Wednesday, 14 May 2014 17:05 Published in Blog

What is PTSD?

Post Traumatic Stress Disorder (PTSD) is a condition that can arise when a person experiences a traumatic or life-threatening event. In these situations our body activates its fight or flight response to respond quickly and accordingly by either fending off the threat or fleeing the dangerous situation. However depending on genetic predisposition and the severity of the trauma some survivors are left with lasting effects on their brain’s ability to properly utilize this response as well as a dysfunctional fear extinction mechanism.

Veterans returning from the battlefield are particularly prone to this type of illness and it continues to be a growing issue as more soldiers return from their deployment.  Symptoms of PTSD include flashbacks, hypersensitivity or the feeling of being “on edge”, as well as avoidance behaviors especially of situations and things that remind the patient of the trauma.  Typically antidepressants and other prescription drugs such as Valium were used to treat PTSD but ultimately these drugs do not solve the problem leading many of these patients to addiction and suicide especially when combined with alcohol.

The Science Behind Why Cannabis Works for PTSD

Cannabis can be an invaluable tool to these patients because its primary constituent THC acts on cannabinoid receptors in the brain. These receptors assist in an important function that is damaged in these patients, the ability to forget. The following clip from the film “The Botany of Desire” describes this somewhat counterintuitive evolutionary adaptation:

https://www.youtube.com/watch?v=WFmhTQTtt04.

The endocannabinoid system (ECS), specifically CB1 receptors, mediate this action in the brain. THC acts as a partial agonist at these receptors eliciting a cascade of cell signaling responses that lead to a rescue of fear extinction learning. CB1 receptors are found primarily in the central nervous system and are found in most of the brain but particularly the action of these receptors in the prefrontal cortex, hippocampus, and the amygdala are what make cannabis so useful for PTSD. These receptors are responsible for maintaining hedonia (state of well-being) as well as opposing hypothalamus pituitary axis (HPA) response to stress, bringing the body back to homeostasis following exposure to stressful stimuli.

Animal Studies

 There has been a large amount of preclinical data gathered that implicates the ECS as a primary target for the treatment of PTSD. A study from 2002 led by Marsicano shows that the CB1 receptors in the amygdala are required for the extinction of fear memories. A further study by Hill in 2005 showed that following chronic stress signaling in the ECS is downregulated. This downregulation impaired reversal learning (the ability to be trained differently to two stimuli based on reward or punishment response) in mice and as anticipated induced perservatory behaviors.  The study also found that the effects of chronic stress were reversed when an exogenous CB1 agonist was applied.  

Human Studies

Human studies using positron emission tomography (PET) scans have revealed that the CB1 receptors of PTSD patients are primarily unoccupied suggesting a deficiency in endocannabinoid signaling. In addition, blood endocannabinoid concentrations in PTSD patients were considerably lower than those that had not experienced trauma.  Further human studies published in 2013 in the journal Neurobiology of Learning and Memory confirmed that THC’s action at the CB1 receptor facilitated fear extinction learning through its interactions with the amygdala, ventromedial prefrontal cortex (vmPFC), and hippocampus.

Future Studies

Recently the federal government has lightened its chokehold on cannabinoid research for PTSD. Last March in an unprecedented move, the DEA gave the University of Arizona the green light to study cannabis use in veterans with the disorder. This approval marks a huge accomplishment for researchers who have had to maneuver a variety of obstacles the federal government has implemented.       

Wednesday, 30 July 2014 09:28 Published in Blog

To date two different cannabinoid receptors, CB1 and CB2, have been identified. Knockout mice for both of these cannabinoid receptors have been created however these mice still exhibit behavioral, biochemical, and electrophysiological responses when cannabinoids are applied, suggesting the presence of other cannabinoid receptor subtypes. These responses are thought to be produced through the three putative cannabinoid receptors GPR18, GPR55, and GPR119.

GPR18

GPR18 is expressed in gastrointestinal, immune and testicular tissues, as well as the striatum, cerebellum, and brain stem. This receptor is activated by N-arachidonoylglycine (NAGly), a metabolite of anandamide.  This receptor is found on microglial cells in the brain where it regulates the initiation of the migration of these cells following CNS injury or inflammation (McHugh, 2012).

GPR55

GPR55 is primarily expressed in the striatum and cerebellum but is also expressed in osteoclasts where it has been shown to regulate bone function. This receptor shares limited conserved regions with CB1 and CB2 however potential binding sites have been identified by homology modeling. The most well studied ligand for this receptor is l-α-Lysophosphatidylinositol or LPI which they have also shown to be implicated in microglial migration using in vitro models of excitotoxicity (Kallendrusch, 2013). 

GPR55 signaling is involved in gastrointestinal function and has also been shown to form heteromers with both CB1 and CB2. In many cancers both GPR55 and CB2 are overexpressed and it is believed that the unique signaling that arises from the CB2-GPR55 heteromer could be what gives rise to the antitumoural properties of THC (Moreno, 2014). 

GPR119

GPR119 is expressed predominantly in the brain, gastrointestinal tract, and pancreas where it has been shown to regulate the secretion of insulin making it an attractive target for the treatment of diabetes. Oral administration of small molecule GPR119 agonists has been shown to improve glucose tolerance in both rodents and humans (Shah, 2010).

 

Sources:

1. Scicho, 2012. "A potential role for GPR55 in gastrointestinal functions"  Curr Opin Pharmacol. Dec 2012; 12(6): 653–658.

2. Moreno, 2014. "Targeting CB2-GPR55 Receptor Heteromers Modulates Cancer Cell Signaling" J Biol Chem. 2014 Jun 18. pii: jbc.M114.561761

3. Kallendrusch, 2013. "The G protein-coupled receptor 55 ligand l-α-lysophosphatidylinositol exerts microglia-dependent neuroprotection after excitotoxic lesion." Glia. 2013 Nov;61(11):1822-31.

4. Shah, 2010. "GPR119 agonists for the potential treatment of type 2 diabetes and related metabolic disorders" Vitam Horm. 2010;84:415-48.

5. McHugh, 2012 "GPR18 in microglia: implications for the CNS and endocannabinoid system signalling" Br J Pharmacol. 2012 Dec;167(8):1575-82

Wednesday, 12 November 2014 15:08 Published in Blog

What is Leaky Gut Syndrome and how is it diagnosed?

Leaky Gut Syndrome (LGS) is an ailment characterized by a variety of symptoms including abdominal pain, fatigue, inflammation, gas, bloating, and intolerance to certain foods. It is thought to be caused by increased permeability of the intestinal lining, which is made up of structures called tight junctions. These structures are comprised of tightly knit cells that are essentially impermeable to fluids preventing the passage of undigested food particles, toxic waste products, bacteria, and viruses into the bloodstream. Researchers believe that this disruption of the seal of tight junctions allows the leakage of these substances into the bloodstream leading to inflammation throughout the body [1]. To determine if a patient has a leaky gut, physicians will usually employ a mannitol-lactulose test in which a solution with these sugars is consumed and the urine produced is collected. The intestine easily absorbs mannitol while lactulose is only slightly absorbed. In a healthy individual urinalysis should indicate low levels of mannitol and high levels of lactulose however in a patient with a leaky gut both sugars will be present in high concentrations.

What processes go awry in LGS?

It has been hypothesized that LGS can be caused by problems with the body’s immune system. In the immune systems of patients with LGS there is a failure in the recognition of bodily structures as self, leading to attack of the host’s tissues by its own immune cells. While not all the factors have been assembled in the understanding of intestinal permeability there are some key factors that have been identified.

Immune cells present in the gut called mast cells have been shown to have an influence on intestinal permeability because they release the cytokine TNF-alpha. In patients suffering from LGS this signaling protein is improperly regulated which leads to inflammation of the gut [2]. In addition there are alterations in what is known as the zonulin pathway in patients with autoimmune disorders. Zonulin signaling is an event in the gut that regulates the structure of tight junctions by modifying the expression of its components and hence altering the permeability of the intestinal barrier. In many autoimmune diseases zonulin is overexpressed leading to a compromised intestinal barrier [3]

How might cannabis alleviate the symptoms of Leaky Gut Syndrome?

Cannabis has a myriad of medicinal effects that have potential applications for alleviating the discomfort associated with LGS. Its ability to act as an antioxidant, influence intestinal permeability, as well as reduce nausea, inflammation, and pain response can be attributed to the relief it provides.

1. Cannabinoids have an influence on intestinal permeability

A study performed in 2011 published in the British Journal of Pharmacology showed that phytocannabinoids, specifically THC and CBD, cause a decrease in intestinal permeability in vitro using measurements of transepithelial electrical resistance (TEER) [4]. In addition the application of these cannabinoids to intestinal epithelial cells caused an increase in the expression of the tight junction protein claudin-1, which is involved in cell-to-cell adhesion. This increase in expression could explain the overall observed decrease in intestinal permeability.

2. Cannabinoids are capable of suppressing the immune system

As previously mentioned dysregulation of immune responses can be partially attributed to the cause of leaky gut. The cannabinoid receptor CB2 is found on the surface of many types of immune cells that cause inflammation. The use of CB2 agonists like THC can result in suppression of the immune system, which could help mitigate some of the autoimmune problems that are associated with LGS [5].

3. Cannabinoids reduce inflammation

Compounds that act as CB1 receptor antagonists such as cannabidiol (CBD) are able of decreasing the expression of a cell signaling protein called tumor necrosis factor alpha (TNF-α) [6]. The production of TNF-α leads to pro-inflammatory responses in the body therefore a reducing its production could greatly reduce intestinal inflammation [7].

Acidic cannabinoids are also capable of reducing inflammation by inhibiting cyclooxygenase (COX) enzymes. These enzymes are responsible for the production of compounds that mediate inflammatory responses such as prostaglandins and thrombaxanes [8] and are also the targets of over the counter non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and acetaminophen.

4. Cannabinoids act as antioxidants

Reactive oxygen species (ROS), compounds with unpaired electrons are prevalent in oxidative stress resulting in cell damage and inflammatory responses. The damaging effects of these compounds can be mitigated by cannabinoids which act as antioxidants in the body and stabilize these reactive molecules. Specifically, the cannabinoids THC and CBD have both been shown to exhibit antioxidant activity capable of neutralizing ROS [9].

5. Cannabinoids produce analgesia

Cells in the gut express the cannabinoid receptor CB2, which is partially responsible for producing the pain-relieving and anti-inflammatory effects of cannabis. In particular cannabis strains high in the terpene β-caryophyllene could provide the most benefit as this compound has been shown to be a functional CB2 agonist [10-11]. Some studies have also suggested that the probiotic L. acidophilus may also be a promising means to heighten these effects as the presence of these bacteria in the gut have been shown to cause an elevation in the expression of the CB2 receptor as well as have a protective role on the intestinal barrier [12-13].

 

Future Studies

The studies presented suggest that the ECS could be a potential therapeutic target in treating patients with LGS however further studies are needed to confirm these benefits. The evidence shown begs the question of the state of the ECS in patients with LGS.  Are irregularities in endocannabinoid signaling part of the pathology of the disease as with other gastrointestinal and autoimmune ailments or are the findings that targeting the ECS could provide relief merely coincidence? Additionally could the use of the probiotic L. acidophilus enhance these therapeutic benefits? Until the federal government truly acknowledges the potential of this miraculous plant for the treatment of this crippling ailment these questions will remain unanswered.

 

References

1. Farhadi, A., Banan, A., Fields, J. and Keshavarsian, A. (2003), Intestinal barrier: An interface between health and disease. Journal of Gastroenterology and Hepatology, 18: 479–497. doi: 10.1046/j.1440-1746.2003.03032.x

2. O’Sullivan M, Clayton N, Breslin NP et al. Increased mast cells in the irritable bowel syndrome. Neurogastro- enterol. Motil. 2000; 12: 449–57.

3. Sapone A, De magistris L, Pietzak M, et al. Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives. Diabetes. 2006;55(5):1443-9.

4. Alhamoruni A, Lee AC, Wright KL, Larvin M, O'sullivan SE. Pharmacological effects of cannabinoids on the Caco-2 cell culture model of intestinal permeability. J Pharmacol Exp Ther. 2010;335(1):92-102.

5. Hegde VL, Nagarkatti M, Nagarkatti PS. Cannabinoid receptor activation leads to massive mobilization of myeloid-derived suppressor cells with potent immunosuppressive properties. Eur J Immunol. 2010;40(12):3358-71.

6. Mechoulam R. Cannabinoids in models of chronic inflammatory conditions. Phytochem Rev 4 2005: 11–18

7. Hollander D. Crohn's disease, TNF-alpha, and the leaky gut. The chicken or the egg?. Am J Gastroenterol. 2002;97(8):1867-8.

8. Ruhaak LR, Felth J, Karlsson PC, Rafter JJ, Verpoorte R, Bohlin L. Evaluation of the cyclooxygenase inhibiting effects of six major cannabinoids isolated from Cannabis sativa. Biol Pharm Bull. 2011;34(5):774-8.

9. Hampson AJ, Grimaldi M, Axelrod J, Wink D. Cannabidiol and (-)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci USA. 1998;95(14):8268-73.

10. Klauke AL, Racz I, Pradier B, et al. The cannabinoid CB2 receptor-selective phytocannabinoid beta-caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic pain. Eur Neuropsychopharmacol. 2014;24(4):608-20.

11. Gertsch J, Leonti M, Raduner S, et al. Beta-caryophyllene is a dietary cannabinoid. Proc Natl Acad Sci USA. 2008;105(26):9099-104.

12. Rousseaux C, Thuru X, Gelot A, et al. Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat Med. 2007;13(1):35-7.

13. García-lafuente A, Antolín M, Guarner F, Crespo E, Malagelada JR. Modulation of colonic barrier function by the composition of the commensal flora in the rat. Gut. 2001;48(4):503-7.

Wednesday, 26 November 2014 15:09 Published in Blog

What is COPD? 

Chronic obstructive pulmonary disease (COPD) is an illness characterized by increased production of mucus and chronic inflammation of the airways resulting in reduced respiratory capacity. The two primary forms of COPD are chronic bronchitis, which produces a long-term cough with mucus, and emphysema, which leads to the progressive deterioration of the alveoli, the air sacs that allow for gaseous exchange in the lungs.

 

How is COPD treated?

COPD is typically treated with two different types of compounds: beta-adrenergic agonists and corticosteroids. Beta-adrenergic agonists are bronchodilators, which relax the smooth muscle surrounding the respiratory tract resulting in an increased diameter of the bronchial passages facilitating airflow. There are two types of beta-agonists: short-acting beta-adrenergic agonists (SABAs) such as albuterol and long-acting beta-adrenergic agonists (LABAs) such as salmeterol. SABAs are typically utilized in the event of an acute attack of shortness of breath while LABAs are used as a prophylactic measure. LABAs are commonly co-administered with corticosteroids such as fluticasone, which acts as a preventative against immune-mediated inflammation of the airways. One such formulation of LABAs and corticosteroids is the drug Advair, a combination of salmeterol and fluticasone.

 

How might cannabis help patients with COPD?

All smoke irritates the lung and aggravates COPD, but vaporized or ingested cannabis could potentially provide many benefits.

 

1. Bronchodilatory effects

Studies performed in the 1970’s at the University of California Los Angeles by Donald Tashkin have shown that both inhaled and orally ingested THC produce bronchodilation for up to two hours after administration [1]. Further investigations by the Respiratory Pharmacology Laboratory in Paris have shown that CB1 receptor activation inhibits cholinergic contraction in a concentration-dependent fashion, offering a possible mechanism for acute bronchodilation associated with cannabis intake [2]. Although smoked cannabis also has this effect, any kind of combustion creates other lung irritants that would be counterproductive for COPD treatment.

 

2. Suppression of the immune system

Those with COPD have a heightened immune response in the lungs and compounds in cannabis can lead to immunosuppression. Studies have shown that THC induces rapid mobilization of a specific subset of white blood cells that arise from bone marrow called myeloid-derived suppressor cells (MDSCs)[3]. These cells exert potent immunosuppressant properties by inhibiting the proliferation and activation of T-cells.  

Additional studies performed at the University of South Carolina School of Medicine support these findings, where they determined that the intraperitoneal (injection into the body cavity) application of THC causes changes in microRNA expression that promotes the suppression of the immune system [4]. Other findings using murine models have shown that intraperitoneal administration of THC results in a reduction of allergen-induced mucus production [5].

 

3. Anti-inflammatory effects

Cannabinoids have anti-inflammatory benefits through a variety of mechanisms. The acidic cannabinoids have a greater anti-inflammatory capacity than their non-acidic counterparts. Specifically studies by Ruhaak, et al., have shown that cannabinoids, in particular the acidic cannabinoids, are capable of inhibiting cyclooxygenases (COX-1 and COX-2); which are the enzymes responsible for the production of inflammatory compounds such as prostaglandins and thrombaxanes. Their investigation found that cannabigerolic acid (CBGA) was the most potent inhibitor of all the cannabinoids tested having an IC50 value of 4.6 x 10-4 M and 2.0 x 10-4 M for COX-1 and COX-2 respectively [6].

Recently studies performed at the University of Sao Paulo using cannabidiol have also shown some potential for improving the symptoms of COPD. They found decreased pulmonary inflammation and improvements in lung function in murine models of inflammatory lung disease using the inflammatory agent LPS, a component of the cell wall in gram-negative bacteria, as the inflammatory agent [7].

Other studies of terpene compounds, the aromatic components found in cannabis show anti-inflammatory benefits as well. In particular, beta caryophyllene has been shown to act as a dietary cannabinoid, attenuating inflammatory responses in various tissues in a CB2 receptor-dependent fashion [8-10]. In addition to being found in cannabis this terpene is also found in high concentrations in black pepper and cloves.

 

Conclusion

These studies indicate that cannabis could potentially act as a means to mitigate acute attacks of bronchoconstriction and may also act as a prophylactic measure for patients with COPD. However, human trials are needed to confirm some of these benefits and until restrictions by the federal government are lifted, a deeper understanding of these mechanisms will remain poorly understood.

 

References

 

1. Tashkin DP, Shapiro BJ, Frank IM. Acute effects of smoked marijuana and oral delta9-tetrahydrocannabinol on specific airway conductance in asthmatic subjects. Am Rev Respir Dis. 1974;109(4):420-8.

2. Grassin-delyle S, Naline E, Buenestado A, et al. Cannabinoids inhibit cholinergic contraction in human airways through prejunctional CB1 receptors. Br J Pharmacol. 2014;171(11):2767-77.

3. Hegde VL, Nagarkatti M, Nagarkatti PS. Cannabinoid receptor activation leads to massive mobilization of myeloid-derived suppressor cells with potent immunosuppressive properties. Eur J Immunol. 2010;40(12):3358-71.

4. Hegde VL, Tomar S, Jackson A, et al. Distinct microRNA expression profile and targeted biological pathways in functional myeloid-derived suppressor cells induced by Δ9-tetrahydrocannabinol in vivo: regulation of CCAAT/enhancer-binding protein α by microRNA-690. J Biol Chem. 2013;288(52):36810-26.

5. Reddy AT, Lakshmi SP, Reddy RC. Murine model of allergen induced asthma. J Vis Exp. 2012;(63):e3771.

6. Ruhaak LR, Felth J, Karlsson PC, Rafter JJ, Verpoorte R, Bohlin L. Evaluation of the cyclooxygenase inhibiting effects of six major cannabinoids isolated from Cannabis sativa. Biol Pharm Bull. 2011;34(5):774-8.

7. Ribeiro A, Almeida VI, Costola-de-souza C, et al. Cannabidiol improves lung function and inflammation in mice submitted to LPS-induced acute lung injury. Immunopharmacol Immunotoxicol. 2014;:1-7.

8. Bento AF, Marcon R, Dutra RC, et al. β-Caryophyllene inhibits dextran sulfate sodium-induced colitis in mice through CB2 receptor activation and PPARγ pathway. Am J Pathol. 2011;178(3):1153-66.

9. Horváth B, Mukhopadhyay P, Kechrid M, et al. β-Caryophyllene ameliorates cisplatin-induced nephrotoxicity in a cannabinoid 2 receptor-dependent manner. Free Radic Biol Med. 2012;52(8):1325-33.

10. Gertsch J, Leonti M, Raduner S, et al. Beta-caryophyllene is a dietary cannabinoid. Proc Natl Acad Sci USA. 2008;105(26):9099-104.