cbd kidney cancer

December 15, 2021 By admin Off

mRNA expression of CB 1 receptors in kidney tumor (T) and surrounding normal tissue (N). Agarose gel showing the presence of a single transcript, corresponding to the expected product size encoding the cannabinoid CB 1 receptor (131 bp, CNR1 ). The mRNA encoding the 110-bp product expected for the cannabinoid CB 2 receptor ( CNR2 ) was undetectable. The expression of SHDA , used as an internal control, is also shown. M, molecular size standards; +, positive control showing the expression of all genes in a pool of cDNAs from 20 different human tissues; −, negative control with no RNA in the reverse transcriptase reaction.

RT-PCR reactions were performed as previously described (Candenas et al. 2001; Varona et al. 2007; Blanco et al. 2008; Larrinaga et al. 2010). Total RNA of ∼30 mg of human renal tissue was isolated in every case according to the method described by Chomczynski and Sacchi (1987). First-strand cDNA was synthesized from 25 μg of total RNA of each human sample using Moloney murine leukemia virus RT and random hexamers according to the manufacturer’s instructions (First-strand cDNA Synthesis Kit; Amersham Biosciences, Essex, UK). The resulting cDNA samples were amplified using PCR with specific oligonucleotide primer pairs designed with the analysis software Primer3 (Rozen and Skaletsky 2000). The sequences of the primer pairs used for human CNR1 and CNR2 are expressed in Table 1 . On the basis of previous experiments on human renal cell carcinoma (Jung et al. 2007; Varona et al. 2007; Blanco et al. 2008), the human gene succinate dehydrogenase complex, subunit A ( SDHA ) was chosen as endogenous reference gene and used to assure that similar amounts of cDNA were used in all RT-PCR reactions. Sequences for SDHA are also displayed in Table 1 . All primers were synthesized and purified by Sigma-Genosys (Cambridge, UK). A pool of cDNAs from 20 different human tissues (Human Total RNA Master Panel; Clontech, Mountain View, CA) was used as a positive control of amplification.

Because many of these antitumoral effects of cannabinoids are mediated through CB receptors, the analysis of the expression of CB 1 and CB 2 receptors in a wide variety of human neoplasms has become of great interest, with some promising results appearing in the recent literature (Flygare and Sander 2008; Alpini and DeMorrow 2009). Although CCRCC is a paradigm of multi–antitumoral-drug-resistant neoplasia, a study on the role of ECS on this tumor is lacking.

This work was supported by grants from the Jesús Gangoiti-Barrera Foundation, Gobierno Vasco (GIC07/84), Ministerio de Educación y Ciencia (CTQ2007-61024/BQU), and SAIOTEK (SA-2008/00046).

All the experiments carried out in this study comply with current Spanish and European Union laws and conform to the principles outlined in the Declaration of Helsinki.

Results.

Negative immunostaining for CB 1 receptor in clear cell renal cell carcinomas (right side). Note that the surrounding non-tumor tissue shows positive immunoreaction in proximal tubules.

Recent works have reported changes in the expression of the CBs in neoplasms of diverse topographies, such as large bowel (Wang et al. 2008), breast (Caffarel et al. 2006), prostate (Sarfaraz et al. 2005), pancreas (Carracedo et al. 2006; Michalski et al. 2008), and liver (Xu et al. 2006). However, studies in vivo are still scarce in human tissues. In addition, ECS dysregulation needs to be evaluated in other human cancer types (Alpini and DeMorrow 2009).

Despite the latest advances in genetics, the biology of renal tumors is still far from being completely understood. This study, which includes the analysis of mRNA and protein [Western blot (WB) and IHC] expression of CB in CCRCCs, is an attempt to shed some light on the underlying mechanisms involved in renal neoplasia.

As we previously observed in human normal kidneys (Larrinaga et al. 2010), tumor tissues expressed mRNA of the CB 1 , whereas the mRNA of CB 2 was absent. Conversely, there was no correlation between CB 1 mRNA and its protein expression because both WB and IHC failed to demonstrate any trait of CB 1 protein in tumor tissue. This finding was constant in all the CCRCCs studied, irrespective of the tumor stage and grade. This result suggests that the protein modification of CB 1 could occur in these tumors at a posttranscriptional level, thus illustrating the importance of not relying only on mRNA level for the evaluation of any protein change. This assertion has also been indicated by several authors in other kidney diseases (Kasinath et al. 2006).

Consecutive slides of the selected blocks in every case were immunostained with CB receptors CB 1 and CB 2 following routine methods in an automatized immunostainer (Dako Autostainer Plus; Dako, Glostrup, Denmark). CB 1 (working dilution 1:1000; ABR Affinity BioReagents) and CB 2 (working dilution 1:200; Cayman Chemical) polyclonal antibodies were used. The specificity of these antibodies in human cells was previously assessed by our group (Agirregoitia et al. 2010; Larrinaga et al. 2010). Negative control slides were not exposed to the primary antibody and were incubated in PBS and then processed in the same conditions as the test slides. Immunohistochemical slides were studied using a Nikon Eclipse 80i microscope (Tokyo, Japan).

( A ) Western blot analysis of CB 1 receptor in human kidney tumor (T) and surrounding normal tissue (N). Lower signal of CB 1 in tumor tissue. Cerebral cortex (Cx) is shown as positive control. ( B ) Western blot of CB 2 receptor in tumor and normal tissues. Absence of CB 2 in both tumor and normal tissues. Jurkat cells (J) are shown as positive control. Molecular masses (kDa) are indicated on the left.

There is increasing evidence that endocannabinoids modulate the activity of enzymes and nuclear factors involved in the control of fundamental processes of cell homeostasis and in neoplastic transformation (Flygare and Sander 2008; Pisanti and Bifulco 2009). Actually, numerous pharmacological studies carried out in vitro and in animal models have proposed antitumoral properties to natural and synthetic CBs (Pisanti and Bifulco 2009).

Very few studies have focused on the ECS in the kidney and its neoplasms. We have found very recently the presence of CB 1 and the absence of CB 2 receptors in human fetal and adult kidneys (Larrinaga et al. 2010). Other authors (Hart et al. 2004) have studied the effect of CBs on renal cancer cell cultures several years ago.

T he endocannabinoid system (ECS) consists of cannabinoid (CB) receptors, endocannabinoids, and the enzymes responsible for synthesis and degradation of their endogenous ligands (Mackie 2008). This system is widely distributed in mammalian tissues and regulates nervous, cardiovascular, digestive, reproductive, immune, and metabolic functions by activating CB 1 and CB 2 receptors (Graham et al. 2009).

Table 1.

Archival material obtained from the files of the Department of Anatomic Pathology, University Hospital of Cruces, University of the Basque Country, Barakaldo, Spain, was used for this study. Representative formalin-fixed and paraffin-embedded material obtained from 20 consecutive CCRCCs including cases with conventional histology and Furhman’s grades 1–3 (Fuhrman et al. 1982) was analyzed.

PCR mixes contained 0.2 μmol primers, 1.5 U of heat-activated thermostable DNA polymerase (Immolase; Bioline, London, UK), the buffer supplied, 2.5 mmol MgCl 2 , 200 μmol dNTPs, and 25 μl cDNA. PCR was performed for 35 cycles with cycling parameters of 15 sec at 94C, 20 sec at 60C, and 20 sec at 72C. The PCR products were separated by agarose gel electrophoresis, and the amplicon sizes were verified by comparison with a DNA mass ladder. mRNA levels for the CB receptors and SDHA were analyzed on each tissue, with each RT-PCR assay being performed in triplicate. The identity of each product was established by DNA sequence analysis.

IHC studies corroborated these data. CB 1 immunostaining was negative in CCRCC and positive in adjacent normal proximal convoluted tubules ( Figure 3 ), whereas CB 2 was absent both in CCRCC and in normal tissue.

WB assays showed that CB 1 receptor expression was practically nonexistent in CCRCC ( Figure 2 ). Two immunoreactive bands were observed in each lane corresponding to normal tissue, one at around 60 kDa, corresponding in size to the putative CB 1 monomer, and a lower molecular mass form at around 37 kDa ( Figure 2A ). The lower band could correspond to a deglycosylation and/or proteolysis product of the 60-kDa-band receptor (De Jesús et al. 2006). The lane on the right shows the presence of similar bands in samples of cerebral cortex, which is used as a positive control for the CB 1 receptor ( Figure 2A ). The CB 2 protein was undetectable both in normal and tumor tissues. Positive staining was, however, observed in Jurkat cells, used as a positive control for the CB 2 receptor, with the appearance of the expected band at 44 kDa ( Figure 2B ).

Primer sequences for CNR1 , CNR2 , and SDHA.

Several studies in cell cultures and in animal models have demonstrated that cannabinoids have important antitumoral properties. Because many of these effects are mediated through cannabinoid (CB) receptors CB 1 and CB 2 , the study of their expression in human neoplasms has become of great interest in recent years. Fresh and formalin-fixed tissue samples of 20 consecutive clear cell renal cell carcinomas (CCRCCs) were collected prospectively and analyzed for the expression of both CB receptors by using RT-PCR, Western blot (WB), and immunohistochemical techniques. RT-PCR assays demonstrated the expression of mRNA encoding the CB 1 in tumor tissue and in adjacent non-neoplastic kidney. Conversely, WB and IHC revealed a marked downregulation of CB 1 protein in tumor tissue; CB 2 was not expressed. The obtained data suggest a possible implication of the endocannabinoid system in renal carcinogenesis. A posttranscriptional downregulation of CB 1 and the absence of expression of CB 2 characterize CCRCC. (J Histochem Cytochem 58:1129–1134, 2010)

Protein Expression of CB Receptors.

We performed a WB analysis of eight CCRCCs. Membrane proteins (10 μg) were solubilized in sample buffer and were resolved by electrophoresis in 12% SDS-PAGE gel. Then, proteins were transferred to polyvinylidene difluoride membranes. Blots were blocked in milk and incubated overnight with the CB 1 (1:250 dilution; catalog ref. PA1-743, ABR Affinity BioReagents, Golden, CO) and CB 2 (1:200 dilution; catalog ref. 101550, Cayman Chemical, Ann Arbor, MI) polyclonal antibodies. Later, the blots were washed and incubated for 2 hr at room temperature with a horseradish peroxidase–conjugated goat anti-rabbit IgG secondary antibody (1:2500 dilution; ABR Affinity BioReagents). Membranes incubated without the primary antiserum were used as negative controls. Immunoreactive bands were visualized using the enhanced chemiluminescence system.

The CB 1 is highly expressed in proximal convoluted tubules of the nephron in both normal adult kidney and mature tubules of fetal kidney (Larrinaga et al. 2010). However, this receptor is not immunohistochemically expressed in the nephrogenic zone of the fetal kidney, where tubular cells are still poorly differentiated (Larrinaga et al. 2010). Interestingly, a parallelism between poorly differentiated tubule cells of fetal kidney and CCRCCs can be raised because CB 1 appears downregulated in a renal tumor that supposedly originates in the proximal nephron (Lam et al. 2005; Lopez Beltran et al. 2006). For this reason, we consider that this CB 1 -related tumor dedifferentiation observed in CCRCCs approaches the tumor to its cell of origin and confirms the current belief on the distinct tumor origin of renal neoplasms expressed in the current WHO classification. Additionally, this immunoprofile may eventually be used as an additional tool with practical interest in the routine diagnosis of CCRCCs.

No PCR product was detectable when the samples were amplified without the RT step, suggesting that genomic DNA contamination was eliminated by DNase treatment. Similarly, no products were detected when the RT-PCR steps were carried out with no added RNA, indicating that all reagents were free of target sequence contamination. Figure 1 shows the negative control with no RNA in the RT reaction.

CB receptors have not been tested to date in renal tumors. They are included in the top ten list of the commonest tumors in males and females and account for ∼4% of adult malignancies (Jemal et al. 2009). Roughly 70% of them are clear cell renal cell carcinomas (CCRCCs) (Lopez Beltran et al. 2009). The 2004 WHO classification of renal tumors in adults links for the first time histology and genetics and attributes the origin of most histological subtypes of renal cancer to distinct parts of the nephron (Lopez Beltran et al. 2006). So, the proximal convoluted tubule cell is considered to be the origin of CCRCC (Lopez Beltran et al. 2006).

The precise role of the CB 1 in renal cancer still remains to be clarified. It should be noted that a similar CB receptor expression profile has been reported recently in human colorectal cancer by Wang et al. (2008). The authors have suggested that CB 1 loss would make cancer cells resistant to the antitumoral effect of endocannabinoids, thus accelerating intestinal tumor growth and biological aggressiveness (Wang et al. 2008). This evidence favors the hypothesis that CB 1 downregulation is a general mechanism in some different cancer types. In this sense, Caffarel et al. (2006) also observed downregulation of CB 1 in human breast cancer cells. However, CB 1 upregulation has also been reported in other human neoplasms, such as prostatic adenocarcinoma (Sarfaraz et al. 2005), hepatocellular carcinoma (Xu et al. 2006), and pancreatic ductal adenocarcinoma (Carracedo et al. 2006; Michalski et al. 2008). Therefore, further studies are needed to clarify the precise mechanisms underlying these apparently divergent results.

In the last decade, several studies in cell cultures and in animal models have demonstrated that CBs have proapoptotic, antiproliferative, antimetastatic, and antiangiogenic effects in various cancer types (Alexander et al. 2009). Although no clinical basis exists to recommend the use of natural/synthetic CBs in patients with renal cancer, this knowledge has spurred a clinical trial examining the efficacy and safety of giving Δ9-tetrahydrocannabinol locally to patients with other neoplasias, such as recurrent glioblastoma multiforme (Guzmán et al. 2006).

RT-PCR revealed the presence of a single transcript, corresponding to the expected product size encoding the cannabinoid CB 1 receptor (131 bp). The identity of the amplified fragment was confirmed by DNA sequence analysis. The CNR1 transcript could be observed in both tumor and surrounding normal tissues assayed after amplification of cDNA for 35 cycles. Conversely, the mRNA encoding the 110-bp product expected for the cannabinoid CB 2 receptor was undetectable in cDNA from tumor or normal renal tissues. The mRNAs of CNR1 , CNR2 , and SDHA genes were all detected in the cDNA pool used as positive control ( Figure 1 ).

This is very important for cancer patients to understand, as many people think CBD oil is not a medicine. They think of it more as a vitamin or a supplement, so they might not let their doctors know they’re using it. Patients might not realize it can be potentially harmful. So, it’s very important to tell your doctor if you’re using CBD oil.

Yes. Epidiolex. It was originally approved in 2018 for the treatment of two conditions, both related to epilepsy: Lennox-Gastaut syndrome and Dravet syndrome. But aside from Epidiolex, no CBD product has been approved by the FDA for any other medical purpose.

All drugs and dietary supplements are regulated by the FDA. But as long as CBD oil is not marketed as a medicine or a dietary supplement, producers can get around that policy. So right now, CBD oil is very unregulated. That means it’s hard to know how much CBD or THC is really in any given product. Certain hemp CBD products have been found to contain significantly less CBD or more THC than advertised.

Third, the plant itself may have higher levels of THC than expected. This could be due to its environment, prolonged flowering periods or cross-contamination and pollination between male and female plants, resulting in offspring with higher THC content. This especially affects hemp plants, which should have less than 0.3% THC levels.

It’s hard to say if CBD oil can alleviate cancer symptoms or cancer treatment side effects, because the studies are pretty mixed and even fewer are standardized.

But the application of this law is pretty jumbled right now. So, while it may be legal to use CBD in a state like Colorado or Alaska, if an employer follows federal regulations, the standardization and quality of a CBD product matters. Because if there’s even a small percentage of THC in that product, then a drug test might come back positive. And this could result in legal issues for the user.

CBD oil (cannabidiol) is everywhere these days. Once available only at novelty or vitamin shops, it’s now also at your local grocery store, pharmacy or even yoga studio.

CBD has a very complex legal status right now.

Does CBD oil have any side effects?

It comes in many forms: oils that are dropped under the tongue, roll-ons that are applied to the skin and even solutions for vaping. Some producers extract CBD oil and add it into foods to create edible products.

Finally, there have been some reports of people getting infections after using CBD and cannabis products. This is especially concerning for immunocompromised patients, who are already susceptible to bacterial and fungal infections.

Have any CBD-oil derived products been approved by the U.S. Food and Drug Administration (FDA) to treat cancer, its symptoms, or the side effects caused by its treatment?

Quality, cleanliness and regulation are the biggest concerns.

Is there any truth to the claims that CBD oil can cure cancer?

Right now, no. There is no evidence that CBD oil can cure cancer.

Is CBD oil even legal?

And in lab studies, CBD has been shown to inhibit certain enzymes responsible for the metabolism of drugs, such as CYP2D6 and CYP3A4. This can affect how drugs work and affect our bodies, either by reducing their efficiency or making them more dangerous. This includes chemotherapy and other medications.

What’s the most important thing cancer patients should know about CBD oil?

What is CBD oil, and how does it differ from marijuana and hemp?

But what is CBD oil exactly, and how does it affect cancer patients? Can it really treat — or even cure — cancer or relieve its symptoms? To separate fact from fiction, we spoke with our Kimberson Tanco, M.D. Here’s what he wants cancer patients to know.

In terms of purity, THC and CBD are both extracted from hemp and marijuana using essentially similar processes. But trace amounts of THC could still end up in CBD oil. And if the THC is at a high enough concentration, it could produce the psychoactive effects that THC is known for.

What are the dangers of using CBD oil?

State laws vary. In Texas, the Compassionate Use Act allows for the use of medical marijuana for certain conditions. Originally only for intractable epilepsy, the law was expanded this year to include cancer and certain neurodegenerative conditions, such as Parkinson’s and multiple sclerosis.

At the national level, any product of marijuana — including CBD — is still technically illegal when used medically. Although the 2018 Farm Bill legalized the production of hemp nationally, that’s only permitted if it’s not marketed for medical use or as a dietary supplement. CBD products intended for medical use should undergo an FDA review process.

There’s still a lot to learn. So always let your health care team know if you are using CBD oil. That way, we can make sure nothing interacts adversely with your cancer treatments or other medications.

Studies on a certain CBD manufacturer showed its products were contaminated with a chemical known as 5F-ADB, which mimics THC. 5F-ADB is classified by the U.S. Drug Enforcement Administration as illegal, potentially addictive and with no accepted medical use.

Have any products using CBD-oil been approved by the FDA to treat anything?

The main difference is that hemp has far less THC than a typical marijuana plant. And unlike THC, CBD is not a psychoactive agent, so there’s less possibility that it will cause the same mental confusion, drowsiness or hallucinations that often come with THC.

Second, if a lab produces both CBD and THC products, there can be cross-contamination — whether it’s through extraction, handling or packaging.

CBD oil can adversely affect liver function. In fact, this is on the warning label for Epidiolex.

A Cochrane meta-analysis of 23 RCTs reviewed studies conducted between 1975 and 1991 that investigated dronabinol or nabilone, either as monotherapy or as an adjunct to the conventional dopamine antagonists that were the standard antiemetics at that time.[41] The chemotherapy regimens involved drugs with low, moderate, or high emetic potential. The meta-analysis graded the quality of evidence as low for most outcomes. The review concluded that individuals were more likely to report complete absence of N/V when they received cannabinoids compared with placebo, although they were more likely to withdraw from the study because of an adverse event. Individuals reported a higher preference for cannabinoids than placebo or prochlorperazine. There was no difference in the antiemetic effect of cannabinoids when compared with prochlorperazine. The authors concluded that Cannabis -based medications may be useful for treating refractory chemotherapy-induced N/V; however, they cautioned that their assessment may change with the availability of newer antiemetic regimens.

The endocannabinoid system has also been shown to play a key role in the modulation of the sleep-waking cycle in rats.[55,56]

This summary contains the following key information:

In an in vivo model using severe combined immunodeficient mice, subcutaneous tumors were generated by inoculating the animals with cells from human non-small cell lung carcinoma cell lines.[23] Tumor growth was inhibited by 60% in THC-treated mice compared with vehicle-treated control mice. Tumor specimens revealed that THC had antiangiogenic and antiproliferative effects. However, research with immunocompetent murine tumor models has demonstrated immunosuppression and enhanced tumor growth in mice treated with THC.[24,25]

Another analysis of 15 controlled studies compared nabilone with placebo or available antiemetic drugs.[40] Among 600 cancer patients, nabilone was found to be superior to prochlorperazine, domperidone, and alizapride, with nabilone favored for continuous use.

Analgesia.

The potential benefits of medicinal Cannabis for people living with cancer include the following:[2]

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PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

A systematic review assessing 19 studies that evaluated premalignant or malignant lung lesions in persons 18 years or older who inhaled Cannabis concluded that observational studies failed to demonstrate statistically significant associations between Cannabis inhalation and lung cancer after adjusting for tobacco use.[11] In the review of the published meta-analyses, the National Academies of Sciences, Engineering, and Medicine (NASEM) report concluded that there was moderate evidence of no statistical association between Cannabis smoking and the incidence of lung cancer.[12]

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

This summary will review the role of Cannabis and the cannabinoids in the treatment of people with cancer and disease-related or treatment-related side effects.

Understanding the mechanism of cannabinoid-induced analgesia has been increased through the study of cannabinoid receptors, endocannabinoids, and synthetic agonists and antagonists. Cannabinoids produce analgesia through supraspinal, spinal, and peripheral modes of action, acting on both ascending and descending pain pathways.[41] The CB1 receptor is found in both the central nervous system (CNS) and in peripheral nerve terminals. Similar to opioid receptors, increased levels of the CB1 receptor are found in regions of the brain that regulate nociceptive processing.[42] CB2 receptors, located predominantly in peripheral tissue, exist at very low levels in the CNS. With the development of receptor-specific antagonists, additional information about the roles of the receptors and endogenous cannabinoids in the modulation of pain has been obtained.[43,44]

In 1937, the U.S. Treasury Department introduced the Marihuana Tax Act. This Act imposed a levy of $1 per ounce for medicinal use of Cannabis and $100 per ounce for nonmedical use. Physicians in the United States were the principal opponents of the Act. The American Medical Association (AMA) opposed the Act because physicians were required to pay a special tax for prescribing Cannabis , use special order forms to procure it, and keep special records concerning its professional use. In addition, the AMA believed that objective evidence that Cannabis was harmful was lacking and that passage of the Act would impede further research into its medicinal worth.[6] In 1942, Cannabis was removed from the U.S. Pharmacopoeia because of persistent concerns about its potential to cause harm.[2,3] Recently, there has been renewed interest in Cannabis by the U.S. Pharmacopeia.[7]

Withdrawal symptoms such as irritability, insomnia with sleep electroencephalogram disturbance, restlessness, hot flashes, and, rarely, nausea and cramping have been observed. However, these symptoms appear to be mild compared with withdrawal symptoms associated with opiates or benzodiazepines, and the symptoms usually dissipate after a few days.

Cannabis Pharmacology.

Cannabidiol (CBD) is an inhibitor of cytochrome P450 isoforms in vitro . Because many anticancer therapies are metabolized by these enzymes, highly concentrated CBD oils used concurrently could potentially increase the toxicity or decrease the effectiveness of these therapies.[5,6]

In a 2016 consecutive case series study, nine patients with varying stages of brain tumors, including six with glioblastoma multiforme, received CBD 200 mg twice daily in addition to surgical excision and chemoradiation.[28][Level of evidence: 3iiiA] The authors reported that all but one of the cohort remained alive at the time of publication. However, the heterogeneity of the brain tumor patients probably contributed to the findings.

Newer antiemetics (e.g., 5-HT3 receptor antagonists) have not been directly compared with Cannabis or cannabinoids in cancer patients. However, the Cannabis -extract oromucosal spray, nabiximols, formulated with 1:1 THC:CBD was shown in a small pilot randomized, placebo-controlled, double-blinded clinical trial in Spain to treat chemotherapy-related N/V.[47][Level of evidence: 1iC]

The endocannabinoid system is believed to be centrally involved in the regulation of mood and the extinction of aversive memories. Animal studies have shown CBD to have anxiolytic properties. It was shown in rats that these anxiolytic properties are mediated through unknown mechanisms.[52] Anxiolytic effects of CBD have been shown in several animal models.[53,54]

In addition, both plant-derived and endogenous cannabinoids have been studied for anti-inflammatory effects. A mouse study demonstrated that endogenous cannabinoid system signaling is likely to provide intrinsic protection against colonic inflammation.[26] As a result, a hypothesis that phytocannabinoids and endocannabinoids may be useful in the risk reduction and treatment of colorectal cancer has been developed.[27-30]

Many animal studies have previously demonstrated that delta-9-THC and other cannabinoids have a stimulatory effect on appetite and increase food intake. It is believed that the endogenous cannabinoid system may serve as a regulator of feeding behavior. The endogenous cannabinoid anandamide potently enhances appetite in mice.[39] Moreover, CB1 receptors in the hypothalamus may be involved in the motivational or reward aspects of eating.[40]

General Information.

To assist readers in evaluating the results of human studies of integrative, alternative, and complementary therapies for people with cancer, the strength of the evidence (i.e., the levels of evidence) associated with each type of treatment is provided whenever possible. To qualify for a level of evidence analysis, a study must:

ASCO antiemetic guidelines updated in 2017 state that evidence remains insufficient to recommend medical marijuana for either the prevention or treatment of N/V in patients with cancer who receive chemotherapy or radiation therapy.[38]

In 1951, Congress passed the Boggs Act, which for the first time included Cannabis with narcotic drugs. In 1970, with the passage of the Controlled Substances Act, marijuana was classified by Congress as a Schedule I drug. Drugs in Schedule I are distinguished as having no currently accepted medicinal use in the United States. Other Schedule I substances include heroin, LSD, mescaline, and methaqualone.

In recent decades, the neurobiology of cannabinoids has been analyzed.[13-16] The first cannabinoid receptor, CB1, was identified in the brain in 1988. A second cannabinoid receptor, CB2, was identified in 1993. The highest expression of CB2 receptors is located on B lymphocytes and natural killer cells, suggesting a possible role in immunity. Endogenous cannabinoids (endocannabinoids) have been identified and appear to have a role in pain modulation, control of movement, feeding behavior, mood, bone growth, inflammation, neuroprotection, and memory.[17]

Another study examined the effects of a plant extract with controlled cannabinoid content in an oromucosal spray. In a multicenter, double-blind, placebo-controlled study, the THC:CBD nabiximols extract and THC extract alone were compared in the analgesic management of patients with advanced cancer and with moderate-to-severe cancer-related pain. Patients were assigned to one of three treatment groups: THC:CBD extract, THC extract, or placebo. The researchers concluded that the THC:CBD extract was efficacious for pain relief in advanced cancer patients whose pain was not fully relieved by strong opioids.[61] In a randomized, placebo-controlled, graded-dose trial, opioid-treated cancer patients with poorly controlled chronic pain demonstrated significantly better control of pain and sleep disruption with THC:CBD oromucosal spray at lower doses (1–4 and 6–10 sprays/d), compared with placebo. Adverse events were dose related, with only the high-dose group (11–16 sprays/d) comparing unfavorably with the placebo arm. These studies provide promising evidence of an adjuvant analgesic effect of THC:CBD in this opioid-refractory patient population and may provide an opportunity to address this significant clinical challenge.[62] An open-label extension study of 43 patients who had participated in the randomized trial found that some patients continued to obtain relief of their cancer-related pain with long-term use of the THC:CBD oromucosal spray without increasing their dose of the spray or the dose of their other analgesics.[63]

Board members review recently published articles each month to determine whether an article should:

Animal studies have suggested a synergistic analgesic effect when cannabinoids are combined with opioids. The results from one pharmacokinetic interaction study have been reported. In this study, 21 patients with chronic pain were administered vaporized Cannabis along with sustained-release morphine or oxycodone for 5 days.[65] The patients who received vaporized Cannabis and sustained-release morphine had a statistically significant decrease in their mean pain score over the 5-day period; those who received vaporized Cannabis and oxycodone did not. These findings should be verified by further studies before recommendations favoring such an approach are warranted in general clinical practice.