Can cannabinoids and particularly CBD be an adjunct therapy for Colorectal Adenocarcinoma?

Adenocarcinoma is the most common type of colorectal cancer.

The inhibition of the cancer cell proliferation and induction of apoptosis in cancer cells by CB1 and CB2 activation has been reported. In a recent study by Cerretani et al., they demonstrated that CBD-induced cytotoxicity in HT-29 cells occurs through a CB1 and CB2 receptor-independent mechanism.

Cytotoxic effects on the cellular viability of HT-29 cells exposed to IC50 of THC, CBD, and CB83 in the presence of AM251 (CB1 antagonist) 1μM and AM630 (CB2 antagonist) 1 μM. The results are expressed as % of control. Data are representative of three independent experiments. Data were statistically evaluated. * p < 0.05 and ** p < 0.01 vs. control.
Source: Int. J. Mol. Sci. 2020, 21(15), 5533

No sign of oxidative stress was evident when CB1 or CB2 agonists were used. CBD increased ROS production which led to apoptotic cell death.

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Antineoplastic properties of cannabinoids

The potential role of phytocannabinoids and the endocannabinoid system (ECS) in confining malignant tumours is among the most discussed topics in the field of medical cannabis.

There are countless anecdotes from patients and even clinical studies (usually small ones) about the effect of cannabinoids on controlling different types of cancer. Many patients also believe that cannabis and its derivatives are effective tools for fighting against cancer. Hence, many cancer patients want to use cannabis for treating their disease.

The state of evidence

It should be noted that there is not enough clinical evidence about the efficacy of cannabinoids on cancer in humans, however, there is plenty of evidence from preclinical studies indicating that cannabinoids and ECS can potentially play a role in treating cancers.

A review by Dr. Hinz and Dr. Ramer published in the British Journal of Pharmacology has summarized the current state of evidence about the interactions (and possible therapeutic effects) between the ECS and tumours as the followings:

Source: Hinz B, Ramer R. Anti-tumour actions of cannabinoids. Br J Pharmacol. 2019;176(10):1384-1394.

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Does CBD inhibit FAAH?

FAAH inhibition by phytocannabinoids

Source: Matthew W. Elmes et al. J Biol Chem. 2015;290(14):8711-8721.

CBD is proposed to inhibit FAAH, which could result in increased anandamide levels thereby, activating CB1, CB2, and TRPV1 receptors1&2. However, more recent research by Elmes et al. demonstrated that THC and CBD inhibit the cellular uptake and catabolism of AEA by targeting Fatty acid-binding proteins (FABPs) with no effect on FAAH3. The fatty acid-binding proteins (FABPs) have been shown to be intracellular transporters for AEA. Anandamide requires transport from the membrane to intracellular FAAH for degredation3.

“THC and CBD did not reduce the proportion of intracellular AEA that is hydrolyzed following uptake, suggesting that the cannabinoids block the delivery of AEA to FAAH but do not affect AEA hydrolysis by FAAH”.

This study also showed that THC inhibits the cellular uptake and catabolism of AEA by targeting FABPs3.

THC and CBD interact with FABP3, FABP5, and FABP7 and bind with similar affinities as endocannabinoids AEA and 2-AG. CBD and THC inhibit both rat and mouse but not human FAAH3.

CBD impact on Acute lymphoblastic leukemia (ALL) of T lineage (T-ALL)

Acute lymphoblastic leukemia (ALL) of T lineage (T-ALL) occurs in 15% of childhood and 25% of adult ALL cases. It represents a highly aggressive cancer that is resistant to chemotherapy and has an increased risk of relapse with long-term remission failure of  ~20% in children and 40% of adult patients.

Cell lines derived from acute lymphoblastic leukemia of T lineage (T-ALL), but not resting healthy T cells, has been shown to be highly sensitive to CBD.

Olivas-Aguirre et al. demonstrated that CBD effects do not depend on cannabinoid receptors or plasma membrane Ca2+-permeable channels. CBD directly targets mitochondria and alters their capacity to handle Ca2+. CBD causes mitochondrial Ca2+ overload, stable mitochondrial transition pore formation, and cell death.

CBD at 30–100 μM induces cell death, while at 10 μM the cells remained alive, but did not proliferate. At low (1 μM) concentration, CBD stimulated cell proliferation and prevented cell death.

Contrasting effects of low and high CBD concentrations justifies further research to better understand CBD effects and its potential role as an adjunct treatment in T-ALL.

References:

  1. Nguyen K, et al. Factors influencing survival after relapse from acute lymphoblastic leukemia: a Children’s Oncology Group Study. Leukemia. 2008;22:2142–2150. doi: 10.1038/leu.2008.251.
  2. Pui CH, Yang JJ, Bhakta N, Galindo C. Global efforts toward the cure of childhood acute lymphoblastic leukemia. Lancet Child Adolesc. Health. 2018;2:440–454. doi: 10.1016/S2352-4642(18)30066-X.
  3. Olivas-Aguirre M, Torres-López L, Valle-Reyes JS, Hernández-Cruz A, Pottosin I, Dobrovinskaya O. Cannabidiol directly targets mitochondria and disturbs calcium homeostasis in acute lymphoblastic leukemia. Cell Death Dis. 2019;10(10):779. Published 2019 Oct 14. doi:10.1038/s41419-019-2024-0.

What do we know about CBDA?

CBDA is one of the cannabinoid acids produced in the trichomes of the cannabis plant. CBDA  can easily be decarboxylated to CBD if exposed to heat. Due to its low stability, synthetic analogs of CBDA have been developed to address this challenge.

CBDA inhibits anandamide cellular uptake. CBDA does not display significant activity as either an agonist or an inverse agonist at the CB1 receptors.

CBDA has shown to inhibit nausea-induced behavior in rats by enhancing the activation of 5-HT1A receptors. CBDA demonstrates 100-fold greater affinity for the 5-HT1A receptors.

Anxiolytic effects of CBDA may require the presence of a specific stressor. Rock et al., reported no anxiolytic effects in rats without a prior explicit stressor however, administration of CBDA (0.1-100 μg/kg) or CBD (5 mg/kg) prevented the FS-induced anxiogenic-like responding.

CBDA shares the capability of CBD to activate the transient receptor potential (TRP) cation channels, TRPV1 and TRPA1, and to antagonize TRPM8, however, it produces these effects with significantly less potency than CBD.

CBDA shows promise as a potential treatment for anticipatory nausea and vomiting and anxiety.

References:

  1. De Petrocellis L, Ligresti A, Moriello AS, et al. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol. 2011;163(7):1479-1494. doi:10.1111/j.1476-5381.2010.01166.x.
  2. Bolognini D, Rock EM, Cluny NL, et al. Cannabidiolic acid prevents vomiting in Suncus murinus and nausea-induced behaviour in rats by enhancing 5-HT1A receptor activation. Br J Pharmacol. 2013;168(6):1456-1470. doi:10.1111/bph.12043.
  3. Bagdy G, Kecskemeti V, Riba P, Jakus RJ Neurochem. 2007 Feb; 100(4):857-73.
  4.  Rock EM, Limebeer CL, Petrie GN, Williams LA, Mechoulam R, Parker LA. Effect of prior foot shock stress and Δ9-tetrahydrocannabinol, cannabidiolic acid, and cannabidiol on anxiety-like responding in the light-dark emergence test in rats. Psychopharmacology (Berl). 2017;234(14):2207-2217. doi:10.1007/s00213-017-4626-5 .

Does CBN help with insomnia?

CBN or cannabinol is a non-enzymatic oxidative by-product of THC.

It has a lower affinity for CB1 and CB2 receptors compared to THC (10% of the activity of Δ9-THC at the CB1 receptors).

CBN has been promoted to assist patients that are suffering from insomnia but this claim has not been substantiated by any clinical trials.

Research by Musty et al., reported that oral ingestion of 50 mg CBN did not induce dizziness or drowsiness in human subjects.

“It appears that CBN increases the effect of delta9-THC on some aspects of physiological and psychological processes, but that these effects are small and cannot account for the greater potency which has been reported when plant material is used”.

As the result of the low affinity of CBN to cannabinoid receptors and limited available evidence, CBN shall not be claimed to be a sedative.

Adequate clinical trials focused specifically on the sedative effects of CBN are required to further evaluate potential other mechanisms that may be responsible for reported anecdotal claims by users.

References:

  1. Health Canada. (2018). Information for Health Care Professionals: Cannabis (marihuana, marijuana) and the cannabinoids. Ottawa: Health Canada.
  2. Merzouki A, Mesa JM. Concerning kif, a Cannabis sativa L. preparation smoked in the Rif mountains of northern Morocco. J Ethnopharmacol. 2002;81(3):403-406. doi:10.1016/s0378-8741(02)00119-8.
  3. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol 2008 01;153(0007-1188; 0007-1188; 2):199-215.
  4. Izzo AA, Borrelli F, Capasso R, Di M,V, Mechoulam R. Non-psychotropic plant cannabinoids: New therapeutic opportunities from an ancient herb. Trends Pharmacol Sci 2009 10;30(1873-3735; 0165-6147; 10):515-27.
  5. Evans FJ. Cannabinoids: the separation of central from peripheral effects on a structural basis. Planta Med. 1991;57:S60–S67.
  6. Musty RE, Karniol IG, Shirikawa I, Takahashi RN, Knobel E. Interactions of delta-9-tetrahydrocannabinol and cannabinol in man. In: Braude MC, Szara S, editors. The Pharmacology of Marihuana. Vol. 2. New York: Raven Press; 1976. pp. 559–563.

The prevalence of problematic use of prescription opioids and Cannabis-Based Medications (CBMs) among chronic pain patients

The concerns about the problematic use of CBMs is one of the most heated debates among healthcare practitioners about integrating CBMs in the treatment protocols of patients suffering from chronic pain. Healthcare Practitioners would like to know how common the problematic use is and if there is any way to detect patients with higher risks for the problematic use.

Although there is no published controlled study, a cross-sectional study conducted in Israel tries to answer these questions.

In a cross-sectional study in two pain clinics in Israel, 888 chronic pain patients were assessed for problematic use of their pain medications (i.e. prescription opioids and CBMs). Researchers used DSM-IV, Portenoy’s Criteria (PC) and Current Opioid Misuse Measure (COMM) to detect the problematic use of opioids and CBMs.

471 patients (53.4%) were treated with opioids and 329 patients (37.3%) were treated with Medical Cannabis exclusively. 77 patients (8.7%) of patients have received both opioids and cannabinoids. The problematic use of opioids or CBMs has been demonstrated in the below chart.

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THCA and its potential pharmacological effects

THCA is generally referred to as an inactive precursor of THC, but research has demonstrated that this chemical compound may have potential therapeutic properties.

Δ9‐THCA is produced naturally in the cannabis plant. It is a non‐psychotropic cannabinoid and its potential to bind to CB1 receptors is still debated.

A more recent study by McPartland et.al. showed that freshly prepared and highly pure Δ9‐THCA (98%) has a low binding affinity for CB1 and CB2 receptors1.

THCA-A has shown to inhibit the release of TNFα in a dose-dependent manner and, weakly inhibit cyclooxygenase enzymes (COX-1 and COX-2) in a high concentration range (mM), compared with nonsteroidal anti-inflammatory medications (NSAIDs)2.

The anti-inflammatory activity of Cannabis extracts on colon epithelial cells of an IBD model is suggested to be derived from THCA3. This study suggested that the anti-inflammatory activity of THCA was at least partially mediated by GPR55 receptor agonism.

It is suggested that Δ9‐THCA enters the CNS and PPARγ is the major target responsible for its neuroprotective and anti‐inflammatory activity4&5. THCA-A binds and activates PPARγ with higher potency than THC5.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731255/figure/bph14019-fig-0001/

Δ9-THCA-A is a partial and selective PPARγ modulator, empowered with lower adipogenic activity than the full PPARγ agonist rosiglitazone (RGZ) and enhanced osteoclastogenic effects in hMSC4. It is proposed that Δ9-THCA-A as a low adipogenic PPARγ agonist, may be capable of improving the symptoms of obesity-associated metabolic syndrome and inflammation4.

Δ9‐THCA has been shown to be neuroprotective in mice treated with 3‐NPA, improving motor deficits and preventing striatal degeneration. It attenuates microgliosis, astrogliosis, and up‐regulation of pro-inflammatory markers induced by 3‐NPA in mice5.

Δ9‐THCA shows potent neuroprotective activity, which warrants its consideration for the investigation of treatments of Huntington’s disease and other neurodegenerative and neuroinflammatory conditions.

REFERENCES:

  1. McPartland JM, McDonald C, Young M, Grant Phillip S, Furkert DP, Glass M (2017). Affinity and efficacy studies of tetrahydrocannabinolic acid A at cannabinoid receptor types one and two. Cannabis Cannabinoid Res 2: 87–95.
  2. Ruhaak LR, Felth J, Karlsson PC, et al. Evaluation of the cyclooxygenase inhibiting effects of six major cannabinoids isolated from Cannabis sativa. Biol Pharm Bull. 2011;34:774–778.
  3. Nallathambi R, Mazuz M, Ion A, et al. Anti-Inflammatory Activity in Colon Models Is Derived from Δ9-Tetrahydrocannabinolic Acid That Interacts with Additional Compounds in Cannabis Extracts. Cannabis Cannabinoid Res. 2017;2(1):167–182. Published 2017 Jul 1. doi:10.1089/can.2017.0027.
  4. Palomares B, Ruiz-Pino F, Garrido-Rodriguez M, et al. Tetrahydrocannabinolic acid A (THCA-A) reduces adiposity and prevents metabolic disease caused by diet-induced obesity. Biochem Pharmacol. 2020;171:113693. doi:10.1016/j.bcp.2019.113693.
  5. Nadal X, Del Río C, Casano S, et al. Tetrahydrocannabinolic acid is a potent PPARγ agonist with neuroprotective activity. Br J Pharmacol. 2017;174(23):4263–4276. doi:10.1111/bph.14019.

Health professional beliefs, knowledge, and concerns surrounding medicinal cannabis – A systematic review

The result of this systematic review indicated that while HCPs (Healthcare Professionals) believed that medical cannabis is a viable useful therapeutic option for patients, they do not have enough knowledge and formal education to make the best decision for their patients. Consequently, they reject to prescribe or support patients to use medical cannabis or they get the information from unreliable sources such as media/news. The result of this systematic review highlights the importance of education for HCPs to ensure to offer the best possible care for patients.

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Cannabis-Based Medications (CBMs) for managing weight loss in patients with advanced cancer

The Effects of Dosage-Controlled Cannabis Capsules on Cancer-Related Cachexia and Anorexia Syndrome in Advanced Cancer Patients: Pilot Study

Loss of appetite and weight among cancer patients are among the most challenging symptoms to be managed by physicians. Moreover, there are not effective appetite stimulant medications in the market and physicians are reluctant to add another medication to highly medicated (chemotherapeutic agents, painkillers, sleep medications, …) advanced cancer patients if they have any doubt about its efficacy or safety profile.

Cannabis has been very well-known for its appetite stimulant effect and pharmaceutical preparations such as Dronabinol were successfully tested for improving appetite in HIV patients.

In this study, Dr. Bar-Sela and his colleagues assessed the effect of Cannabis capsules (THC: CBD 20:1 ratio) for the first time among patients with advanced cancer. The planned starting dose was 20 mg of cannabinoids (19 mg THC, 1 mg CBD) per day for six months, however, if patients could not tolerate it, the dose was reduced to 10 mg per day. In total, 24 patients were enrolled for the trial, however, only 6 of them received the capsules for more than 6 months.

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