induced peripheral neuropathy, as well as directly treating glioblastoma. An April 2021 article reported the company was preparing to conduct a Phase 1/2 clinical study in Israel with CBD and other cancer drugs against glioblastoma; they already have preliminary approval and are awaiting final approval from an Israeli hospital and the Ministry of Health.

Pascal Biosciences has locations in both the United States and Canada and is also focused predominantly on using cannabinoids to treat glioblastoma. However, they are unique for their research into combining cannabinoids with immunotherapy drugs to enhance their effectiveness. The cannabinoid products appear to be semi-synthetic and not just pure extracts of the cannabis plant. The company plans to enter human clinical studies for glioblastoma sometime in 2021. A September 2020 press release announced that Pascal was planning to begin safety testing for their immunotherapy drug, although the exact timeline was not noted.

It is truly extraordinary how many pharmaceutical companies are pursuing the use of cannabinoids to treat cancer. This unprecedented interest is a testament to the strength of the scientific evidence and the real potential for efficacy. While cannabis-based pharmaceutical options for cancer treatment will inevitably emerge, patients must always have access to the full-spectrum THC-rich and CBD-rich products of their choosing through local medical cannabis programs. It would not be good for patients or society at large for pharmaceutical cannabis products to be the only options. Nonetheless, it is excellent that so many companies are involved in researching cannabis for cancer, as this work will accelerate the production of clinical trial data and further the discovery of effective protocols for cancer treatment.

The post The Pharmaceutical Companies Exploring Cannabis as a Cancer Treatment appeared first on The Cannabis for Cancer Declaration.

Both primary phytocannabinoids, tetrahydrocannabinol (THC) and cannabidiol (CBD), have been shown to kill PC cells. A study conducted in 2006 by researchers with Complutense University in Spain found that THC induced programmed cell death (apoptosis) in four PC cell lines via activation of CB2 receptors. Tumors generated in mice exhibited slower growth in response to THC or a synthetic cannabinoid (JWH) than with no treatment.

A 2018 study led by Dr. Marco Falasca with Curtin University in Perth, Australia found that CBD worked with the chemotherapeutic agent gemcitabine to extend survival of cancerous mice by three times compared to gemcitabine alone or no treatment. The treatment combination also reduced pancreatic tumor cell proliferation in the mice, and CBD helped prevent resistance of the cancer cells to gemcitabine’s effects.

The latest preclinical study was published in 2020 in the International Journal of Molecular Sciences, and confirmed the ability of THC and CBD to inhibit proliferation of PC cells and suppress tumor growth in animals. Interestingly, by decreasing levels of a protein that inhibits immune function, the THC and CBD may have boosted the destruction of PC cells by immune cells. In the chart below, CT are the control mice that received no treatment, while “Can” mice received cannabis oil containing a 1:1 THC:CBD blend. WT (wild-type) means normal, non-modified mice with natural CB1 and CB2 cannabinoid receptors present.
 

 
There is emerging human evidence that CBD could help fight pancreatic cancer. A case series published in August 2020 by Austrian doctors followed nine patients who used CBD for PC. All but two also received standard chemotherapy, and the most common dose was 400mg per day. The average overall survival was 11.5 months, about twice as long as would have been expected based on comparison to a different population-based study. Given the demonstrated ability of CBD to synergize with chemotherapy to inhibit PC growth, it is not surprising that survival benefits have been reported.

Dr. Falasca, who conducted the above 2018 study, is currently seeking to conduct a human trial of CBD with PC patients. Donations are currently being accepted on GoFundMe to support the trial . The Cannabis for Cancer Declaration strongly encourages you to donate what you can to help make this happen. There are rarely direct opportunities to assist such important research on cannabis and cancer. If you cannot donate, sharing this information is also tremendously helpful. With further research and more awareness, the possibility of cannabis becoming a mainstream tool for fighting cancer becomes ever greater.
 

The post Cannabis and Pancreatic Cancer – New Research and Upcoming Clinical Trial appeared first on The Cannabis for Cancer Declaration.

Spontaneous Regression of Septum Pellucidum/Forniceal Pilocytic Astrocytomas — Possible Role of Cannabis Inhalation

A 2011 article published by doctors with the Division of Pediatric Neurosurgery at BC Children’s Hospital in Canada was the first to link some form of cannabis intake with tumor regression. Two children with astrocytoma tumors underwent surgery to remove the tumors, although a small amount of residual tumor tissue was left in each case. After the first three years of follow-up, one tumor remained the same while the other slightly increased in size. During the second three-year surveillance period, both tumors regressed, despite the absence of conventional treatment. As the authors stated, “The tumors regressed over the same period of time that cannabis was consumed via inhalation, raising the possibility that the cannabis played a role in the tumor regression.”

Cannabis Extract Treatment for Terminal Acute Lymphoblastic Leukemia with a Philadelphia Chromosome Mutation

This 2013 case study was apparently the first to examine the impact of tetrahydrocannabinol (THC)-rich cannabis oil on cancer. A 14-year-old female patient with an aggressive form of leukemia initially received chemotherapy and radiation treatments for nearly three years; however, these measures failed to stop the cancer and the patient was placed in palliative home care. Cannabis oil was used as a last resort. The first dose was given on February 21, 2009. Prior to this, from February 4th to the 20th, the patient’s leukemic blast cell count rose from 51,490 to 194,000. Even after beginning the oil, the count continued to rise, peaking at 374,000 on February 25th. However, there was subsequently a sharp decrease in blast count, which correlated with an increase in the cannabis doses. By Day 39, the blast count had dropped to 300. The total treatment lasted 78 days, at which point the leukemic blast cells were almost completely gone. Unfortunately, the patient passed away from a bowel perforation that was reportedly caused by side effects from the high doses of previously administered chemotherapy. The doctors concluded:

“These results cannot be explained by any other therapies, as the child was under palliative care and was solely on cannabinoid treatment when the response was documented by the SickKids Hospital. The toxicology reports ruled out chemotherapeutic agents, and only showed her to be positive for THC when she had ‘a recent massive decrease of WBC from 350,000 to 0.3′ inducing tumor lysis syndrome, as reported by the primary hematologist/oncologist at the SickKids Hospital.” Tumor lysis syndrome can result from the toxins released when cancer cells are killed.

*Note: Hemp oil refers to THC-rich cannabis oil in this context, not hemp-derived CBD-rich oil

Interestingly, a report in 2016 from German doctors at the University Hospital Tübingen further supported the potential of THC to fight leukemia. They stated, “We have anecdotal evidence that THC may have contributed to disease control in a patient with acute undifferentiated leukemia.” The nature of this evidence was quite indirect though, as the doctors extracted blood plasma from an elderly patient treated with dronabinol (synthetic THC) and then cultured leukemia cells in the plasma. The patient received no other anticancer treatment. Doctors found there was an inhibitory effect of the plasma on the cells, and stated, “This observation argues for an antileukemic activity of dronabinol in vivo [in this case, in vivo refers to a human, not animals]. Indeed, one concern about using cannabis to treat cancer is that effective anticancer doses are not possible to obtain. This study offers evidence alleviating that concern. However, it was not entirely clear if a control experiment was conducted (testing dronabinol-free plasma on Jurkat leukemia cells). In any case, it was concluded that the study supported THC as a potential low-toxic therapy option for a subset of acute leukemia patients.

Medical Cannabis in the Palliation of Malignant Wounds – A Case Report

A case report describing a patient with recurrent squamous cell carcinoma who used vaporized cannabis and topically-applied cannabis oil was published in 2017 by a physician with the University of Toronto (full text here). Although the patient was mainly seeking pain relief, there was indication of an antitumor effect. Vaporization of 0.5g to 1.0g of dried cannabis (7.25% THC/8.21% CBD) allowed him to discontinue some pain medications and tremendously reduce others. He switched to topical use of a cannabis-infused sunflower oil (5.24% THC/8.02% CBD) after vaporization became impractical. As the chart below shows, the tumor size was increasing rapidly until it reversed course once topical treatment commenced.

The report’s author stated, “Before the use of topical MC oil, the patient’s wound was growing rapidly. Yet, after a few weeks, a modest regression of his malignant wound was observed while the patient used topical MC. This secondary outcome suggests that topical MC may promote antineoplastic activity as per the findings of Casanova et al. [referring to a study showing cannabinoid receptor activation reduces skin tumor growth].” Unfortunately, the patient still passed away from apparent metastasis of the cancer. This is not surprising; the oil used here was substantially weaker than oils reportedly used by other skin cancer patients – 13% vs. 50-80% in more concentrated extracts. Furthermore, the patient ingested very little cannabis internally. This action would have been needed to potentially fight metastasis. Nonetheless, the charted growth of the tumor strongly suggests an antitumor effect of cannabis.

Case Report: Clinical Outcome and Image Response of Two Patients With Secondary High-Grade Glioma Treated With Chemoradiation, PCV, and Cannabidiol

A pair of case reports published in January 2019 by Brazilian doctors examined the use of CBD along with surgery, chemotherapy, and radiation for high-grade gliomas. Patient 1, a 38-year-old male, was diagnosed with Grade II astrocytoma in August 2010 after a partial surgical resection. Subsequent chemotherapy with temozolomide from 2011-2013 prevented regrowth until 2015, leading to recontinuation of a lower dose of temozolomide in March 2015. Proving ineffective, the dose was increased in June 2015, yet the tumor continued to grow. The temozolomide was discontinued in January 2016 and another surgery was planned, followed by radiation and a new combination of chemotherapy known as PCV (procarbazine, lomustine, and vincristine) which lasted six cycles (administered for 5 days every 28 days). After the second surgery, the diagnosis had progressed to Grade IV glioblastoma. At this time CBD was also administered at a dose of 300-450mg/day. The patient experienced few symptoms of nausea or fatigue and was still able to practice sports.

One month after the end of the chemotherapy and radiation, a phenomenon known as pseudoprogression occurred (increased swelling and inflammation), which resolved after a short period. As the authors state, pseudoprogression “does not represent a progression of the disease, and is often a marker of longer survival, presumably because it represents a robust response to treatment… The anti-inflammatory and neuroprotective actions of CBD may be related to the absence of side effects associated with PSD, such as headache, or changes relevant to tumor location.” The CBD used during the study, which lasted around 2 years, was from a full-spectrum hemp-derived CBD oil containing less than .3% THC. During their first year of treatment, patients also vaporized THC-rich cannabis flower.

Patient 2, also a 38-year-old male, was diagnosed with Grade II oligodendroglioma in April 2014 after surgical biopsy, with MRI showing an expansive, infiltrative lesion. He received temozolomide from September 2014 to July 2015, with no growth until an MRI revealed increased dimensions in February 2016. At this time the patient received a partial surgical resection, radiation, and six cycles of the PCV combination therapy. After this surgery, the glioma had progressed to Grade III. CBD was administered alongside the PCV at doses of 100-200mg/day. Like Patient 1, this patient was able to still practice sports and had few symptoms of nausea and fatigue.

The authors concluded, “Although this study only had two cases, it is interesting to note the good clinical and radiological evolution that might be related to this therapeutic association. Future randomized placebo-controlled trials with a larger number of patients are needed to confirm the study findings.”

Report of Objective Clinical Responses of Cancer Patients to Pharmaceutical-grade Synthetic Cannabidiol

 
A 2018 case series analyzed 119 cancer patients over a four-year period who used a synthetic form of CBD. One of the researchers involved was Dr. Wai Liu, whose preclinical work showing how CBD and other nonpsychotropic cannabinoids (cannabigerol, cannabigevarin, and their respective acid forms) fight leukemia has attracted some significant media attention. Clinical responses were observed in 92% of the patients, based on reductions in circulating tumor cells or reduction in tumor size. Most patients used between 20-60mg CBD per day. Several particularly notable cases were highlighted by the authors. For example, brain scans were included from a five-year-old with anaplastic ependymoma who underwent surgery, chemotherapy, and radiation. These treatments exerted no substantial effects as of January 2016. He began taking 20mg CBD per day in February 2016. A scan in April showed tumor progression, but subsequent September and December 2016 scans revealed substantial regression (60% volume decrease between February and December).

Other notable cases are quoted below.

“72/male – Prostate Cancer – Patient has had cancer immunotherapy, sono and photodynamic therapy (14) which was successful. On resumption of testosterone injections his prostate specific antigen (PSA) levels increased to 16. We started him on CBD early in 2015 at a dose of 10 drops twice a day (10mg), three days on and three days off. There was a reduction in circulating tumor cells (CTCs) with CBD alone from an initial 8.1 cells/7.5mL to 5.9 cells/7.5mL, then steady reduction over the course of 12 months of 4.8, 4.2, then 3.2 cells/7.5mL. He is still under treatment.”

“68/female – Breast cancer with bone metastases – Patient was diagnosed in March 2014 with progressive disease. She started local radiotherapy. We started her on CBD in January 2015, all subsequent scans showed stable disease. She has had no treatment other than CBD following radiotherapy.”

“65/female – Oesophageal cancer – Patient was diagnosed in May 2016. She had a stent put on place at that time and was given an expected survival of three months. Since then, she has been on CBD as the only treatment, and she has continued to refuse all standard treatments and investigations. We last saw her in November 2016, when she was looking well and had in fact regained weight. She died in January 2018.”

“65/female – Breast cancer – Patient was diagnosed in November 2009, and refused all conventional treatments and investigations. On examination she had a large fungating lesion 15cm in diameter in the left breast, and also palpable left axillary nodes. She began treatment with CBD in October 2014. We persuaded her to have radiotherapy in November 2014. She only agreed to have half the recommended treatment course. She has continued on CBD alone and on her last appointment the tumour in her left breast was 2cm in diameter, with no palpable axillary nodes.”

“62/female – Breast cancer – We first saw this patient in May 2014 and she has been on CBD, as the only treatment, since October 2014. We carried out various CTC tests in October 2014 which showed 10.6 cells per 7.5mL. Subsequent tests in July and October 2015, November 2016 and October 2017 showed CTCs to be 7.3, 6.8, 5.0 and 3.9 cells/7.5mL, respectively. Patient is currently stable with no symptoms.”

“67/female – Lobular breast cancer – Patient was diagnosed in November 2012. We first saw her in March 2014, we gave her CBD in October 2014, which is the only method of treatment. Initial CTCs in October 2014 was 9.3 cells per 7.5mL. Follow-up measurements in September 2015, March 2016 and March 2017 have been 7.5, 6.8, and 3.0 cells/7.5mL, respectively. All standard clinical investigations and scans have been normal since the beginning of 2015.”

Concomitant Treatment of Malignant Brain Tumours With CBD – A Case Series and Review of the Literature

Doctors affiliated with a hospital in Austria published a case series in the journal Anticancer Research in 2019 which documented the experiences of nine patients with brain tumors who used CBD as a component of their treatment. The doctors concluded, “By the time of the submission of this article, all but one patient are still alive with a mean survival time of 22.3 months (range=7-47 months). This is longer than what would have been expected.” The longer survival time is most logically indicative of a direct anticancer effect. Survival was also extended in the double-blind, placebo-controlled trial discussed at the end of this article.

Striking Lung Cancer Response to Self-Administration of Cannabidiol: A Case Report and Literature Review

 
Doctors with the Royal Stoke University Hospital in England published a case report in 2019 about a man who used CBD and subsequently experienced shrinking of his lung tumor. He was diagnosed with lung cancer in autumn 2016 and his oncologist gave him 6-12 months to live without treatment. Given the patient’s age of 83, he declined the treatment to maintain his quality of life. He did nothing until a friend suggested he try CBD oil, so he began using a legal version purchased from a health store in September 2017, starting with 2 drops (1.32mg CBD) twice daily for a week and then 9 drops (6mg CBD) twice daily until the end of September. It is unclear if this dosing continued into October. Before using CBD, his cancer measured between 30-40mm, which was apparently the primary tumor. In November 2017, a CT scan revealed near total resolution of the apparent primary tumor and showed most lymph nodes were normal size.

The doctors concluded, “In summary, the data presented here indicate that CBD may have had a role in the striking response in a patient with histologically proven adenocarcinoma of the lung as a result of self-administration of CBD oil for a month and in the absence of any other identifiable lifestyle, drug or dietary changes.” Another scan from January 2018 showed further stability; although this scan was not shown, the original diagnostic scan and post-CBD November 2017 scan were included and shown below.

 
Pre-CBD October 2016

Post-CBD November 2017

Dramatic Response to Laetrile and Cannabidiol (CBD) Oil in a Patient with Metastatic Low Grade Serous Ovarian Carcinoma

Another case study in 2019 by doctors with the UC San Diego Moores Cancer Center and UC San Diego School of Medicine reported on an 81-year-old patient with metastatic low grade serous ovarian carcinoma (LGSOC). In April 2017, the patient underwent surgery to have some cancerous tissue removed, and a May 2017 CT scan revealed several more soft tissue masses. The cancer was officially diagnosed as LGSOC, being positive for both estrogen and progesterone receptors.

Doctors recommended chemotherapy, but the patient declined due to concerns about quality of life. She instead pursued treatment with Laetrile tablets (500mg orally four times per day) and CBD oil (1 drop sublingually each evening) starting in May 2017. Her CA-125 level was measured to ascertain the status of the cancer, and immediately began to decline after the dual therapy started, as shown by the chart below. The potential contribution of each therapy is discussed later.

Another CT scan in July 2017 showed a decrease in the size of several masses. In November 2017, a further scan showed “dramatic reduction” in disease burden, as all identified lesions were almost completely resolved. The final assessment noted in this article occurred in December 2018 and revealed continued response to treatment.

This case is complicated by the combined use of Laetrile and an apparently very low dose of CBD that was not fully characterized. However, the authors noted that Laetrile, a semi-synthetic version of amygdaline (a naturally-occurring compound in some plants), has not been shown to be effective against cancer in any clinical trials. It is also a dangerous compound that is not recommended due to the risk of cyanide poisoning. Given this evidence, it is unlikely that Laetrile exerted any anticancer effect. However, there has seemingly never been a report of such a low dose of CBD exerting an anticancer effect before, raising the possibility this case may have been a spontaneous remission. Nonetheless, the previously discussed lung cancer case also involved low-dose CBD ingestion, so it’s possible that in some cases, especially among elderly patients, even low doses of CBD may produce an anticancer effect.

Cannabidiol Possibly Improves Survival of Patients with Pancreatic Cancer: A Case Series

The same team that published the peer-reviewed paper “Concomitant Treatment of Malignant Brain Tumours With CBD – A Case Series and Review of the Literature”, discussed earlier, also published a case series in 2020 featuring patients with pancreatic cancer who used CBD. While this paper has apparently not undergone the full peer-review process yet, the results come from a team with a previously published peer-reviewed article on similar subject matter. Nine patients were followed; all used chemotherapy along with CBD except for two who only used CBD. The daily dose was usually 400mg CBD, and the average overall survival was 11.5 months. As with the previous case series, survival was significantly extended with this protocol. The doctors concluded that overall survival was about two times longer than reported in a recent population-based study of pancreatic cancer patients.

The Effect of Cannabis in the Treatment of Hodgkin’s Lymphoma in a Pregnant Patient – Extensive Case Report and Literature Review

In 2021, a case report of a Romanian woman who used cannabis to treat Hodgkin’s lymphoma during pregnancy was published in the Journal of the Balkan Union of Oncology by doctors with the University of Oradea. The full PDF is found here. The patient was diagnosed with Stage IIB Hodgkin’s lymphoma (HL) in 2009 and treated with chemotherapy and radiation, which led to incomplete remission as a persistent 2cm tumor remained in the thorax. The cancer was largely dormant until 2014 after the patient became pregnant, when an MRI scan and biopsy revealed an apparently new tumor in the thorax, which was again confirmed to be HL and apparently measured 15 x 13cm. The patient refused the recommended chemotherapy and the child was eventually born by C-section.

In 2015, the patient became pregnant again and refused to terminate the pregnancy. The HL continued to progress, and symptoms were managed primarily with analgesic treatments. At 26 weeks of this second pregnancy, the patient began using cannabis oil topically and orally, ingesting between 1mL and 5mL 3 times per day. The potency and constituents of the oil were not reported, and it is unclear whether the oil was dominant in THC or CBD. Nonetheless, the patient’s pain and quality of life improved, and, apparently, the dimensions of the 15 x 13cm thorax tumor reduced to 8.3cm (the description of the reduction in this case is obscure). Sometime after the second baby was delivered by C-section, the patient’s condition progressed to Stage IV HL, and she began using a variety of conventional treatments in 2016 and 2017 including chemotherapy, immunotherapy, and surgery. She apparently did not use any treatments from 2017 to 2019, and resumed chemotherapy in 2019. It was unclear if she was still using cannabis at this time. As of the article’s publishing, it is also unclear what the patient’s status is.

Despite the particular complexity of this case, the fact the patient experienced a reduced tumor burden while taking cannabis oil is notable. The authors stated, “Cannabinoids affect many essential cellular processes and signaling pathways which are crucial for tumor development, as they can induce cell cycle arrest, promote apoptosis, and inhibit proliferation, migration and angiogenesis in tumor cells. In this way we explain the macroscopic tumor reduction in this patient after starting oral medical cannabis.” More information will eventually be included here if able to be obtained.

A Phase 1b Randomised, Placebo-Controlled Trial of Nabiximols Cannabinoid Oromucosal Spray with Temozolomide in Patients with Recurrent Glioblastoma

This trial by the pharmaceutical company GW Pharmaceuticals initially had details revealed in a press release in 2017, and in February 2021 was finally formally published in the British Journal of Cancer. 21 patients were randomized to receive chemotherapy and placebo or chemotherapy and phytocannabinoids in Part 2 of the study (Part 1 was an open-label structure; all patients in Part 2 were different from those participating in Part 1). The phytocannabinoid formulation was nabiximols, also known as Sativex, which is about a 1:1 formulation of THC and CBD containing 2.7mg/spray THC and 2.5mg/spray CBD. Patients started with one spray per day and worked up to a maximum of 12 sprays per day, resulting in a maximum dose of 32.4mg THC and 30mg CBD per day.

The 1-year survival analysis showed that 10 of 12 (83.3%) of patients in the nabiximols group were still alive, compared to 4 of 9 patients (44.4%) in the placebo group. At 2 years, the survival rate was 50% in the nabiximols group and 22% in the placebo group. The median overall survival was estimated to be 21.8 months in the nabiximols group and 12.1 months in the placebo group.

Weaknesses in this trial include the low number of participants and the confounding factor of two patients in the placebo group dying within the first 40 days. However, the results are still impressive and most likely demonstrate an anticancer effect of phytocannabinoids in the treatment of glioblastoma.

Summary

It is clearly remarkable that so many case studies have been published concerning an anticancer effect of phytocannabinoids. Given that both phytocannabinoids and endocannabinoids are consistently shown in preclinical studies to kill or inhibit numerous types of cancer cells through similar mechanisms, it is not surprising that phytocannabinoids appear to be producing responses in humans. Furthermore, since at least 2008, patients have been reporting through various media that high doses of phytocannabinoids have induced full or partial remissions of their cancers. Frankly, it is beyond logical possibility that phytocannabinoids have never, in a single case, produced an anticancer effect in humans. The number of coincidences required for that to be the reality are just too much.

Even though phytocannabinoids can clearly fight cancer in at least some cases, there is still far more to learn about phytocannabinoid therapy for cancer. What are the ideal dose protocols for different patients with different cancers? What types of cannabis should be used? Is there the possibility that cannabis could interfere with some treatments, as has been indicated with immunotherapy? For now, there are no clear answers and it will take a long time to get them. However, one thing is clear. Cancer patients anywhere in the world should be allowed to use cannabis medicine under their doctor’s supervision, and willing terminal cancer patients should be provided free or low-cost cannabis medicine given the very real chance it could save or extend their lives. Many patients do not have time to wait, not even a single day, and the evidence is more than strong enough to justify access to cannabis medicine now.

The post Published Case Studies and a Clinical Trial Showing Cannabis Produces Anticancer Effects in Humans appeared first on The Cannabis for Cancer Declaration.

A key requirement in the FDA’s ODD application is a summary of all relevant scientific data, including preclinical and clinical studies. Without a reasonable level of medical plausibility that a treatment would actually work against the targeted rare disease, there would be no justification to grant ODD. While such designation does not guarantee a drug will end up as a viable treatment, it does suggest a therapy has at least a minor chance of working in humans. Therefore, the fact that numerous cannabis-associated drugs have been granted ODD for the direct treatment of various cancers is a testament to the real potential of cannabis compounds, primarily cannabinoids, as cancer therapies.

No cannabis products intended to treat cancer have been approved by the FDA yet, but the fact that so many have been granted ODD makes it hopeful that one of them may be approved sometime in the next five years. The first apparent designation ever granted for a cannabinoid as an anticancer agent occurred on August 20, 2014 for Benuvia Therapeutics. It concerned cannabidiol (CBD) as a treatment for glioblastoma multiforme, one of the most aggressive brain tumors. The full appearance of the designation on the FDA’s website is featured below, while smaller screenshots are subsequently featured.

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The next ODD for a cancer application of CBD was also granted to Benuvia Therapeutics, except the designation was for the treatment of glioma more broadly rather than glioblastoma multiforme specifically, which is an advanced glioma.

GW Pharmaceuticals (also listed as GW Research Ltd.) is the creator of Epidiolex, the FDA-approved cannabis-derived CBD-rich pharmaceutical product intended to treat seizures associated with rare epileptic conditions like Dravet syndrome. Interestingly, Epidiolex started out as a drug with ODD for treatment of Dravet syndrome, and it successfully moved from simple designation to full-scale approval after clinical trials were completed. This example shows it is possible for a cannabis-based drug to be approved through this framework.

GW Pharmaceuticals has also been exploring the potential of cannabinoids to treat cancer, particularly glioblastoma. The preliminary results of a controlled trial published in 2017 showed that combining tetrahydrocannabinol (THC) and CBD with chemotherapy effectively extended the lives of glioblastoma patients, with median survival of 550 days in the cannabis-treated group, and 369 days in the placebo group that only received chemotherapy. Not surprisingly, GW received ODD for the treatment of glioma with THC and CBD back on December 3, 2015.

In addition to the above clinical trial, significant preclinical evidence suggests THC and CBD could fight glioma. One of the first studies indicating an anticancer effect of THC was published in 1998 and showed that it induced apoptosis in glioma cells. CBD was also shown to induce apoptosis in glioma cells in 2004 by Italian researchers. Both cannabinoids were further demonstrated to synergize with each other to produce greater-than-additive anticancer effects against glioblastoma cells in a 2010 study.

Another company called AXIUM Pharmaceuticals received ODD on January 8, 2018, for the use of THC and CBD to treat glioblastoma multiforme. More information on their progress toward approval is not apparent.

Yet another company exploring cannabinoids for the treatment of glioma is Diverse Biotech. They received ODD for CBD to treat glioblastoma on April 28, 2020. Several months later, they received another designation for CBD bonded with temozolomide, a standard chemotherapy drug for treating gliomas.

While most ODD filings relate to glioma brain tumors, there are two others that concern different cancers. On November 17, 2019, Tetra Bio-Pharma received ODD for the use of THC to treat hepatocellular carcinoma (HCC), the most common form of liver cancer. As THC has been shown to induce apoptosis in HCC cells and shrink HCC tumors in mice, it is certainly worth exploring whether these results could translate to humans.

Most of the medical attention related to cannabis has focused on cannabinoids like THC and CBD. However, other classes of compounds exist within the cannabis plant, including flavonoids. These compounds also possess tremendous medical promise, including potentially as cancer treatments. A study published in July 2019 by researchers from various universities in Massachusetts, including Harvard Medical School, found that a flavonoid derivative of cannabis known as FBL-03G induced apoptosis in pancreatic cancer cells and delayed pancreatic tumor progression in animals. This appeared to constitute at least partially the scientific rationale for the ODD granted to Flavocure Biotech for their cannabis-derived flavonoid drug, known as Caflanone (the brand name for FBL-03G).

With the wide range of ODDs granted to cannabis-based drugs, it is undeniable that the prospect of cannabis treating cancer is being taken seriously at the highest levels. Only with more clinical trials will any of these designations possibly be granted marketing approval, so hopefully they are conducted as quickly and thoroughly as possible.

The post Orphan Drug Designations from the FDA for Cannabis Compounds as Cancer Treatments appeared first on The Cannabis for Cancer Declaration.

Immunotherapy is a growing field of oncology that uses drugs to restore or boost the ability of the immune system to fight cancer. These therapies hold promise for treating cancers that are resistant to chemotherapy and radiation. Some evidence suggests that natural compounds like phytocannabinoids derived from cannabis may stimulate anticancer functions of the immune system, in addition to their more well-defined actions of directly killing cancer cells and inhibiting proliferation.

The Immune System and Cancer

Cells of the immune system can be broken down into those of myeloid lineage and lymphoid lineage. Myeloid lineage immune cells include neutrophils, the most numerous type of immune cell in the body, which seek out and destroy microorganisms. Other myeloid cells include macrophages, which are longer-lived than neutrophils and clear away many kinds of cellular debris in addition to ingesting and killing microorganisms. Lymphoid cells (lymphocytes) include natural killer (NK) cells, B cells, and T cells. B cells are distinct for their ability to produce antibodies, which help other leukocytes and immune system components kill invading cells; they are activated specifically by helper T cells.

Another type of T cell, the cytotoxic T cell, shares the ability of NK cells to kill virus-infected cells or cancer cells, although T cells require activation by other cells whereas NK cells do not. However, many cancer cells are resistant to regular NK cells or cytotoxic T-cells, but a special type of lymphocyte known as a lymphokine-activated killer cell (LAK cell) can destroy some resistant cancer cells. LAK cells appear to derive from either NK cells or a subtype of T-cells, and can share some features with either type of precursor cell. The most important feature of LAK cells is their greater ability to kill tumor cells. Thus, they are a major focus of potential immunotherapy approaches.

How CBD and THC Interact with the Immune System and Cancer

Research suggests that phytocannabinoids may improve the efficiency of LAK-mediated cancer cell destruction. A 2014 study published in Biochemical Pharmacology applied cannabidiol (CBD) to lung cancer cells and found that it caused the increase of intercellular adhesion molecule-1 (ICAM-1) on the surface of the cancer cells. ICAM-1, as the name implies, can help cells adhere to each other, and is involved in many biological processes. The increase in ICAM-1 caused cancer cells to become more susceptible to lysis (cell breakdown and destruction) by LAK cells, as there were essentially more targets for the LAK cells to bind to. Specifically, the LAK cells appeared to bind to ICAM-1 through lymphocyte function-associated antigen 1 (LFA-1), a protein on leukocytes that facilitates their adhesion to other cells. Tetrahydrocannabinol (THC) and an analog of the endocannabinoid anandamide also increased ICAM-1 levels and led to increased killing of cancer cells by LAK cells, although the level of ICAM-1 increase was less than that induced by CBD. Importantly, all three cannabinoids had very little to no effect on ICAM-1 levels in healthy lung cells and did not lead to increases in LAK-mediated lysis of those cells. Both cannabinoid receptors, CB1 and CB2, were integral to the increased ICAM-1.

A 2019 study by researchers from the United States and Japan examined how CBD interacted with immunotherapy treatment for Burkitt lymphoma (BL). BL cell lines were altered to express higher levels of a protein called AF1q, which drives cancer growth and confers resistance against immunotherapeutic drugs. The mechanism of resistance was posited to be reduction of ICAM-1 expression, and apparently by increasing ICAM-1, CBD reversed drug resistance. The authors concluded, “CBD holds potential to enhance the efficacy of immunotherapy for BL.”

THC possesses well-demonstrated anti-inflammatory properties, which appear to exert some inhibitory effects against skin cancer. A 2015 study by researchers with the University of Bonn in Germany applied THC to two mouse melanoma cell lines, finding that THC had no effect on cell proliferation. However, when the cells were injected into mice and tumors developed, THC-treated mice had 50% smaller tumor volumes. The shrinkage was due to reduced infiltration of macrophages and neutrophils. Therefore, the anticancer effects in this case seemed to be largely driven by effects on the immune system.

CBD has also been shown to reduce breast tumor growth and metastasis at least partially through anti-inflammatory effects. A 2015 study conducted at Ohio State University determined that CBD impaired the recruitment of tumor-associated macrophages in primary tumors and lung metastases in mice through reduced production of pro-inflammatory cytokines. Tumor-associated macrophages are involved in pro-tumor effects like generation of blood vessels to tumors, enhanced tumor cell invasion, and suppression of anticancer functions of NK cells and T-cells.

Another benefit was revealed in a 2020 study published in the International Journal of Molecular Sciences, which examined the effects of THC and CBD on pancreatic cancer cell growth. Both phytocannabinoids were effective at inhibiting proliferation of the isolated cancer cells as well as suppressing tumor growth in mice. The anticancer effect was apparently at least partially through reduction of an immune checkpoint pathway. Such pathways help regulate the immune system and prevent excessive activation. The checkpoint affected was the PD-1/PD-L1 pathway, which involves the binding of a molecule called programmed death-ligand 1 (PD-L1) to programmed cell death protein-1 (PD-1) on T-cells to cause inactivation and death. This is normally a healthy process, but when cancer cells overexpress PD-L1, they stop T-cells before they can carry out their anticancer functions. In fact, blocking PD-1 on T-cells is a key target of immunotherapy drugs, including nivolumab which is further discussed below. Therefore, the demonstrated ability of both THC and CBD to reduce expression of PD-L1 on pancreatic cancer cells may help T-cells destroy them. The researchers stated, “The inhibition of PD-L1 expression by CBD and THC will enhance the anti-tumour immune response induced by immune checkpoint blockade in pancreatic cancer.”

The effects of phytocannabinoids on the PD-L1/PD-1 pathway may extend to other cancers, as CBD has also been shown to reduce PD-L1 on the surface of glioblastoma cells, which was reportedly associated with increased cell death of the cancer cells.

THC’s anti-inflammatory and immunosuppressive effects are not always linked to good outcomes. In 2000, researchers from the University of California, Los Angeles, School of Medicine administered THC to mice with lung cancer and found that it accelerated tumor growth. This effect was linked to THC-induced increase of anti-inflammatory cytokines (IL-10 and TGF-beta) and a decrease in interferon-gamma, an immune system protein involved in antitumor effects. The activation of CB2 receptors by THC was the apparent cause of modulated cytokine expression.

Similar results were reported in a 2005 study, where THC enhanced tumor growth in a mouse model of breast cancer by suppression of the antitumor immune response via CB2 activation and enhancement of the anti-inflammatory cytokines IL-4 and IL-10.

The immunosuppressive effects of THC may be relevant in regards to interfering with immunotherapy. A 2019 study conducted in Israel examined patients with melanoma, non-small cell lung cancer, and renal clear cell cancer who used the immunotherapy drug nivolumab with or without predominantly THC-rich cannabis. Cannabis use was associated with a reduced response rate to the immunotherapy drug, although it did not affect the key outcomes of progression-free survival or overall survival. Quite interestingly, the authors noted a “possible paradoxical interaction related to THC level, as patients who had high‐THC‐percentage products had a better [response rate] to immunotherapy compared with those with low‐THC‐percentage products.”

It is also somewhat paradoxical that THC shows interference with nivolumab, as this immunotherapy drug works by blocking PD-1, the target of PD-L1, the latter of which is shown to be inhibited by THC in pancreatic cancer cells. Also, despite THC’s interference with response to the drug, no impact on patient survival was seen, potentially indicating THC was working against the cancer in other ways. In addition, since this study did not include pancreatic cancer patients, it may be that THC would show better results in that cancer type, so more research is critical to ascertain if synergy may be observed in that or other cancers. In any case, special care must be taken when using any phytocannabinoids alongside immunotherapy drugs due to the real potential for negative interactions.

Overall, the ability of phytocannabinoids to reduce inflammation may help prevent the development of some cancers. However, evidence also shows that phytocannabinoids, especially THC, may facilitate cancer development through immune system suppression, so more research is needed to clarify when the effects are beneficial or detrimental.

How 2-AG Interacts with the Immune System and Cancer

The previously mentioned study of CBD and THC upregulating ICAM-1 pointed to the potential of anandamide to work with the immune system to improve clearance of cancer cells. The other primary endocannabinoid, 2-arachidonoyl glycerol (2-AG), may also help the immune system fight cancer, although the effects are less clear. A study published in 2019 found that 2-AG substantially reduced pancreatic tumor growth in mice via activation of CB1 receptors. 2-AG also promoted the maturation of dendritic cells (DCs) via CB1 receptor activation. DCs help activate T-cells and trigger antitumor activity, and are a growing target of immunotherapy. However, the DC maturation was only observed in isolated DCs and in vivo mouse spleen DCs, not tumor tissue. Other immune cells called myeloid-derived suppressor cells (MDSCs) which suppress T-cells and are linked to tumor progression were increased in tumor tissues after 2-AG administration.

Although the immune effects of 2-AG are inconsistent, the fact that 2-AG effectively suppressed growth of pancreatic tumors in mice suggests that its anticancer effect is greater than any potential procancer effect. It seems that the positive impact of 2-AG on DC maturation outside the tumor, or the direct antiproliferative effects on pancreatic cancer cells themselves, outweighs the negative impact of increasing MDSCs. The researchers noted that gemcitabine, a chemotherapy drug used for pancreatic cancer that reduces MDSCs, may be effectively combined with 2-AG for synergy. Despite the disparate impacts on immune function, it was still suggested that 2-AG “may be a promising new drug for cancer immunotherapy.”

An earlier study in 2015 in the journal Life Sciences also demonstrated conflicting effects of 2-AG on the immune microenvironment surrounding tumors. In bladder cancer cells, the activation of CB1 and CB2 receptors by 2-AG resulted in several immunological effects. Secretion of tumor necrosis factor-alpha (TNF-α), a small signaling protein (cytokine) involved in inflammation, was increased, as was the expression of selectins on the surface of the cancer cells, which are involved in adhesion. The selectin increase may have explained the third observation; the adherence of T-cells to cancer cells. However, selectins are largely associated with metastasis, whereas TNF-α is linked with both pro- and anti-tumoral effects. While the role of 2-AG in bladder cancer progression is especially unclear, more research is needed with animals, as the function of cannabinoids in living organisms can often be quite different than observed in cells. For example, although 2-AG was associated with the theoretically negative effect of increasing MDSCs in pancreatic cancer tumors in a previously mentioned study, administration of the endocannabinoid in mice shrunk the tumors, indicating a net anticancer effect.

The Role of Cannabinoid Receptors in the Immune System and Cancer

The development of blood vessels to tumors, known as angiogenesis, is integral to the continued growth of solid cancers past a certain point. Macrophages contribute to angiogenesis by releasing compounds that drive the growth of new blood vessels to tumors. A 2016 study determined that activation of CB1 and CB2 receptors on human lung macrophages with synthetic cannabinoids reduced the release of numerous growth factors like vascular endothelial growth factor-A, vascular endothelial growth factor-C, and angiopoietins (Ang1 and Ang2). However, activation of receptors by 2-AG was not effective in decreasing these compounds, although the researchers stated that 2-AG might affect other aspects of macrophage function not tested in this study. In any case, the inhibition of vascular remodeling induced by macrophages may be another mechanism by which cannabinoid receptors interfere with tumor growth.

Further evidence for the function of cannabinoid receptors in facilitating anticancer functions of the immune system was revealed in a 2016 study by researchers from the United States, Germany, and South Korea. It examined the disparate impact of CB1 and CB2 receptors on the development of hepatocellular carcinoma (HCC), a form of liver cancer. The CB1 receptor was associated with cancer development while the CB2 receptor was associated with blocking cancer development, as indicated by experiments where CB1 or CB2 receptors were inactivated in mice. Specifically, CB2 receptor inactivation decreased recruitment of hepatic T-cells with known antitumor effects by reducing expression of cytokines. Therefore, it appears that the CB2 receptor is involved with helping recruit T-cells to liver tumors to fight them.

Phytocannabinoids and Cancers of the Immune System

Leukemias and lymphomas are cancers of the immune system which involve various immune cells that begin replicating in an uncontrolled manner and fail to develop into healthy, functional cells. In 2005, researchers in London demonstrated that THC induced apoptosis (programmed cell death) in three leukemia cell lines. The next year, a study showed CBD induced apoptosis in both leukemia and lymphoma cells. Importantly, CBD reduced the size of lymphoma tumors in mice, indicating that even in the context of the living tumor microenvironment it was still effective.

Yet further, the phytocannabinoids CBD, cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabigevarin (CBGV), and cannabigevaric acid (CBGVA) were shown in a 2013 study published in Anticancer Research to stop the proliferation of leukemia cells, although CBD and CBG were the most potent among those compounds.

Summary

There is clearly a quite complex relationship between endocannabinoids, phytocannabinoids, the immune system, and cancer, as evidenced especially by the ability of THC to either promote or inhibit cancer growth through immune system interactions. Despite the negative observed effects of THC, most studies indicate anticancer effects of THC in both cell and animal studies, not to mention human cases. Furthermore, the latest meta-analysis of cannabis use and cancer risk, published in August 2020, found that cannabis use was associated with a slightly reduced risk of most cancers, except for testicular cancer. The most reasonable explanation is that the anticancer functions of THC, other phytocannabinoids, and terpenes overwhelm immunosuppressive effects of THC and the carcinogenic properties of compounds in cannabis smoke.

The post The Relationship Between The Endocannabinoid System, Phytocannabinoids, The Immune System, and Cancer appeared first on The Cannabis for Cancer Declaration.

The Endocannabinoid System Changes in Disease States

Many cells in the human body possess cannabinoid receptors, known as CB1 and CB2 receptors, with some regions of the body featuring higher concentrations of receptors than other parts. These receptors are proteins that convey signals from outside a cell to inside a cell after being activated by endocannabinoids, the natural ligands of cannabinoid receptors. Central nervous system (CNS) cells express especially high levels of CB1, while cells within the immune system have especially high levels of CB2. While receptor amounts may vary across the body, and different individuals have natural variations as well, there are more-or-less “normal” expression levels of cannabinoid receptors in different tissues. These quantities of cannabinoid receptors do not always stay the same – they change in response to different conditions, including the emergence of disease states. For example, when Parkinson’s disease patients were compared to healthy controls, CB1 receptor levels were both upregulated (increased) and downregulated (decreased) in different brain regions. In Alzheimer’s patients, CB1 expression in certain brain areas was found to increase in the early stages of the disease, but decrease in the later stages, which the authors suggested was due to the ECS trying to compensate against diminished neural function before being overwhelmed by disease progression.

Conversely, in Huntington’s disease (HD), CB1 receptors continuously decrease in certain brain areas as HD progresses, whereas CB2 receptors in brain immunity-related cells called microglia increase. In the case of HD, the CB1 decrease was clearly correlated with disease severity, while CB2 receptors appeared to confer neuroprotection, as demonstrated by the harm that came from deleting them and the benefits observed when activating them in animal studies.

In addition to receptors, the endocannabinoids themselves (as well as synthesizing and degrading enzymes) are modulated in several diseases. It may even be that endocannabinoid deficiency could be the cause of certain conditions, as explored in this 2016 article about clinical endocannabinoid deficiency. For example, lower levels of anandamide, one of the primary endocannabinoids, are associated with chronic migraines. Conversely, excessive levels of endocannabinoids may contribute to some diseases, such as obesity. Changes in cannabinoid receptor density and endocannabinoid levels have been observed in many kinds of cancer and are explored below.

The Endocannabinoid System and Brain Cancer

A comprehensive study published in 2012 by Chinese researchers analyzed receptors and endocannabinoids present in normal tissue, low-grade glioma brain tumors, and high-grade gliomas. These tumors originate from supportive glial cells in the nervous system. Normal tissue featured decreased anandamide levels compared to the gliomas, but the other primary endocannabinoid, 2-AG, was increased. Both CB1 and CB2 receptors also increased significantly, although the authors noted that other research has found little or no change in CB1 expression of glioma tumors compared to normal tissue. In any case, results from this study are shown below (N = non-tumor tissue, L = low-grade glioma tissue, H = high-grade glioma tissue).

While the role of the CB1 receptor appears murkier, studies seem to agree that CB2 receptor expression increases as malignancy grade (a measure of metastatic and growth potential) increases. Whether this is a protective mechanism or a malignant development is unclear, but another study published in the journal Child’s Nervous System looking at expression of the CB1 receptor gene in children with low-grade gliomas supports the protection theory at least for that receptor. Researchers performed extensive molecular analysis on primary untreated tumors from pediatric patients who underwent subtotal (incomplete) surgical removal and found that high CB1 receptor expression was ultimately associated with spontaneous tumor involution (shrinkage) or stability, as indicated by at least 10 years of follow-up with patients. It was concluded that high expression levels of CB1 may make the tumors more susceptible to the antitumor effects of endocannabinoids like anandamide, which could cause shrinkage, a theory in line with many studies showing how activation of CB1 receptors inhibits cancer. The possibility that CB2 upregulation may also be protective is bolstered by the fact that CB2 activation is linked to inhibition of glioma cell invasion.

The Endocannabinoid System and Breast Cancer

There are several forms of breast cancer differentiated by the presence or absence of different receptors (ERα, PR, and HER2) on the cancer cells. Depending on the type, CB1 and especially CB2 receptors vary. For example, in HER2+ breast cancer, a 2015 study examining hundreds of breast tumor samples determined an association between high CB2 protein expression and decreased overall survival. This was backed up by another study which indicated a positive correlation between histologic grade of breast tumors and CB2 receptor mRNA expression, while normal breast tissue had hardly any CB2 expression. It is important to note here that some studies examine the mRNA that codes for cannabinoid receptor proteins rather than the proteins themselves, although some research (described in the Discussion of the linked article) indicates a correlation between cannabinoid receptor protein levels and the associated mRNA. In this case, the fact that both high CB2 protein expression and high CB2 mRNA expression is correlated with more aggressive disease bolsters the correlation.

While CB1 receptor mRNA was also present in the above study, levels were even lower than in normal breast tissue, contrary to CB2 receptor mRNA which was significantly higher than CB1 receptor mRNA in all the tested cell types. Due to the abundance of CB2 receptors found in breast cancer subtypes resistant to conventional therapies, researchers suggested the possibility that selective targeting of CB2 receptors could be a novel treatment option, as they had demonstrated the phytocannabinoid tetrahydrocannabinol (THC) induced apoptosis in breast cancer cells via CB2 activation. In contrast to results seen in HER2+ breast cancer, a 2017 study linked higher CB2 protein expression with better recurrence-free survival in ERα+ and ERα- breast cancer patients (chart shown below), along with demonstrating that CB2 activation inhibited invasion of both cell types. This is notable as 60-70% of breast cancers are ERα+. Also of note, anandamide has been shown to inhibit proliferation of ERα+ cells, although through CB1 activation rather than CB2.

The Endocannabinoid System and Colorectal Cancer

The importance of the CB1 receptor in colorectal cancer (CRC) was illuminated in a study with mice, in which loss or inhibition of CB1 receptors through genetic or pharmacological means accelerated tumor growth and activation of those receptors reduced tumor growth. Other animal evidence has also pointed to CB1 receptors acting as tumor suppressors in CRC. These observations were further supported in a small human study conducted by Italian researchers, in which patients with metastatic and non-metastatic colorectal cancer were analyzed to determine differences in CB1 receptor protein expression. Patients with metastatic disease had a lower level of CB1 receptors than those without metastasis, indicating that dysfunctional CB1 signaling may contribute to the spread of cancer cells. The authors concluded, “drugs able to induce CB1 receptor expression can be helpful in order to set new anticancer therapeutic strategies.”

As for endocannabinoids, a study in 2003 pointed to the possible role of endocannabinoids in controlling CRC growth in humans. Biopsies of colon tissue from patients with CRC were analyzed and compared with healthy tissue, finding that 2-AG and anandamide increased significantly in both the precancerous polyps (adenomas) and tumors themselves. They also confirmed in isolated cell studies that treating CRC cells with both endocannabinoids directly, or just inhibiting their degradation as an alternative way to increase their levels, reduced cell proliferation. Due to these and other observations, researchers concluded, “These findings are in agreement with the presence of both [cannabinoid receptor] subtypes in colon normal mucosa and CRC and suggest that endocannabinoids, present in high amounts in CRCs and, particularly, colorectal adenomas, might function as endogenous inhibitors of cancer growth.”

Lending further support to this theory was a 2008 study published in the Journal of Molecular Medicine which found that chemically-inducing precancerous colorectal lesions (known as aberrant crypt foci [ACF]) in mice significantly increased 2-AG levels as well as increased anandamide levels in a nonsignificant way. The researchers suggested this was a protective event for several reasons, including that further increasing the levels of 2-AG and anandamide by inhibiting their degradation decreased formation of ACF, and both endocannabinoids also directly inhibited proliferation of colorectal carcinoma cells. These researchers also referenced an article on the anti-obesity drug Orlistat, which inhibits 2-AG biosynthesis, and its ability to increase precancerous colorectal lesions in mice. Given the results of their study, they theorized Orlistat may have caused the lesions by decreasing 2-AG and counteracting its protective function.

The Endocannabinoid System and Liver Cancer

Hepatocellular carcinoma (HCC) is the most common form of liver cancer. An extensive 2019 study in Oncology Letters compared HCC tissues with non-cancerous counterpart controls to determine differences in both cannabinoid receptor expression and endocannabinoid levels. The results showed that anandamide and 2-AG were respectively downregulated and upregulated in the cancerous tissue, while the CB1 and CB2 receptor proteins were also respectively downregulated and upregulated.

There appears to be variable function of cannabinoid receptors in HCC, as demonstrated by researchers in the United States, Germany, and South Korea. In mice with chemically-induced HCC, CB1 inactivation suppressed cancer cell proliferation, whereas CB2 inactivation increased cancer cell proliferation, suggesting that CB1 receptors exerted a pro-cancer role and whereas CB2 receptors yielded anticancer effects. Interestingly, the inactivation of CB2 receptors reduced the recruitment of specific immune cells (CD4+ T cells) with antitumor properties, indicating that CB2 receptors may mediate an anticancer function of the immune system. The pro-cancer effect of CB1 was further demonstrated in a 2015 study that showed CB1 blockade resulted in fewer HCC tumors in mice.

Despite the negative effects of CB1 receptors suggested in these studies, another one that analyzed HCC tissue and nontumor tissue from patients determined that CB1 and CB2 receptors were both upregulated in the cancerous tissue, but to different extents in different people. Those HCC patients who had higher expression of CB1 and CB2 receptors experienced significantly better disease-free survival than patients with low expression levels, leading researchers to conclude, “Our results indicate that CB1 and CB2 have potential as prognostic indicators and suggest possible beneficial effects of cannabinoids on prognosis of patients with HCC.” While there are disparate results concerning the CB1 receptor and HCC, the CB2 receptor has more consistently been shown to be upregulated and confer an anticancer effect.

The Endocannabinoid System and Lung Cancer

Depending on the subtype of a particular cancer, even within the same organ, the ECS appears to change in different ways. A study published in 2016 examined cancerous and adjacent normal tissue specimens from patients with two subtypes of non-small cell lung cancer, squamous cell carcinoma (SCC) or adenocarcinoma (AC). Substantial differences in endocannabinoids, receptor expression, and metabolizing enzymes were found between the two cancerous tissues and normal tissue. Both anandamide and 2-AG were upregulated in in SCC, but downregulated in AC. Interestingly, the metabolizing enzymes had significantly increased in SCC and AC as well, which would theoretically cause lower levels of both endocannabinoids in both cell types, yet only AC tissue was observed to present those lower levels. Of additional interest, the CB1 and CB2 receptors only increased in AC cells, whereas receptor expression in SCC cells was largely unchanged, but other receptors that interact with endocannabinoids, including TRPV1 (VR1) and GRP55, were upregulated in both types.

The researchers also discussed several studies showing anticancer effects of cannabinoid receptor activation, and stated, “Data from the literature confirm that endocannabinoids control the fundamental processes of cell homeostasis and neoplastic transformation, which agree with our results.” Indeed, in cell and animal studies, both endocannabinoid degradation inhibitors and endocannabinoids themselves, including anandamide and 2-AG, inhibited invasion of lung cancer cells and tumors.

The Endocannabinoid System and Pancreatic Cancer

Pancreatic cancer is one of the most aggressive cancers in existence, and finding new ways to target it is paramount to improving patient outcomes. In a 2006 study which demonstrated how THC induced apoptosis in pancreatic cancer cells via CB2 receptor activation, researchers also found that normal pancreatic tissue had markedly low cannabinoid receptor expression. Pancreatic tumor biopsies and isolated cancer cell lines had much higher CB1 and CB2 levels (as demonstrated by mRNA and protein analysis), yet the CB1 receptor appeared to be uninvolved in antitumor effects.

Two years later, another study by German and American researchers found that high CB1 receptor expression was correlated with shorter survival of pancreatic cancer patients, whereas CB2 receptors were not significantly implicated in survival, yet both receptors were generally upregulated in the cancerous tissue compared to normal tissue. The study also noted that low levels of the endocannabinoid metabolizing enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) were correlated with shorter survival. Since these enzymes break down the endocannabinoids anandamide and 2-AG, lower levels theoretically would facilitate higher levels of endocannabinoids. However, both anandamide and 2-AG were found unchanged between cancerous and normal tissue. The paradoxical nature of this example is made starker by the fact that 2-AG has been found to inhibit pancreatic cancer cell proliferation via CB1 receptor activation. Due to this and similar reports, researchers from the previously mentioned study believe it is worth clinically testing cannabinoids in the treatment of pancreatic cancer.

The Endocannabinoid System and Prostate Cancer

The current research demonstrates complex interactions between the ECS and prostate cancer. A 2005 study compared normal prostate cells with five different prostate cancer cell lines, finding that all the latter cells expressed higher levels of CB1 and CB2 receptor proteins than normal cells. Further experiments demonstrated that activation of CB1 and CB2 receptors was important for the induction of cell death. However, as seen in pancreatic cancer, a study conducted in 2009 linked comparatively high CB1 receptor expression with greater disease severity (more metastases, larger tumor size, and rate of cell proliferation) as well as shorter survival. The 15-year probabilities of survival from prostate cancer were substantially higher in the low CB1 expression group than the high CB1 expression group. In the chart below, “Events” corresponds to deaths specifically from prostate cancer, not other causes. CB1IR<2 corresponds to relatively low expression, while CB1IR≥2 corresponds to relatively high expression.

Another study conducted by some of the same researchers as above found similar conclusions. By analyzing data from 419 prostate cancer patients, high expression of CB1 receptors in tumors was associated with worse pathology at diagnosis and poorer disease-specific survival.

Although there was a negative association between survival and CB1 expression, both anandamide and 2-AG have been shown to inhibit prostate cancer cell growth and induce apoptosis through activation of CB1 receptors.

The Endocannabinoid System and Skin Cancer

The three most common types of skin cancer are basal cell carcinoma, squamous cell carcinoma, and melanoma. Each type originates from a particular type of skin cell. The interaction between cannabinoids and melanoma appears to be the most studied area. A 2006 study examined 61 melanoma biopsy samples, finding that 36 expressed significant levels of CB1 and CB2 receptor proteins; 10 samples each expressed significant levels for CB1 or CB2 receptors, and only 5 did not show either receptor. In cell lines, normal melanocytes had similar levels of CB1 expression as the cancerous melanoma cells, but only the latter also expressed CB2 receptors. In support of this, a 2012 study published in the Journal of Cancer Research and Therapeutics that examined melanoma and normal skin tissues found that CB2 expression was upregulated in the cancerous tissue. This may be a good thing, as a study two years later indicated that activation of CB2 receptors inhibited the metastatic potential of melanoma cells. The researchers stated, “Our data identify CB2 as a potential target in reducing the number of brain metastases originating from melanoma.”

Alternatively, another study demonstrated anandamide toxicity against melanoma cells via CB1 receptor activation, an effect that was potentiated when a FAAH inhibitor was added. The 2006 study mentioned above demonstrated that CB1 and CB2 activation reduced proliferation of melanoma cells while not affecting the growth of healthy cells.

A 2015 study from researchers at the University of Bonn in Germany utilized mice with genetically deleted cannabinoid receptors (known as CB1/2 receptor knockout mice) to ascertain if the ECS was involved in the pathogenesis of skin cancer. Tumors that were chemically induced in the knockout mice developed similarly to tumors in wild-type mice, which have normal expression levels of cannabinoid receptors. While this result would suggest a lack of involvement of cannabinoid receptors, THC was still effective in inhibiting tumor growth in wild-type mice with transplanted mouse melanoma cells, but not knockout mice with the same cell transplants. This indicates a cannabinoid receptor dependent effect. Therefore, although the receptors appeared uninvolved in melanoma progression or inhibition, their additional stimulation by an exogenous compound had an anticancer effect.

Counter to the above study, a 2017 study that tested human melanoma cell lines found that genetic deletion of CB1 receptors reduced the number of viable melanoma cells, migration, and colony-forming ability, leading researchers to state that “the CB1 receptor might function as tumor-promoting signal in human cutaneous melanoma.”

A comparison of normal human skin and squamous cell carcinoma tissue found that CB2 receptors were upregulated in the cancerous tissue, akin to the observation seen in melanoma. The upregulation occurred at both the mRNA and protein levels.

It is worthy to note that anandamide has also been shown to induce cell death in non-melanoma skin cancer cells, although interestingly through a mechanism of action unrelated to the cannabinoid receptors.

The Endocannabinoid System and Lymphoma and Leukemia

One of the areas where cannabinoid receptors are expressed with special abundance is the immune system, so it makes sense that cancers of this system like lymphoma and leukemia would influence ECS activity. Lymphoma and leukemia both involve white blood cells, known as leukocytes. In lymphoma, a subset of leukocytes known as lymphocytes (which include T-cells, B-cells, and NK cells) grow uncontrollably and can form solid tumors or swelling, usually in the lymph nodes, spleen, or liver. Lymphomas most commonly involve B-cells. In leukemia, there can be overproduction of either immature lymphocytes or myeloid blast cells, the latter of which can differentiate into red blood cells, platelet-producing cells, or non-lymphocyte white blood cells. The immature, abnormal cells are produced in the bone marrow, where they can eventually crowd out normal cells and cause damage associated with the lack of functioning cells. These leukemic cells can also become disseminated in the blood but do not generally form solid tumors, unlike lymphomas. Therefore, in lymphoma, cancer cells are mainly in lymph nodes or other tissues, while in leukemia, the cells are mainly in the blood or bone marrow. Further differentiations among lymphoma and leukemia are decided by the specific cell types involved and the level of maturity and aggressiveness of the involved cells. For example, acute leukemias tend to involve high numbers of immature cells that replicate rapidly, whereas chronic leukemias feature more mature cells that reproduce less quickly.

Several studies have determined that upregulation of CB1 and/or CB2 receptors occurs in lymphomas. A 2008 study by Swedish researchers examined several non-Hodgkin’s lymphoma samples including small lymphocytic lymphoma/B cell chronic lymphocytic leukemia (SLL/CLL), marginal zone lymphoma (MZL), diffuse large B cell lymphoma (DLBCL), FL, precursor‐B acute lymphoblastic lymphoma (pre‐B ALL), mantle cell lymphoma (MCL), immunocytoma (IC) and Burkitt lymphoma (BL). Most of these samples had higher CB1 and/or CB2 receptor mRNA than normal tissue. Interestingly, when an anandamide analog known as R(+)‐methanandamide was tested on MCL, CLL, and BL cell lines, it only induced cell death in the first two types, which happened to overexpress the mRNA of both cannabinoid receptors. BL had relatively low CB2 receptor mRNA levels, which may have contributed to its resistance, as it was demonstrated that activation of both CB1 and CB2 receptors was critical to the anticancer effect of R(+)‐methanandamide in the MCL and CLL cells. These conclusions agreed with results from an earlier study the researchers conducted, where MCL cells expressing CB1 and CB2 receptors were susceptible to cell death from cannabinoid receptor agonists, but cells expressing only CB1 or only CB2 were resistant.

A 2007 study found that normal T-cells had low protein expression of CB2 receptors, but T-cells associated with non-Hodgkin’s lymphoma showed much higher CB2 expression. A similar observation was recorded for B-cell non-Hodgkin’s lymphoma. However, a 2011 study published in the European Journal of Haematology determined that CB2 receptor expression was not associated with treatment outcomes in patients with diffuse large B-cell lymphoma.

The potential importance of the ECS in controlling white blood cell counts was elucidated in a 2014 study that compared MCL tumor tissues with non-malignant B-cells. In agreement with other studies, CB1 and CB2 receptor mRNA was upregulated in tumors, while FAAH was downregulated, which theoretically could lead to accumulation of anandamide. Of particular interest, low CB1 receptor mRNA and high FAAH expression (and thus potentially lower anandamide levels) in a subset of cases correlated with abnormally high levels of lymphocytes and white blood cells, indicating that anandamide may reduce these excessive numbers via CB1 receptor activation.

A 2016 study from researchers at the Medical University of Vienna supported the results of previous studies, finding that B-cells associated with CLL had higher expression of CB1 and CB2 receptor mRNA than healthy B-cells. This was determined by analyzing peripheral blood samples from patients with CLL compared to healthy volunteers. Patients with comparatively high levels of CB1 receptor mRNA expression had shorter average overall survival than patients with low CB1 receptor mRNA expression; 153 months to 277 months, respectively. CB2 receptor mRNA was not correlated with survival. In this case, the researchers were unable to confirm an association of cannabinoid receptor proteins with survival, which they attributed to a problem with their protein detection compounds, but noted that other studies found a correlation between cannabinoid receptor mRNA expression and protein expression. In any case, despite the poor association of CB1 expression with survival, further tests showed that activation of CB1 or CB2 receptors with synthetic agonists reduced viability of CLL cells.

Summary

As the research demonstrates, the relationship between the ECS and various forms of cancer is far from consistent. Some cancer cells exhibit higher or lower amounts of cannabinoid receptors or endocannabinoids than their normal cell counterparts, although either CB1 and/or CB2 receptors do tend to upregulate more often in cancer. The answers to why these changes happen are not certain, and likely differ depending on the type of cancer or a patient’s unique genetic situation. In some cases, the ECS may be functioning as a protective mechanism against cancer development, or the cancer itself is somehow exploiting the ECS to enhance growth.

There have been several instances where cannabinoid receptor upregulation was associated with poorer survival outcomes, yet even in these cases, activation of those receptors by cannabinoids is repeatedly demonstrated to yield anticancer effects. It could be that in the absence of enough cannabinoids to substantially activate them, cannabinoid receptors may facilitate cancer growth, possibly by strengthening activation of survival pathways. More research is certainly needed to elucidate how cannabinoid receptors could contribute to tumor growth. However, there are also several studies showing that high receptor expression is associated with better outcomes, which further supports the theory of the ECS possessing a protective role against cancer.

As for cannabinoids as direct cancer treatments, the vast majority of studies show cannabinoid receptor activation causes anticancer effects. Many animal studies and case studies conducted in humans show that cannabinoid administration (including synthetic, endogenous, and phytocannabinoids) reduces tumor growth. If the ECS was only involved in pro-cancer effects, it makes little sense that its stimulation is so consistently shown to impede various forms of cancer. Furthermore, a lack of cannabinoid receptor expression appears correlated with resistance to cell death from cannabinoids, which lends additional support to the protection theory.

While the ECS is almost certainly not significantly dysregulated in all cancers, it is remarkable how many studies describe its entanglement with such a wide spectrum of cancers. Overall, the current research is clear that the ECS is differentially modulated depending on the form of cancer, and compounds that activate the ECS exert anticancer effects. With further research, it may be possible that cannabinoid treatments could be tailored depending on the nature of ECS dysregulation. The growing interest in this field improves hope that more research will be conducted.

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