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.

Friday, 19 February 2016 06:27 Published in Blog

Skunky, fruity, floral, the bouquet of smells associated with cannabis can be highly diverse and varied from cultivar to cultivar. This diversity comes from the fragrant molecules found in cannabis called terpenes. There are over a hundred different terpenes found in cannabis, which have evolved with the cannabis plant as a defense mechanism against bacteria, fungi, insects, and other pests. They also serve as the building blocks for more complex molecules like the cannabinoids.

The Chemistry of Terpenes

Terpenes are volatile hydrocarbons that carry an aroma and are made up of small five carbon components called isoprene units. There are also similar molecules found in cannabis called terpenoids, which are modified terpenes where oxygen atoms have been incorporated or methyl groups have been added or removed. Often times the term terpenes is used more broadly to include terpenoids. Terpenes can be further categorized into three different subtypes: monoterpenes, diterpenes, and sesquiterpenes. 

 

 

Screen Shot 2016-01-07 at 11.25.56 PM

Photo taken from: http://www.ochempal.org/wp-content/images/I/isopreneunit.png

Monoterpenes are the simplest type of terpene and are made up of two isoprene units. An example of a common monoterpene found in cannabis is myrcene, which has been hypothesized to enhance the ability of THC to cross the blood-brain barrier giving certain strains their punch. Myrcene acts as a powerful analgesic and its effects are counteracted by the opiate antagonist naxolone (Narcan) suggesting that its pain relieving properties are due to interactions with the opiate system [1]. Strains that are dominant in myrcene tend to produce sedating effects [2].  Sesquiterpenes are terpenes containing three isoprene units. Perhaps the most common sesquiterpene found in cannabis is β-caryophyllene, the only terpene known to bind to the cannabinoid receptor CB2. Studies in mice show that the actions of β-caryophyllene at this receptor are capable of enhancing the pain relieving and anti-inflammatory actions of the cannabis plant [3-4]. Diterpenes are composed of two monoterpene subunits or four isoprene units. An example of a diterpene is phytol, which is a degradation product of chlorophyll and hence found in nearly all cannabis. This terpene increases the expression of GABA, an inhibitory neurotransmitter associated with relaxing effects, by blocking its degradation. Just beginning to describe the various classes of terpenes you can see the building potential for synergy towards certain effects while antagonizing others.

The Entourage Effect: How terpenes modify the effects of cannabinoids

Dr. Ben Shabat et al demonstrated the earliest evidence of an entourage effect in 1998 with their work on endogenous cannabinoids [5]. This work showed that activity at cannabinoids receptors could be enhanced when there were multiple inactive fatty acid derivatives present. A few years later in 2001, John McPartland and Ethan Russo published a paper titled “Cannabis and Cannabis Extracts: Greater Than the Sum of Their Parts”. This publication extended this entourage concept presenting early evidence that terpenes enhanced the effects of the cannabinoids [6]. This work was further refined later by Russo in August of 2011 when he published “Taming THC: potential cannabis synergy and phytocannabinoid terpene entourage effects” in the British Journal of Pharmacology. This paper proposed that the terpenes in cannabis were capable of modulating the effects of cannabinoids and offered many possible mechanisms by which terpenes could induce this action [7]. The table below shows just some of the terpenoids native to cannabis, their pharmacological activity, as well as the cannabinoids they might synergize with. 

.

Terpenoid

Found In

Pharmacological Activity

Synergistic Cannabinoid

Limonene

Lemon

1. Immunostimulant when inhaled

2.Anxiolytic via 5HT-1A

3.Apoptosis of breast cancer cells

4.Effective against acne causing bacteria

5.Dermatophytes

6.Gastro-oesophageal reflux

 

1. CBD

2. CBD

3. CBD, CBG

4. CBD

5. CBG

6. THC

Pinene

Pine

1. Anti-inflammatory via PGE-1

2. Bronchodilatory in humans

3. Acetycholinesterase inhibitor, aiding memory

 

1. CBD

2. THC

3. CBD, THC?

 

Myrcene

Hops

1.Blocks inflammation via PGE-2

2.Analgesic, antagonized by naxolone

3.Sedating, muscle relaxant, hypnotic

4.Blocks hepatic 

carcinogenesis by aflatoxin

1. CBD

2. CBD & THC

3. THC

4. CBD & CBG

Linalool

Lavender

1.Anti-anxiety

2.Sedative upon inhalation in mice

3.Local anesthetic

4.Analgesic via adenosine A2A

5.Anticonvulsant/anti-glutamate

6.Potent anti-leishmanial

 

1. CBD, CBG?

2. THC

3. THC

4. CBD

5. CBD, THCV, CBDV

6. ?

Beta Caryophyllene

Black Pepper

1.Anti-inflammatory via PGE-1

2.Gastric cytoprotective

3.Anti-malarial

4.Selective CB2 agonist

5.Treament of pruritus

6. Treatment of addiction

 

1. CBD

2. THC

3. ?

4. THC

5. THC

6. CBD


Caryophyllene Oxide

Lemon Balm

1.Decreases platelet

aggregation

2.Antifungal in

Onchyomycosis comparable to

ciclopiroxolamine and

sulconazole

3.Insecticidal/anti-feedant

 

1. THC

2. CBC & CBG

3. THCA & CBGA

Nerolidol

Orange

1.Sedative

2.Skin penetrant

3.Potent antimalarial

4.Anti-leishmanial activity

 

1. THC & CBN

2. -

3. 

4. ?

Phytol

Green Tea

1.Breakdown of chlorophyll

2.Prevents vitamin A

teratogenesis

3. GABA via

SSADH inhibition

1. -

2. -

3. CBG

 

Terpenes are capable of reducing undesirable effects while enhancing others. Many of the monoterpenes found in cannabis such as (-)-alpha-pinene, (+)-3-carene, p-cymene, terpineol, and eucalyptol can inhibit the enzyme acetylcholinesterase (AChE) enhancing acetylcholine function, which is an important neurotransmitter involved in memory [8]. This suggests that some of the negative effects of THC on memory could be counteracted if these terpenes are present in significant concentrations. This could be particularly beneficial for conditions such as Alzheimer’s, where a combination of decreased cholinergic function and neuroinflammation leads to the progressive deterioration of memory.

Indica & Sativa

The work of Karl Hillig at the University of Indiana in 2004 was the first to demonstrate that terpene profiles are not a viable means to distinguish between different cannabis species. His work, along with Russo and McPartland's completely changed the world of cannabis by changing the way we classify the effects of strains. For decades the terms indica and sativa have been applied to suggest a couch-lock or uplifting effect respectively, however these labels are often incorrect and merely reflect the plants morphology and growth patterns. For example, one could have a plant that grows short and squat like an indica but is dominant in limonene and pinene which are associated with more energizing strains. There are likely many classes of cannabis based on the dominant terpenes present rather than three main categories of cannabis (indica, sativa, hybrid). To further dispel the indica sativa myth, one of the most popular “sativa” varietals is Jack Herer. The dominant terpene in this strain is terpinolene, which has been shown in studies to have a sedating effect, completely the opposite of what one would call uplifting [9-10].

JackHererShield

 

Terpene Tailoring: Formulating the right medicine for your condition

This deeper understanding of cannabinoid and terpenoid synergy has allowed for the optimization of cannabis therapeutics. Breeders can now create varieties that produce enhanced benefits by crossing strains with terpene profiles that are known to be effective for certain ailments. In the realm of extractions many processors have begun adding isolated terpenes to their products to boost certain desired effects. For example, if one had gut inflammation they might add additional β-caryophyllene to the final product since it elicits its anti-inflammatory action via the CB2 receptor, which is widely expressed in the gastrointestinal tract [11]. While these are great ideas based on our current understanding, further studies are needed to hone in on the most beneficial terpene profiles for a given condition. 

 

References

 

1. Rao VS, Menezes AM, Viana GS. Effect of myrcene on nociception in mice. J Pharm Pharmacol. 1990;42(12):877-8.

2. Russo EB. Treatment with cannabis and cannabinoids: Some practical aspects and controversies. O'Shaugnessy's Winter Issue 2016

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

4. 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.

5. Ben-shabat S, Fride E, Sheskin T, et al. An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur J Pharmacol. 1998;353(1):23-31.

6. McPartland, J.M. and Russo, E.B. 2001. Cannabis and Cannabis extracts: greater than the sum of their parts? Journal of Cannabis Therapeutics 1:103-132.

7. Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011;163(7):1344-64.

8. Miyazawa M, Yamafuji C. Inhibition of acetylcholinesterase activity by bicyclic monoterpenoids. J Agric Food Chem. 2005;53(5):1765-8.

9. Hillig, Karl W. A chemotaxonomic analysis of terpenoid variation in Cannabis. Biochemical systematics and ecology 32.10 (2004): 875-891

10. Ito K, Ito M. Sedative effects of vapor inhalation of the essential oil of Microtoena patchoulii and its related compounds. J Nat Med. 2011;65(2):336-43.

11. Wright KL, Duncan M, Sharkey KA. Cannabinoid CB2 receptors in the gastrointestinal tract: a regulatory system in states of inflammation. Br J Pharmacol. 2008;153(2):263-70.