Sylvia C. Bagge
RN, BSN, PHN
The persistently activated immune system is an emerging clinical challenge in the medical management of a new cohort of people living with HIV infection for years and occasionally, decades. Oxidative damage to tissues and organs is caused by reactive forms of oxygen and nitrogen released by pro-inflammatory cells that are present past the acute phase of inflammation.
In this patient cohort, the set of disease processes normally associated with aging are now the cause of decline and death versus HIV infection itself. These conditions, called non-HIV related co-morbidities include conditions such as cardiovascular disease, osteoporosis, coagulation disorders, Chronic Obstructive Pulmonary Disease (COPD), liver disease, kidney disease, cognitive impairment, cancer, immunosenescence (early aging of the immune system) and early frailty.
Clinical attention was drawn to the issue of Chronic HIV-Related Inflammation (CHRI) by the Smart Study (N ENGL J MED 2006; 355: 2283-2296). This study was originally designed to determine if intermittent interruption of anti-retroviral therapy (ARV) improved health by decreasing pharmaceutical toxicity. The study was stopped because of higher than expected co-morbities in the treatment interruption group. However, it was discovered that inflammatory markers were elevated even with a suppressed viral load. While the major question of HIV infection used to be how to activate the immune system, a new question has surfaced of how to quiet the immune system and simultaneously promote its natural functioning.
Through a review of literature, this paper suggests that the potential therapeutic effects of CBD may be well-matched to the therapeutic profile required by the problem of immune-dysregulation associated with CHRI. This paper views the problem of CHRI as disruption in a homeostatic control system (HCS). If this is true, then the appropriate therapy must promote the restoration of on-off cycling and stability in that HCS.
CHRONIC HIV-RELATED INFLAMMATION AS A QUANTUM DISEASE PROCESS USING THE LENS OF HOMEOSTASIS
This paper defines homeostasis as a balance in on-off signaling, supporting a “steady state”, in which the body’s resources used (inputs) are equal to the functions necessary for survival (output). The steady state establishes internal conditions that minimize the effect of external changes. In other words, the least amount of energy is being utilized to comfortably support an organism’s survival.
According to the current paradigm, the presence of HIV, even in the case of an undetectable viral load, creates a continuous “error signal” in the external environment of the extracellular fluid. The body responds by continuously activating the immune system, utilizing a greater amount of energy. As a result, the operating point shifts to a place at which the body’s expenditures are greater than its income. This allows survival of the organism in the short-term, but the new operating point is unsustainable.
According to this paradigm, the continuously activated inflammatory response is responsible for the early aging associated with long-term HIV infection. It must be noted here that early aging in this population is also likely to be related to ongoing exposures to pharmaceutical toxicities, and in many cases, recreational drug toxicities, poor nutritional status, and chronic exposure to trauma.
Homeostasis teaches us that the body is always moving from one state to the next, as balance is never a fixed point. An understanding of this continuous flux helps us see more deeply into the unique disease process in each individual. Though a pure balanced state is never possible, even in a healthy person, it inspires creative ways to nudge the body back toward a steady state, allowing its impeccable wisdom to flourish.
Current anti-inflammatory treatment options, such as non-steroidal anti-inflammatory drugs (NSAIDS) and steroids are often not options for people with long-term HIV due to their high risk status for liver and kidney failure, and gastrointestinal bleed. Additionally, pharmaceuticals aimed at turning off the inflammatory processes do not address the dysregulation that is cycling out of balance on a positive feedback loop.
Here, the original concepts of quantum disease process (QDP) and quantum antidote (QA) are introduced and defined. A QDP involves the dysregulation of a homeostatic system, resulting in signaling that is simultaneously on and off. CHRI is a QDP because the underlying problem is poor immune-modulation. This presents a treatment dilemma because an appropriate antidote must have the effect of modulation versus correction.
A QA responds to the dysregulation of on-off signaling by promoting stability within the body’s own homeostatic control system. The literature indicates that cannabinoids, and CBD in particular, has been shown to have an immune-modulatory effect, suppressing and activating immune activity as needed.
The concept of a QDP replaces the need to identify one-single causative agent of a disease if one cannot be identified with evidence based practice. The concept of QDP aims to capture a person’s combined biological, social, and economic experience as causative of disease. In a new paradigm, medical providers are not under pressure to narrow the causes of a disease down to one only unless it is appropriate to narrow down to one. The QA might be simpler than we expect. For example, the disease of malnutrition can be cured with on-going access to organic food.
Although some diseases certainly do have a single causative agent, most diseases today are explained only by understanding the individual that presents him or herself to us as a patient. Catagories are also necessary, but they should be secondary to meeting the “in-the-flesh” person. We have long passed the earlier days of the pharmaceutical industry when many diseases could be cleared with a “magic bullet.” Amazingly, there are still many conditions that can be cured with the “magic bullet”, and for that we give thanks.
This paper suggests that CBD is worth further study as a potential quantum antidote for the quantum disease process of CHRI.
CHRONIC INFLAMMATION AS A CURRENT AND UPCOMING PUBLIC HEALTH CRISIS ASSOCIATED WITH THE AGING POPULATION
Non-HIV-related co-morbidities is the term given to the diseases normally associated with aging that are experienced by the HIV-infected person treated with ARV more often than their non-HIV-infected counterparts.
As the general population ages, delivery systems will need to provide adequate care for the increasing number of people living with one or more chronic illnesses. In its choice of pharmaceuticals as a primary mode of treatment, our current medical industry has created an internal obstacle called polypharmacy.
Polypharmacy refers to the shocking length of physician-required medication lists for nearly every patient with a chronic condition. The pill-burden is especially unreasonable for the HIV-infected patient. Chronic conditions such as cardiac disease, renal disease, and diabetes are nearly all treated with pharmaceuticals. Physicians often require prophylaxis for opportunistic infections that have occurred in the past, such as toxoplasmosis and cytomegalovirus, translating into additional on-going pharmaceuticals on the list. Antiretroviral therapy (ARV) is comprised of a cocktail most commonly containing three additional pharmaceuticals on the list. Pharmaceuticals also are used to treat the various palliative goals such as control of pain, itching, nausea and many other symptoms.
This patient is also high risk for being prescribed even more pharmaceuticals for mental health diagnoses and additional viral infections such as hepatitis C. Additionally, there are ongoing risks to patient safety with potential drug interactions and errors.
Current modes of health care delivery will need re-organization in order to address the massive numbers of people living with chronic, manageable disease states. The cognitive impairment associated with long-term HIV and other chronic conditions contribute to self-care deficits and mental health conditions that are very difficult to manage, and cause immense physical and mental suffering.
The natural and sophisticated neuroprotective effects of CBD are discussed later in this paper, and suggest an appropriate match to the these important needs.
In the past, the health insurance and pharmaceutical industries have played a role in health care delivery. However, the health-insurance industry is now an industry of health-care denial, and the options offered by the pharmaceutical industry provide excellent remedies for only a portion of our current health problems.
Plants have potential to produce great amounts of medicine with a self-sustaining funding stream. They can create true economic value at the local level, and contribute many reliable products and wealth-generating projects to the entire economy. This is the inherent power of plant-based medicine.
CHRONIC HIV-RELATED INFLAMMATION (CHRI)
The immune system is a complex communication system of on-off signaling. The presentation of the immune system in medical textbooks tends to focus on the signaling pathways that activate immune response. Some mechanisms by which the inflammatory response can be suppressed are well known. For example, prostaglandin inhibition is the mechanism of action for many over-the-counter anti-inflammatory medications. The mechanisms by which balance is re-stored to the immune system, however, are less understood.
The term “inflammation” usually brings images of acute inflammation to mind, such as pain, swelling, and redness to an injured area of tissue. There are many reasons why people living with long-term HIV-infection treated with ARV have higher than normal inflammation, as measured by the Smart Study (2006).
Perhaps the hardest thing to see about this is the easiest thing to see: this population is aging and has gone through multifactorial wear and tear. Therefore, higher than normal levels of inflammation should be anticipated for this population of people, as many are now entering older adulthood. This incredible group of people have each experienced many illnesses, and have endured an unbelievable amount of extremely demanding medical treatments including surgeries, radiation, pharmaceutical and many others. Additionally, these usually frail people continue to spend as much time waiting for medical services on an on-going basis as one would working a full time job.
Fundamental to the problem of a chronically activated immune-system are the persistent presence of chemicals messengers activating chemical pathways during acute inflammation. Cytokines are involved in cell-to-cell communication, inflammatory response, and activation of overall immune-response. Cytokines such as interleukin 1 (IL-1) and interleukin 6 (IL-6) are pro-inflammatory and signal to continue the inflammatory response, and other cytokines, such as interleukin 4 (IL-4) and interleukin 10 (IL-10) are anti-inflammatory. Examples of other important chemical mediators involved in CHRI include C-reative protein (signals ongoing inflammation) and D-dimer (signals increased coagulation). Please see the article “HIV Infection, Inflammation, Immunosenescence, and Aging”, by Dr. Steven Deeks (Annual Review of Medicine. 2011. 62: 20.1-20.15) for a complete discussion.
Dr. Steven Deeks (2011) reports that many of the T cell abnormalities found in the people with long term HIV infection are similar to those occurring for the general population. The immune system itself goes through changes associated with aging. This occurs for everyone. but it occurs for people with HIV-infection at an earlier age. The immune system’s aging is marked by a dysregulation of the thymus, and is associated with generation of either too few or too many T-cells.
The physiological effects of chronic inflammation at the local level include such problems such as increased permeability of blood vessels, causing third-spacing of fluid (swelling), coagulopathies (dysregulation of clotting), and life-threatening events such as deep vein thrombosis (DVT).
At the systemic level, the oxidative damage causes a decreased number of healthy cells, decreased cell division, early cell death, and cell malfunction, all of which contribute to the body’s decreased ability to respond appropriately to stress and insult. This process mirrors the cellular changes associated with the normal aging process.
THIS IS YOUR BRAIN AND IMMUNE SYSTEM ON CBD
The body of literature suggesting the immune-modulatory, anti-inflammatory, and neuroprotective potential of CBD is well documented. The therapeutic profile of CBD matches the problem list associated with CHRI. This section will review a portion of the literature discussing the aspects of CBD relevant to CHRI.
CBD interacts mainly with receptors (CB2) belonging to the endocannabinoid system that are located outside of the brain and central nervous system. This accounts for CBD’s non-psychoactive effect, where as the famous cannabinoid,THC, interacts with the endocannabinoid system’s CB1 receptors that are located both in the central nervous system and throughout the body.
It should be noted here that no compounds in Cannabis sativa (Hemp is Cannabis sativa) interact with the respiratory centers of the brain. This explains why cannabis does not cause respiratory depression, or the lack of drive to breathe that is associated with opiate overdose.
Three selected therapeutic effects of CBD found in the literature will be reviewed here, including its neuroprotective anti-oxidant effect, its immune-modulating effect, and its anti-inflammatory effect.
The neuroprotective anti-oxidant effect of CBD has been studied extensively due to its ability to reduce inflammation of brain tissue in glioblastoma. As noted above, CB2 receptors are not expressed in brain tissue, However, in cases of tissue injury or inflammation, CB2 receptors are expressed on the microglial cells of the brain (Mackie et al 2008, Holland, ed. 2010). As CBD is lipid-soluble, it is able to penetrate brain tissue. This suggests a palliative and curative potential for inflammatory conditions associated with brain tissue.
Currently HIV-associated Neurocognitive Disorder (HAND) is an umbrella term referring to neurocognitive disorders that are both directly caused by viral penetration of the CNS, such as HIV-associated dementia (HAD), and those disorders not directly caused by the virus. According to the current paradigm, HIV penetrates brain tissue soon after initial infection, but CNS infection is checked until CD4 T-cell functioning fails. At this point, HIV infection in the CNS begins to progress, leading to HIV-associated dementia (Williams et al 2002).
The presentation of HIV-dementia is slightly different for each person, but often involves slowed response, slowed mental functioning, imbalance in gait and mobility, irritability, and forgetfulness.
ARV is frequently initiated in asymptomatic patients, as it is thought that ARV will have a neuroprotective effect upon CNS tissue, and neurocognitive impairment can potentially be slowed. However, although AZT does have CNS penetrating ability, currently used combinations of ARV, known as HAART (highly active antiretroviral therapy) have only some penetrating ability.
A study by Sean B. Rourke et al was presented at the 2012 Conference on Retroviruses and Opportunistic Infections, addressing the CNS penetrating ability of ARVs. The study compared viral load in the plasma to viral load in the cerebrospinal fluid as an indicator of how well ARVs are suppressing infection in the CNS, concluding that the HAART is the best current treatment to slow the progression of HAD. This study and many other sources of current literature indicate that the combination of several pharmaceuticals, all of which have a little CNS-penetrating ability, are likely to suppress progressive infection in the CNS via successful suppression of viral load in the plasma.
Understanding HIV disease from the QDP perspective, the brain and central nervous system are not necessarily healthy, and the disease process is not necessarily slowed, if the patient is asymptomatic and the viral load is suppressed in the CSF. An effective antidote for the complex and individualized disease process of dementia must go deeper than this, must look at the risks and toxicities associated with ARV, and must evaluate if enough evidence exists that health is likely to improve with treatment for most people.
The best performance expected from ARVs in preventing HIV-associated dementia is a theoretical slowing down of the disease process. It is difficult to maintain adherence to a complex ARV regimen if the best that can be expect is the slowing down of his or her disease.
A pathway that is common to the neurodegeneration associated with many disease processes is called excitotoxicity, and is marked by over-active glutamate receptors on nerve cells, signaling a pathway resulting in cell-death from destructive enzymes. CBD’s ability to modulate this phenomenon is thought to underpin its neuroprotective abilities (Holland, ed. 2010).
Project CBD (projectcbd.org) is an organization started by Dr. Fred Gardner to provide strains of CBD-rich cannabis and conduct research. Project CBD reports the following:
“Cannabidiol provides potent and long-lasting neuroprotection through an anti-inflammatory CB1 receptor-independent mechanism, suggesting that cannabidiol will have an palliative action and open new therapeutic possibilities for treating cerebrovascular disorders (projectcbd.com/science).”
Mechulum et al. (2007) discuss the findings of a 2003 study by Braida et al, investigating damage to cells following cerebral ischemia in gerbils. The results showed complete survival of neurons in CBD-treated gerbils following cerebral ischemia, though the mechanism of protection was not clear.
The literature also suggests strongly that CBD is a neuroprotective anti-oxidant, and may actually promote the generation of new neurons (projectcbd.com/science). Mechulum et al. (2007) report that CBD exerts a combination of neuroprotective, anti-oxidative, and anti-apoptotic (preventing cell-death) effects. CBD appears to be involved in a signaling pathway for neuroprotection in response to a neurodegenerative pathway associated with the compound B-amyloid.
CBD is reported to limit the cell-death related to plaque formation in the brain associated with Alzheimer’s Disease. Julie Holland, MD (2010) discusses three studies (Iuvone et al 2004, Marchalant, et al 2008, Marchalant, Rosi, and Wenk 2007) that report this finding, as well as CBD’s association with improved memory.
According to Mechulum et al. (2007), CBD’s anti-oxidant effects appear to be independent of receptor activity, and are associated with the its plant-based phenol properties. CBD, is a type of phenol called resorcinol. This group references a study by Hampton et al (1998) that found CBD to prevent oxidative damage due to hydroperoxide equally or better than vitamin C or Vitamin E.
The second area discussed in the literature suggesting that CBD may have potential in the management of CHRI is its immune modulating effect. In addition to findings relevant to the phytocannabinoid (plant-based) CBD, much of the literature discusses findings relevant to CB2 receptor activity, which can involve both phytocannabinoids and endocannabinoids (endogenous ligands that interact with endocannabinoid receptors).
Mackie et al (2008), the Institute of Medicine (1999), and Mechulum et al (2007) suggest the potential immune-modulating activity of CBD. One major indicator of this is the wide expression of the CB2 receptors on the cells of the immune system, including B cells, natural killer cells, monocytes, neutrophils, and T cells. The abundance of CB2 expression on immune cells is suggestive of its importance in normal immune functioning. The institute of Medicine (1999) states that cannabinoids “…modulate the immune-system in various ways-in some cases enhancing and in others diminishing the immune response” (p. 59).
Another indicator in the literature of CBD’s immune-modulating effect is its varying effect upon inflammatory bio-markers based upon varying conditions. For example, the Institute of Medicine (1999) reports that in human cell cultures, interferon production is increased by low concentrations of CBD and decreased by high concentrations of CBD.
Russo and Guy (2006) make reference to two studies, including Cabrol (2001) and Malfait (2000) that found CBD to have a significant modulating effect upon the immune system.
Finally, the anti-inflammatory effects of CBD found in the literature will be discussed. The mechanism of CBD’s anti-inflammatory effect is not well known (Mechulum et al. 2007). CBD’s weak interaction with CB2 receptors suggests that its profound therapeutic effects are likely related to complex mechanisms such as regulation of the activities of non-cannabinoid receptors, receptor-independent mechanisms, such as with its anti-oxidant effect, and as a possible modulator of the overall endocannabinoid system (Russo and Guy, 2006).
The institute of Medicine (1999) reports that cannabinoids both increase and decrease cytokine activity, based upon conditions. Cannabinoids have been shown to have an effect upon interleukin-1 (IL-1), tumor necrosis factor (TNF), and interleukin-6 (IL-6). The report states that this cytokine-modulating activity is central to the anti-inflammatory effects of cannabinoids.
Mackie et al. (2008) reports that CB2 receptor activity may suppress neutrophil migration during inflammation, providing a possible contributing factor to CBD’s anti-inflammatory effect.
Mechulum et al. (2008) report that synovial cells from mice that were treated with CBD were found to release significantly less TNF-a, a pro-inflammatory cytokine that is responsible for the mediation of arthritis. This report concluded that the anti-arthritic effects of CBD are likely due to a combination of an immunosuppressive effect, involving T-helper-1 response and anti-inflammatory, involving the suppression of TNF-a. The authors also noted other anti-inflammatory effects were observed, including neutrophil and macrophage suppression in the presence of arthritic inflammation.
The LD-50 associated of a compound measures the lethal dose of a substance and indicates potential for toxicity by establishing the dose at which 50% of subjects die. The LD-50 of Cannabis sativa has been studied in monkeys, demonstrating a lethal dose that is far, far greater than anyone can realistically consume (Grotenhermen 2003), providing an excellent safety profile.
CBD is worthy of further study as a quantum antidote for the quantum disease process of CHRI.
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