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Immunosuppression Mediated by MDMA and THC
Lake Forest College
Lake Forest, Illinois 60045
Natural hallucinogens are an area of interest for researchers trying to understand the potential beneficial effects for treating different disorders. Research on hallucinogens such as psilocybin, LSD, MDMA, and cannabis are aimed at a multitude of therapeutic targets such as depression, PTSD, and palliative care. However, there are concerns regarding use in patients who have suppressed immune systems, and this immunomodulation varies for each compound and is not well known. The cross interactions of hallucinogens with other drugs and the consequences of how they might affect the human body is also concerning to researchers. While some studies have been done on the effects of THC, and to an extent on the effects of MDMA, there is a lack of information available on the long-term effects regarding immunomodulation and ￼THC.
The effects of drugs on the immune system involves complex defense methods. The body uses a wide variety of cells, each with different kinds of receptors that influence how the cell responds. This article first describes the background information about two drugs that may interact with cells in many ways. The two drugs, THC and MDMA, are complex molecules with a history of drug abuse, so it is important to understand what they are and how they generally affect humans. Understanding how the immune system normally functions and how it is impaired is important for comparing it to an immune system with hallucinogens. Finally, understanding what receptors are affected helps to understand the underlying mechanisms that cause THC and MDMA to suppress the immune system.
Introduction to MDMA and Cannabis
Ecstasy, or 3,4-methylenedioxymethamphetamine, is a stimulatory hallucinogenic drug most commonly seen in nightclubs (Palamar 2017). MDMA produces minor visual hallucinations, sweating, headaches, nausea, and an increased serotonin levels (Hagino, et al. 2011). In the body, MDMA is metabolized in the liver and acts on several regions of the brain and immune system (Kalichman et al. 2015). MDMA acts as a serotonin and dopamine agonist, as the backbone benzene and amine are connected by a three-carbon chain. The structure of serotonin and dopamine is mimicked in MDMA, with the backbone benzene and amine connected by a three-carbon chain. Serotonin build-up can occur because of MDMA present in the synaptic cleft, which can result in serotonin toxicity (Nelson 2007). MDMA is a Schedule 1 drug, indicating that it has a high potential for abuse, severe safety concerns, and no conventionally accepted therapeutic use. Although this is the case, there is current interest in MDMA as a therapeutic target for disorders such as PTSD, anxiety, and depression (Byock 2018).
The main psychoactive ingredient of cannabis is Δ-9-tetrahydrocannabinol (THC). THC is present in all three species of the plant including indica, ruderalis, and sativa. Cannabis is used recreationally and medicinally by both adolescents and adults. The use of cannabis is widespread, as evidenced by legalization efforts and ballot initiatives supporting the use of recreational and medical marijuana. Cannabis can be ingested in a multitude of ways, including in a pill form, as a food ingredient, as a purified oil, or it can be smoked. These methods of ingestion have varying effects on the body, since the drug content of each method differs (Bredt et al. 2002). There are also many types and strains of cannabis, which are bred to produce different levels of THC content and possibly other contents as evidenced by marijuana dispensary selections and the creative names to accompany them. Each method might have different effects on immunosuppression due to their THC content. Symptoms of THC ingestion include appetite stimulation, mild psychotropic hallucinations, relaxation, euphoria, and anxiety (Wiley et al. 2005). Cannabis is also a favored target for therapeutic use, with a more profound interest in how cannabinoids work in the current literature regarding their interactions with cellular receptors and medical usage (Bredt et al. 2002; Castaneda et al. 2013; Yun J. et al. 2017). Cannabis can induce hunger and suppress the immune system, which is a primary reason for its interest regarding palliative care and as a new appetite stimulant over other current drugs (Wiley et al. 2005; Roth et al. 2015). Like MDMA, cannabis is a Schedule 1 drug, severely limiting its use in research both legally and ethically. Despite these roadblocks, interest in the drug remains high, as some states have opted to legalize it regardless of federal prohibition of the substance.
Modulation of the Immune System
The immune system utilizes different responses to targeting an infection. These responses are known as the adaptive and innate immune response mechanisms. The innate immune system is a fast-response mechanism, using natural killer (NK) cells, macrophages, and dendritic cells. These cells become active when swelling occurs, and are important first responders to prevent infection (Vagasi et al. 2018). NK cells are reactive to stress via endocrine and neurocognitive pathways, but do so to act preemptively against possible pathogens introduced to the cellular environment (Bigler et al. 2015). Transmembrane proteins are shown to be of use in preventing prolonged activation of B lymphocytes. The regulation of B lymphocytes in the immune system is needed for preventing the destruction of tissues, inhibiting of T-reg cells, and signaling to other immune response cells (Sido et al. 2016). The transmembrane protein GARP, along with TGF-β, modulates the response of B-cell activation. This leads to apoptosis and controls cellular differentiation (Wallace et al. 2018). Different cells control adaptive immunity, which takes place when B lymphocytes produce antigens in response to foreign antibodies and attack the foreign invader. This process is much slower than the innate immune response, but the benefits of this process are invaluable. Once the same antigen is encountered, the memory B lymphocyte hastens a response which prevents sickness. This is the basis for vaccination, which is an artificial adaptive immune target.
Long-term stress is a well-known cause of temporary immune deficiency. Exogenous stress from work, school, anxiety, sleeplessness, and depression are all sources of chronic stress that can lead to weakened immunity (Liu et al. 2018). During periods of stress, the body regulates multiple glucocorticoid hormonal pathways involving cortisol and the hypothalamus HPA axis (Vagasi et al. 2018). Prolonged release of stress hormones downregulates innate immune system activity and makes a person vulnerable to infection (Liu et al 2018). Initially, however, stress hormones cause inflammation and promote immune function, evidenced by an increase in interleukins and proinflammatory factors in patients with depression (Liu et al. 2018). Receptor surface expression is also involved in the rapid response of epinephrine in activating the immune system (Bigler et al. 2015). Dysregulation of B lymphocytes can lead to the development of autoimmune disorders, where the immune system improperly attacks targets (Wallace et al. 2018). Allergens and the body’s own cells can be targeted inappropriately. Examples of this include multiple sclerosis, psoriasis, and Parkinson’s disease. To prevent this, cells express TGF-β to tolerate the immune system (Wallace et al. 2018). The tools used by the immune system for communication and regulation are responsible for serious dysfunction, resulting in problems like autoimmune disorders or immunosuppression.
Drugs like THC and MDMA are a primary focus in this review because they are both psychotropic substances that are used recreationally and medicinally (Byock 2018; Palamar 2018). THC’s use as a drug is well researched, and it is legalized in some states. MDMA is less well known, but there is interest in its use with PTSD and depression. Because of the drugs’ hallucinogenic effects and how they impact the body, it is thought that these drugs are responsible for some immunomodulation (Bredt et al. 2002). In fact, there is evidence of these drugs directly affecting the immune system, which makes them a topic of interest regarding therapeutic development (Roth et al. 2015; Karmaus et al. 2012) and epidemiologic study. In addition, the latent stress they may produce in users of the drug could indirectly affect the immune system. Some research has analyzed the use of THC and MDMA on the immune system in a controlled environment, but less research exists on the role of drugs like these when used in combination with other illicit substances, or under long term usage. This more realistically would reflect the situation of drug abusers who may ingest multiple substances along with either MDMA or THC, or of a hospital setting, where the use of these compounds long term also reflects a realistic outlook on medicinal use. Long term medicinal use of MDMA and THC needs to be further researched.
Receptors targeted by THC and MDMA
Control of immune system pathways is regulated by many cells and receptors. Cannabinoid receptors CB1 and CB2, MDMA receptor Tarr1, and stress hormones all play a role in mediating immune responses (Roth et al. 2015; Nelson et al. 2007).
Cannabinoid receptors (CB receptors) are important for immunomodulation. There are two types of CB receptors, known as CB1 and CB2, and both are responsible for immunomodulation. Receptors for CB1 are expressed in the brain and the immune system (Wiley et al. 2005). The receptor CB2 is expressed within and on the cell membrane surface of different types of immunomodulating cells, such as B lymphocytes, monocytes, and lymphocytes. The CB1 receptor is expressed by B cells and monocytes as well. However, B cells are different in that they will express protein associated with the CB2 receptor outside of the cell, while all other types of immune system cells express protein on the inside of the cell membrane (Castaneda et al. 2013). The CB receptors are involved in immunomodulation and potential suppression of B lymphocytes and NK-cells, and likely do so by multiple pathways of regulation (Karmaus et al. 2013). CB2 receptors in mice models have been shown to affect neurons in addition to having immunosuppressive actions (Yun et al. 2017). The cell surface receptors on immune cells regulate not just B-cell activity and proliferation, but also phagocytosis and antigen identification (Castaneda et al. 2013).
For MDMA, not as much research has been done to identify different receptors that are responsible for immunomodulation and bind to MDMA. However, there is preliminary evidence to suggest such a receptor. The receptor Taar1 has been identified as a lipid binding receptor in the CNS. Different lipids and MDMA can bind to it, suggesting that this is one method by which MDMA regulates hallucinogenic effects. However, receptor Taar1 is also expressed in lymphocytes, which suggests a potential immunomodulatory capacity for MDMA (Nelson et al. 2007). Receptors CB1, CB2, and Taar1 are responsible for immune system regulation, and their expression and binding affects the bodies’ response to both pathogens and its own cells.
Our Immune system & Hallucinogens
The immune system is inhibited by hallucinogens such as THC and MDMA (Pacifici et al 2000). THC binding to CB1 and CB2 receptors each have an inhibitory effect on B lymphocytes and monocytes in a few different ways (Castaneda et al 2013). Expressed receptors which bind to THC are internalized inside of the cell after activation, and CB protein collects inside of the cell, or outside if it is a B cell (Castaneda et al. 2013). This protein expression causes B lymphocytes and monocytes to inhibit T cells (Sido et al. 2016b). Monocytes are also responsible for activating dendritic cells that activate T-cells (Roth et al. 2015). THC also upregulates endocannabinoid expression in the hypothalamus, which promotes 2-AG (a ligand) expression. This ligand is an immunosuppressant that reduces the expression of various interleukins including IL-6 and IL-2, and TNF-a while also reducing lymphocyte proliferation. In addition, both B lymphocytes and T cells will produce 2-AG and inhibit the immune response (Sido et al. 2016a). Endocannabinoid expression also upregulates the sense of hunger, linking the effect of hunger to CB1 binding (Wiley et al. 2005). While not directly related to the immune system, the same receptor and endocannabinoid promotion is involved in both pathways and shows that THC binding will occur for both immunosuppression and the hunger response.
MDMA also has an inhibitory effect on the immune system. The number of CD4/8 T-cells is reduced by the presence of MDMA, with a small increase in the number of NK cells (Pacifici et al. 2000). The presence of pro-inflammatory cytokines and leukocytes is also reduced by the presence of MDMA, which is thought to be mediated by the hypothalamic-pituitary-adrenal axis with corticosterone (de Paula et al. 2014). The HPA is also thought to play a role in immunomodulation because of Tarr1 receptor . As mentioned previously, these receptors are expressed on lymphocytes and are thought to be one way that MDMA directly affects immune suppression. Leukocyte proliferation and count did decrease in the presence of MDMA, showing that MDMA does have an inhibitory effect (de Paula et al. 2014).
Effects of THC and MDMA on Infection
Infections are exacerbated by depressed immune systems. Without a working army of cells to fight off infection, the body of any animal would not withstand the onslaught of foreign invaders. Since THC and MDMA have been shown to lead to immunosuppression, it seems likely that infectious diseases could be more dangerous as they are more effective at fighting the body’s immune system. A review of some diseases that are examined in the context of hallucinogenic THC and MDMA use are elaborated to provide information about the immune system suppression that may take place.
THC and MDMA both impair immune response under infection in most cases. In myeloid cells, the cell surface receptor expression of CB2 had an immunosuppressive effect by reduction of innate immune mRNA expression and reduced proliferation of NK cells, which negatively affected the immune response to influenza in mice (Karmaus et al. 2013). In γHV-68 infection of mouse macrophages, MDMA reduced the response of the innate immune system by reducing monokine production (Nelson et al. 2008). This shows that some viral infections negatively impact the immune system in the presence of a hallucinogen (Kalichman et al. 2015). In contrast, the immune system fighting diseases such as HIV seem to not be impacted by hallucinogens like THC. Short term use of smoked cannabis in HIV-infected human patients had a clinically significant effect on immune response and expression of T-cells (Bredt et al. 2002). In long term exposure to THC, macaques infected with SIV had lower IgE positive B lymphocytes but were not significantly more likely to be adversely affected by SIV infection (Wei et al. 2016). This comparison of HIV and the simian counterpart SIV with diseases such as influenza indicate that there are differences in how hallucinogenic compounds and immune system modulation affect each other.
Compounds like MDMA and THC differ in many ways but are similar in their depressive action on the immune system. While THC is well researched in immunomodulation using cannabinoid receptors and other pathways related to them, MDMA clearly lacks the same body of robust research. MDMA research primarily focuses on psychotherapeutic applications (Byock 2018) while THC focuses on appetite stimulation and pain management for patients with HIV or in need of palliative care (Bredt et al. 2002). The use of hallucinogens like THC and MDMA in treatment should take their immunosuppressive action into consideration. In mice models, the use of MDMA and ethanol together weaken the immune system by reducing cytokine production, inducing a suppressive effect (Pacifici et al. 2000). THC administered to mice who have influenza produces an immunosuppressive effect which impairs the response to the pathogen (Karmaus et al. 2013). Although shown in mice, this information shows that precaution may be needed for patients such as recreational drug users, patients susceptible to the flu, and patients who may use traditional hallucinogens to treat psychiatric issues. Whereas with patients possibly infected with HIV or who have autoimmune disorders, use of hallucinogens may be more beneficial and in their interest.
An issue not well addressed by the current research is the long-term effects of MDMA and THC for therapeutic use, or the long-term immunological consequences of recreational use. While some research has addressed the long-term consequences (Kalichman et al. 2015; Wei et al. 2016), less address the long-term implications of medicinal hallucinogenic use. The information described here supports a different view of immunomodulation, where long-term usage of these drugs is more likely to result in negative effects on the immune system. Therefore, to understand the immunological consequences of MDMA and THC use, more effort needs to be focused on long-term consequences, as they accurately reflect treatment of chronic conditions. In addition, the effects of combining different drugs with MDMA and THC are not well known. The combined drugs seem to suppress the immune system in tandem with one another (Pacifici et al. 2000) in some studies, and this likely reflects real world effects on patients who would abuse drugs in this manner. Long-term usage of hallucinogens need to be evaluated thoroughly to ensure the safety of any potential therapeutic drug, to evaluate the trade-offs of such treatment, and to improve understanding of less common treatments.
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