Cannabinoids Vs. Cancer: A Cellular War

There is a lot of information to suggest cannabis and its extracts may be useful in the treatment of cancer. Many of you, our readers may not have the most expert knowledge of human biochemistry or in particular cellular biology so we have asked our research director to explain on a cellular level how cannabinoids can work in synergy with your Endocannabinoid system to fight cancer.

Feel free to share and discuss this information with your doctors, consultants, friends and family.

What occurs at the cellular level when a cancer patient ingests cannabinoids?

The molecule of Tetrahydrocannabinol (THC) appears to be a natural fit for the CB1 cannabinoid receptor on the cancer cell surface. When THC enters into contact with this receptor the cell generates ceramide that disrupts the mitochondria, thus closing off the main energy source for the cell. This disruption of the mitochondria releases both ‘cytochrome c’ and ‘reactive oxygen species’ into the cytosol, thus hastening cell death. It is notable that this process is specific to cancer cells. Healthy cells have no reaction to THC at the CB1 receptor site. The increase in ceramide also disrupts calcium metabolism in the mitochondria, further hastening cell death.

The other cannabinoid also known to be effective in killing cancer cells is cannabidiol (CBD). The primary job of CBD in the cancer cell is to disrupt the endoplasmic reticulum through the interference of calcium metabolism, pushing calcium into the cytosol. This always results in cell death. Another pathway for CBD to cause cancer cell death is the “Caspase cascade”, which breaks down proteins and peptides in the cell. When this happens the cell cannot survive. Again, these processes are specific to cancer cells, normal cells are not affected.

Certain cannabinoids can destroy cancerous tumours by working symbiotically with our body’s endocannabinoid system: this is a simple yet fundamental premise.

The endocannabinoid system (ECS) was discovered by researchers in the 1940s and by the late ‘60s its basic structure and functionality had been mapped out. Today we now know that the ECS is a comprehensive system of biochemical modulators that maintain homeostasis in all body systems including the central and peripheral nervous systems, all organ systems, somatic tissues, and all metabolic biochemical systems, including the immune system.

This homeostatic matrix is not just limited to humans and the endocannabinoid system has been found in every chordate creature which have existed in the past 500 million years. The ECS is a fully mature biochemical process that has maintained health and metabolic balance for most of the history of life itself.

The two major interactive systems within the ECS are:

1) The cannabinoid receptors that we find on all cell surfaces and neurological junctions;
2) The endocannabinoids that fit the receptors to trigger various metabolic processes.

Looking at a cannabinoid receptor distribution map one can see that CB1 receptors, which are most sensitive to anandamide, are found in the brain, spinal nerves, and peripheral nerves. CB2 receptors, preferred by 2-Arachidonoylglycerol (2-AG), are found largely in the immune system, primarily the spleen. Both CB1 and CB2 receptors are found throughout the rest of the body including the skeletal system.

Interestingly, for commercial application, 2-AG or CBD can grow new bones. Cancellous bone, also known as ‘spongy’ or ‘trabecular bone’, is one of the two types of bone tissue found in the human body. Cancellous bone is found at the ends of long bones, as well as in the pelvic bones, ribs, skull, and the vertebrae in the spinal column.

It is also worth mentioning that both anandamide and 2-AG can activate either CB1 or CB2 receptors. The potential for bone fracture healing, with further research, cannot be understated.

The nature of the endocannabinoids are more similar in function to neurotransmitters, but structurally are characterised as eicosanoids in the family of signalling sphingolipids. These signalling cannabinoids keep track of metabolic systems throughout the body and this information is shared with both the nervous system and the immune system, so that any imbalance is corrected insitu. If the body is in a chronic disease state or is being subject to emotional stress, the immune system can lose control of any compromised systems. It is here that phytocannabinoids can provide much needed additional support to the stressed body in returning it to health. The cannabis plant provides exogenous analogues of the body’s primary signalling cannabinoids. Tetrahydrocannabinol (THC) is mimetic to anandamide, and cannabidiol (CBD) is mimetic to 2-AG, and has the same affinity to CB1 and CB2 receptors, providing the body with the additional support for the immune and endocannabinoid systems. By way of explanation: a receptor is a protein molecule that receives a signal by binding to a chemical (its “ligand”). Affinity is a measure of the strength of attraction between a receptor and its ligand.

In a sense, exogenous phytocannabinoids boost the body’s own endocannabinoid system by amplifying the response from the immune signalling system by two possible modes:

1) Bonding with the cannabinoid receptors;
2) Regulation of many physiological processes, (such as certain cannabinoid’s powerful neuroprotective and anti-inflammatory actions) quite apart from the effect on the receptor system.

It is interesting to note here that the phytocannabinoids and related endocannabinoids are structurally different but functionally similar. Anandamide and 2-AG are eicosanoids while THC and CBD are tricyclic terpenes.

The National Institutes of Health (NIH) in the U.S.A has reported that THC is best known because of its signature psychotropic effect. A recent NIH report remarks that THC is an effective anticancer treatment, an appetite stimulant, analgesic, antiemetic, anxiolytic, and sedative. Many published research articles and personal testaments show the efficacy of cannabis extracts in bringing about cancer remission. However, only a few point to the mechanism by which the cancer cells die.

There are two structures in most cells that sustain life; one is the mitochondria, and the other is the endoplasmic reticulum. The mitochondria primarily produce adenosine triphosphate (ATP) that provides the necessary energy for life. The endoplasmic reticulum (ER) is a loosely bound envelope around the cell nucleus that synthesises metabolites and proteins directed by the nuclear DNA that nourish and sustain the cell.

In every cell there is a family of interconvertible sphingolipids that specifically manage the life and death of that cell. This profile of factors is called the ‘Sphingolipid Rheostat’. If ceramide (a signaling metabolite of sphingosine-1-phosphate) is high, then cell death (apoptosis) is imminent. If ceramide is low, the cell will be strong in its vitality. Very simply, when THC connects to the CB1 or CB2 cannabinoid receptor site on the cancer cell, it causes an increase in ceramide synthesis which drives cell death. A normal healthy cell does not produce ceramide in the presence of THC, thus is not affected by the cannabinoid.

The cancer cell dies not as a result of the use of cytotoxic chemicals but because of a change in the mitochondrial activity with respect to ATP. Within most cells there is a cell nucleus, numerous mitochondria (hundreds to thousands), and various other organelles in the cytoplasm. The purpose of the mitochondria is to produce energy (ATP) for cell use. As ceramide starts to accumulate, turning up the Sphingolipid Rheostat, it increases the mitochondrial membrane pore permeability to cytochrome c, a critical protein in energy synthesis. Cytochrome c is pushed out of the mitochondria, killing the source of energy for the cell.

Ceramide also causes genotoxic stress in the cancer cell nucleus generating a protein called p53, whose job it is to disrupt calcium metabolism in the mitochondria. If this weren’t enough, ceramide also disrupts the cellular lysosome, (the cell’s digestive system that provides nutrients for all cell functions). Ceramide, and other sphingolipids, actively inhibit pro-survival pathways in the cell leaving no possibility at all of cancer cell survival.

Thus, the key to this process is the accumulation of ceramide in the system. This means taking therapeutic amounts of cannabinoid extract, steadily, over a period of time, keeping metabolic pressure on this cancer cell death pathway. The precise details of the quantities and the rate at which they are taken has yet to be fully defined.

How did this cancer cell death pathway come to be? Why is it that the body can take a simple plant enzyme and use it for healing in many different physiological systems? These are serious questions currently yet unanswered by modern evolutionary biology.

The endocannabinoid system exists in all animal life waiting for its matched exocannabinoid activator to be delivered.

This is of considerable importance. Our own endocannabinoid system includes all cells and nerves; it is the messenger of information flowing between our immune system and the central nervous system (CNS). It is responsible for neuroprotection, and micro-manages the immune system. This is the primary control system that maintains homeostasis and hence our wellbeing.

Endocannabinoids have their origin in nerve cells at the synaptic junction. When the body is compromised through illness or injury it signals continuously to the endocannabinoid system and directs the immune system to bring about healing. If these homeostatic systems are weakened, it should be no surprise that exocannabinoids perform the same function. They help the body in the most natural way possible.

To best understand this we visualise the cannabinoid as a three dimensional molecule, where one part of the molecule is configured to fit the nerve or immune cell receptor site, just like a key in a lock. There are at least two types of cannabinoid receptor sites, CB1 (CNS) and CB2 (immune). In general CB1 activates the CNS messaging system, and CB2 activates the immune system, but it’s much more complex than this. Both THC and anandamide activate both receptor sites. Other cannabinoids activate one or the other receptor sites. Among the strains of cannabis, C. sativa tends toward the CB1 receptor, and C. indica tends toward CB2. More research is clearly required as there is so much conjecture in this field on this subject. So sativa strains could be said to be more neuroactive, and indica strains more immunoactive. Another factor here is that sativa strains are dominated by THC cannabinoids, whilst indica strains may proportionally possess higher levels in CBD (cannabidiol). Nevertheless, it is common for an indica strain to contain less than 1% CBD of total cannabinoid composition in the final flower.

It is known that THC and CBD are biomimetic (relating to or denoting methods that mimic biochemical processes) to anandamide and AG-2, that is, the body can use both interchangeably. Thus, when stress, injury, or illness demand more from endogenous anandamide than can be produced by the body, its mimetic exocannabinoids (phytocannabinoids derived from cannabis) are utilised. If the stress is transitory, then the treatment can be transitory. If the demand is sustained, such as in cancer, then treatment needs to provide sustained pressure of the modulating agent on the homeostatic systems.

Typically CBD gravitates to the 5-HT1A and vanilloid receptors. CBD stimulates production of anandamide and AG-2, endogenous cannabinoids that are agonists for CB-1 and CB-2 receptors. From there, immune cells seek out and destroy cancer cells. Interestingly, it has been shown that THC and CBD cannabinoids have the ability to kill cancer cells directly without going through immune intermediaries. THC and CBD assume control the THC and CBD assume control of the lipoxygenase pathway to directly inhibit tumour growth. As a side note, it has been discovered that CBD inhibits anandamide re-uptake. The implication being that cannabidiol helps the body preserve its own natural endocannabinoid by inhibiting the enzyme that breaks down anandamide.

In 2006, researchers in Italy demonstrated how cannabidiol (CBD) kills cancerous cells. CBD stimulates what is known as the ‘Caspase Cascade’, thereby killing the cancer cell. First, let’s look at the nomenclature, then to how Caspase kills cancer. Caspase is an aggregate term for all cysteine-aspartic proteases. The protease part of this term comes from prote (from protein) and -ase (destroyer). Thus the Caspases break down proteins and peptides in the moribund cell. This becomes obvious when we see Caspase-3 referred to as “the executioner”. In the pathway of apoptosis, other Caspases are brought in to complete the cascade.

Even when the cascade has completed its action and the cancer has expired, CBD is still at work healing the body. Cannabidiol also shuts down the Id-1 gene that allows metastatic lesions to form. Fundamentally this means that treatment with phytocannabinoids not only kills cancer through numerous simultaneous pathways, but can also prevent metastasis.

Nature has designed the perfect medicine that fits exactly with our own immune system of receptors and signalling metabolites to provide rapid and complete immune response for systemic integrity and metabolic homeostasis. It is clear that this represents a significant opportunity for developing innovative therapeutics for treating cancer.