Cannabinoid Based Cancer Treatments

[in vivo]

Cannabinoids display 'antitumor properties such as inhibition of cancer cell growth, induction of apoptosis and blocking the processes involved in tumor progression, such as angiogenesis, and cell migration. These effects might involve several signaling pathways being both cannabinoid receptor-dependent or independent' (Pisanti 2009).

 

When a person reads the above quote they may feel it's the end of the story. Cannabis kills cancer. But is that really where the story ends? Pro-cannabis researchers and pro-cannabis activists seem to have differing opinions on the answer. Many activists are promoting cannabis that's high in THC for any and all types of tumors. Researchers suggest that THC appears to have a great deal of potential in the treatment of a large number of cancer cell lines, but that it's not always the best cannabinoid to choose for a cancer based treatment. Why is that?

 

The level of expression (the number of) of cannabinoid receptors (CBRs) in tumor cells appears to be a fundamental factor to the overall effectiveness of cannabinoid based cancer treatments. Most cannabinoids are CBR activators. These CBRs are 'doing all the work' so to speak. It is not the cannabis or cannabinoids themselves that have anticancer properties, it is the cannabinoids ability to latch onto and activate the appropriate receptors. The activation of these receptors unleashes a cascade of events and mechanisms, some of which are advantages in slowing the progression and inducing apoptosis in tumor cells. CBR activation is fundamental to all cannabinoid based treatments. If this sounds relatively straight forward, that's because in a way it is. In order for cannabinoids to elicit any anticancer effects they must be able to activate the specific CBRs in the tumor cells. The higher the expression level of receptors, the greater impact that cannabinoids that activate those receptors have in the treatment. If there are no receptors to activate in the target area, or the cannabinoids being used are more effective at activating a different receptor, the treatment is likely to be relatively unsuccessful. (Pisanti 2009)

 

Equally vital is the awareness that tumor cells with low or undetectable expression levels of CBRs are resistant to any anticancer effects that cannabinoids may elicit, and the immunosuppression resulting from the systemic application of cannabinoids have been shown to enhance tumor growth in some cancer cell lines (like some types of breast cancer). (Pisanti 2009)

 

This paper will attempt to point to some of the research in relation to cancer, the endocannabinoid system (ECS), and natural cannabinoids that activate it. It may surprise some readers to learn that there is a growing number of legal and natural cannabinoids which originate outside of the cannabis plant. Many of these are cheap, highly available, and share a number of anticancer characteristics to cannabinoids in cannabis via the activation of similar receptors.

 

The primary targets or mechanisms of action in cannabinoid based cancer treatments involve the activation of CB1 and CB2 receptors. It seems likely that one reason THC has proven to be relatively effective (particularly when combined with other cannabinoids) is based on the fact that it's a CB1 and CB2 activator. However, THC activates CB1 much more efficiently than CB2, which is why other cannabinoids might be better options for treatments that would benefit from CB2 activation.

 

In addition to the activation of CB1 and CB2, some cannabinoids also activate TRPV1 which has been shown to induce apoptosis in tumor cells. Another target worthy of mention is GPR55. Unlike the other receptors which we are attempting to activate in cancer treatments, GPR55 activation by natural compounds in the body (as well as exogenous sources) actually leads to the proliferation of tumor cells, so it is beneficial to block GPR55 rather than activate it. Luckily enough there are cannabinoids that block GPR55. Both CBD and magnolia officinalis extracts block the activation of GPR55 and slow the proliferation of tumor cells. (Pisanti 2009)

 

 

Here is a list of cannabinoids with some of the relevant receptors that they target:

 

• THC – CB1/CB2 partial activator with CB1 selectivity (more potent CB1 activator), TRPV1 activator

• CBN – CB1/CB2 partial activator with CB1 selectivity (weaker than THC)

• CBG – CB2 activator, AEA reuptake inhibitor

• CBD – TRPV1 activator, GPR55 blocker, raises AEA and 2-AG levels, AEA reuptake inhibitor

• CBDA – TRPV1 activator

• Anandamide (AEA) – CB1/CB2 partial activator with CB1 selectivity

• 2-Arachidonoylglycerol (2-AG) – CB1/CB2 partial activator (weaker than AEA)

• Beta-caryophyllene (dietary cannabinoid, also found in holy basil, balsam copaiba, etc) – full CB2 activator

• Magnolia officinalis (magnolol/honokiol) – CB1/CB2 partial activator, GPR55 blocker

• Echinacea purpurea (new cannabinoid group of alkylamides) – CB2 partial activators

• Kava-Kava (yangonin) – CB1 partial activator

 

 

CB1                                            CB2                               TRPV1                                 GPR55 (blockers)

THC                                            THC                                THC                                             CBD

CBN                                            CBN                                CBD                                        m. officinalis

m. officinalis                                CBG                               CBDA

kava-kava                          beta-caryophyllene

2-AG                                      m. officinalis

AEA                                 echinacea purpurea

                                                    AEA

                                                   2-AG

 

 

This is not a definitive list, but there might be a few cannabinoids listed that many patients aren't familiar with.

 

The first two I'll point out are AEA and 2-AG. These are endocannabinoids (natural cannabinoids in the human body). These are listed for a few select reasons. They are CBR activators with anticancer characteristics that are naturally produced by the body. That knowledge on its own might not mean much, but coupled with the knowledge of inexpensive ways of increasing endocannabinoid levels it can be quite useful information. Dietary linoleic acid has been shown to raise levels of both AEA and 2-AG. This is an inexpensive way to increase the body's own natural cannabinoids. CBD also raises levels of both AEA and 2-AG via FAAH inhibition. In addition, CBD, CBG, and CBC are all AEA reuptake inhibitors (which raise AEA levels).

 

Next is beta-caryophyllene. Beta-caryophyllene is of value in that it is a full CB2 activator that is naturally found in a number of dietary sources. It can also be found in concentrated levels in a variety of essential oils and nutritional supplements. In some treatments (like some types of breast cancer) CB2 activation is likely of greater importance than CB1.

 

One of the most highly researched in regards to anticancer potential is the magnolia officinalis. Magnolia officinalis root bark has been used in Chinese medicine for 2000 years. It contains magnolol and honokiol which are both cannabinoids with anticancer characteristics. They activate CB1, CB2, and also block GPR55. A point worth mentioning is that they are both known to target apoptosis, which might make their addition to any cannabis based (specifically THC) treatment potentially beneficial.

 

The final two are echinacea purpurea (CB2 activator) and kava-kava (CB1 activator). These are both relatively new discoveries and there isn't much information about their specific characteristics in regards to cancer treatment, but as CB1 and CB2 are both targets, it might be safe to assume that these have potential as well.

 

So now that we are familiar with our targets (receptors) and our weapons (cannabinoids) let's see how this all relates to some types of cancer:

 

Breast Cancer

• CB1 expression level is lowered

• CB2 expression level rises

• AEA and 2-AG via CB1 activation reduces cell proliferation

• THC immunosupression and non CBR mechanisms have been shown to increase tumor growth and metastisis in some cell lines.

• THC induces apoptosis via CB2 activation (better options for CB2 activation)

• CBD inhibition and apoptosis via CB2 and TRPV1

• Magnolia officinalis cannabinoids have a great deal of positive research in this treatment

• THC might not be the most appropriate cannabinoid for this treatment. (Reader is advised to review research on individual cancer cell lines in relation to this topic in the provided citations.)

Prostate Cancer

• CB1 and CB2 expression levels rise

• TRPV1 expression levels rise

• AEA via CB1 and CB2 inhibits proliferation

• THC induces apoptosis via non CBR

• Other cannabinoids have been shown to induce apoptosis via CB1 and CB2

• Magnolia officinalis cannabinoids have a great deal of positive research in this treatment

• Many cannabinoids might be well suited

Skin cancer

• No information on changes of expression levels, but CB2 is highly expressed in the skin

• Cannabinoids have been shown to inhibit growth via CB1 and CB2 activation

• Beta-caryophyllene from essential oils can be used in topical applications

• Magnolia officinalis cannabinoids have a great deal of positive research in this treatment

 

Pancreatic Cancer

• CB1 and CB2 expression levels rise

• THC induces apoptosis via CB2 and ceramide

• Magnolia officinalis cannabinoids have a great deal of positive research in this treatment

• Many cannabinoids may be well suited

 

Glioma and Brain Cancer

• CB2 expression levels rise (CB1 level of expression in brain is high)

• THC induces apoptosis via CB1 and CB2

• THC reduces proliferation via CB1

• THC inhibits cell invasion via non CBR mechanisms

• Other cannabinoids have been shown to induce apoptosis via CB2 and COX-2 inhibition

• Magnolia officinalis cannabinoids have a great deal of positive research in this treatment

• THC is prime candidate

 

GI/Colon Cancer

• CB1 expression levels rise in gastrocarcinoma

• CB2 expression levels rise in colon carcinoma

• AEA induces cell death via COX-2 (colorectal carcinoma)

• AEA synergism with 5-fluorouracil

• Other cannabinoids inhibition via non CBR mechanisms

• Other cannabinoids induce apoptosis via CB1 and CB2

• Magnolia officinalis cannabinoids have a great deal of positive research in this treatment

• Loss of CB1 accelerates intestinal tumor growth

 

Hematological Cancer

• CB2 expression levels possibly rise

• AEA induces apoptosis via TRPV1 (other TRPV1 agonists)

• AEA growth inhibition and apoptosis via CB1 and CB2

• THC induces apoptosis via CB2

• CBD growth inhibition and apoptosis via non CBR

 

 

It also seems important to stress the potential relevance of treatment schedules. This is a point that directly relates to the expression level of CBRs, which we now understand the role of. The average lifespan of a cannabinoid receptor is around 0.5 seconds. Their level of expression is constantly in flux. Patients who have consumed cannabis for extended periods of time are familiar with the fact that a "tolerance" is quickly established to cannabinoids. The same is true for patients during cancer treatments. This is in large part due to the level of cannabinoid receptors being lowered and becoming fatigued by the constant exposure to exogenous cannabinoids. It is also commonly accepted among those who consume cannabis daily that abstaining from cannabis for 24-48hrs lowers a person's tolerance and increases the effects elicited by cannabinoids.

 

How does this relate to cancer treatments? Well, some research suggests that the efficacy of a cannabinoid based treatment is influenced by the dosing schedule. Most cancer treatments recommend 1000mg of cannabinoids daily. Is that the most effective schedule? Is it possible that incorporating 'off days' and abstaining from cannabinoids might allow the CBRs to recover and increase the efficacy of the overall treatment? Scientific research indicates this to be the case. (Scott 2013)

 

 

Due to the reduction of receptor expression levels as well as receptor fatigue from overexposure to CBR activators, it has been shown that it might be significantly more effective to incorporate a 'day off' every fourth day in which no cannabinoids are consumed. This allows the expression levels of CBRs to rise and allows them to recover from fatigue, in turn this has been shown to increase the efficacy of subsequent cannabinoid applications. This might be something worth considering for those involved with these types of treatments. (Scott 2013)

 

This paper isn't meant to be definitive, but I hope it provides patients with some potentially useful insight into cannabinoid based cancer treatments. The ways in which we discuss the potential of cannabinoids have a direct impact on current treatments. When a claim is made that 'cannabis cures cancer' that statement taken at face value is potentially dangerous in some scenarios. Cannabis doesn't kill cancer in the traditional sense, or similar to the way that chemotherapy does. Chemotherapy targets and kills practically everything. That is one reason why cannabinoids offer so much more potential in cancer treatments. Cannabinoids, some of which can be found in cannabis, can be used to coax the body into slowing these cells down and convincing them to kill themselves in a nontoxic way. But it's important to know how to use them by understanding which ones to use. This is gained by identifying the specific receptors that are being targeted. Once the targets have been identified a combination of activators can be utilized to activate those targets. This message is lost when we speak about the use of cannabis in cancer treatments in an inappropriate manner. Just talking about this more accurately might increase awareness which might have the potential to increase the efficacy of current cannabinoid based treatments.

 

It is highly recommended to review some of the citations (available online for free) as they provide much more detailed information.

 

 

 

References:

 

Guindon, Josée, and Andrea G. Hohmann. "The endocannabinoid system and cancer: therapeutic implication." British journal of pharmacology 163.7 (2011): 1447-1463.

 

Pisanti, Simona, and Maurizio Bifulco. "Endocannabinoid system modulation in cancer biology and therapy." Pharmacological Research 60.2 (2009): 107-116.

 

Alvheim, Anita R., et al. "Dietary Linoleic Acid Elevates Endogenous 2‐AG and Anandamide and Induces Obesity." Obesity 20.10 (2012): 1984-1994.

 

Ligresti, Alessia, et al. "Kavalactones and the endocannabinoid system: The plant-derived yangonin is a novel CB< sub> 1</sub> receptor ligand." Pharmacological Research 66.2 (2012): 163-169.

 

Amiel, Eitan, et al. "β-Caryophyllene, a compound isolated from the biblical balm of gilead (Commiphora gileadensis), is a selective apoptosis inducer for tumor cell lines." Evidence-based complementary and alternative medicine 2012 (2012).

Gertsch, Jürg, et al. "Beta-caryophyllene is a dietary cannabinoid." Proceedings of the National Academy of Sciences 105.26 (2008): 9099-9104.

 

Fried, Levi E., and Jack L. Arbiser. "Honokiol, a multifunctional antiangiogenic and antitumor agent." Antioxidants & redox signaling 11.5 (2009): 1139-1148.

 

Seo, Jae-Uk, et al. "Anticancer potential of magnolol for lung cancer treatment." Archives of pharmacal research 34.4 (2011): 625-633.

 

Xu, Huanli, et al. "Targeting apoptosis pathways in cancer with magnolol and honokiol, bioactive constituents of the bark of Magnolia officinalis." Drug discoveries & therapeutics 5.5 (2011).

 

Rempel, Viktor, et al. "Magnolia Extract, Magnolol, and Metabolites: Activation of Cannabinoid CB2 Receptors and Blockade of the Related GPR55." ACS Medicinal Chemistry Letters 4.1 (2012): 41-45.

 

Izzo, Angelo A., et al. "Inhibitory effect of cannabichromene, a major non‐psychotropic cannabinoid extracted from Cannabis sativa, on inflammation‐induced hypermotility in mice." British journal of pharmacology 166.4 (2012): 1444-1460.

 

Scott, Katherine Ann, et al. "Enhancing the Activity of Cannabidiol and Other Cannabinoids In Vitro Through Modifications to Drug Combinations and Treatment Schedules." Anticancer research 33.10 (2013): 4373-4380.

Edited March 18, 2014 by in vivo

[in vivo]

This is the makings of a paper I'm interested in writing. Consider this my submission for peer review.

 

Does the way in which we speak about cannabinoid based treatments matter? I'd argue that it does and that by speaking about them more accurately we might increase awareness, and more importantly potentially increase the efficacy of current cannabinoid based cancer treatments.

Edited March 19, 2014 by in vivo

[in vivo]

Modulation of CB1 cannabinoid receptor functions after a long-term exposure to agonist or inverse agonist in the Chinese hamster ovary cell expression system

 

This is a study as far back as '98 showing the issues with CBRs overexposure to agonists. Schedule really looks like it makes a difference.  

[GregS]

Nice work. Are you a student?

[in vivo]

I'm not currently a student. I'm just interested in bridging the gap between current research and current treatments. This is my response to the PGT show last Thursday. I had gone through most of this previously with a NF1 patient.

 

I actually explained it a little differently with him. With his situation we're in it for the long haul. NF1 is a genetic condition that doesn't currently have a cure or treatment. It can produce hundreds of fibromas and they're currently causing GI complications/pain as well as always having the concern that they may spread to the brain. So it's the fibromas we're targeting.

 

My suggestions were:

dietary linoleic acid to increase AEA and 2-AG (daily)

CBD around 10mg sublingual spray (daily)(it was in short supply and we're stretching it out)

magnolia officinalis extract (200-600mg daily)

THC two days, then THCA two days: botanical extract 1000mg (daily) or (THC two days, two days off)

 

Also advised to find echinecea purpurea and kava-kava. Basically we're throwing everything at it we can. The THCA I'm on the fence about. I'm concerned it might be a waste. Due to some of the GI issues it was advised, but if there was no immediate relief after the first two days of THCA treatment it was advised to discontinue THCA and just rotate two days on two days off. I also think that there should notice a difference each time the THC administration is resumed after two days off. It might be more 'fun' and potentially less exhausting. But that's just based on associations through my own experiences.    

[GregS]

Why not go to school and get credentialed?

[in vivo]

Not to sound helpless but one of my excuses is that I never enrolled to the Selective Services which disqualifies me for Federal grants and loans for schooling. I took a couple semesters a little over a year ago but then was forced to double down in other areas based on life events. I got along well with some of the professors and have been pondering how I might get one of them to game the system to allow me access to more research. Maybe audit some classes and not do the work or something. 

 

It seems unfortunate that the practicing physicians that cater to this market don't spend more time getting this type of information out to the public. I've got a full back piece on me of the lord of knowledge and remover of obstacles so I guess that qualifies me to step up to the plate.  

 

 

 

Or it just takes a certain level of ignorance which I'm sure I excel at. It just seems to me like this might be a more accurate description than what I've heard or read about from the majority of pro-cannabis sources. I'm all about this plant, which is what most pieces focus on. I just think people are more important, and that valuable information is being lost in translation.