medical marijuana

A review of mechanisms in medical marijuana: the endocannabinoid pathway, receptors, tetrahydrocannabinol, and cannabidiol 

Virginia Thornley, M.D., Neurologist, Epileptologist

@VThornleyMD

April 28, 2018

Introduction

The Cannabis sativa plant has been known since the beginning of time. It can be traced back 5000 years ago when it was first known to man to alleviate common complaints. It came into the American pharmacopeia in the 19th century then abolished in the 1930’s, likely not coincidentally as the era of prohibition was lifted. It is known to treat ailments such as chronic pain and migraine. In the middle ages, it was used to treat headaches, vomiting, diarrhea, bacterial infections and pain from rheumatological conditions. It was previously known for its psychoactive properties.  It is recently making a resurgence in popularity regarding its medical value. The issue is a topic of hot debate as state laws are at odds with federal laws. Currently, as of April 2018, it is still recognized as a category 1 drug, meaning it is not officially proclaimed to have any medical value despite the long rich history of treating medical symptoms. It is lumped in with other drugs of abuse such as heroin and cocaine.

Background on the Cannabis sativa plant and their metabolites

The Cannabis sativa plant is abundantly rich in phytocannabinoids, the most commonly known and used for its therapeutic value are cannabidiol and tetrahydrocannabinol. The endocannabinoid pathway is comprised of receptors that are coupled with G proteins and cannabinoids (1). In the Cannabis sativa plant, there are 80 phytocannabinoids that can bind to a cannabinoid receptor.

There are 8 major cannabinoids including cannabigerolic acid, delta-9-tetrahydrocannabolinic acid A, cannabidiolic acid A, delta-9-tetrahydrocannabinol, cannabigerol, cannabidiol, cannabichromene, and tetrahydrocannabivarin in the different strains of Cannabis sativa (1).

Ehlsoly, et al, classified it into 11 categories: cannabigerol, cannabichromene, cannabidiol, ∆9-trans-tetrahydrocannabinol, ∆8-trans-tetrahydrocannabinol, cannabicyclol, cannabielsoin, cannabinol, cannabinodiol, cannabitriol, and miscellaneous. ∆9 -trans-tetrahydrocannabinol , cannabinol, and cannabidiol are the most well-studied and well-known.

Cannabidiol is extracted from the hemp portion of the plant considered a male part of the plant, there are no psychoactive properties in cannabidiol. Psychoactivity is defined as anything above 0.3% of THC. Tetrahydrocannabinol is derived from the female portion of the plant, particularly the flowers. Conditions are such that in nurseries only a certain amount of sunlight is given to the plants so that specific strains can be grown. Some plants will be richer in cannabidiol, others will be more THC pure and other swill have an equal amount of CBD and THC but it depends on how the plants are grown and under what conditions.

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Endocannabinoid pathway

It is through the endocannabinoid pathway that one gets the sense of well being after exercise or eating chocolate. It is not through endorphins, serotonin or noradrenergic neurotransmitters as they are too large to cross the blood-brain barrier. Tetrahydrocannabinol acts as a mimetic of Anandamide while cannabidiol acts as a mimetic of 2-Arachidinoylglyerol (or 2-AG). The endocannabinoid system works through cannabinoids, the receptors, transporters, and enzymes.

Receptors

The phytocannabinoids work on cannabinoid receptors. The endocannabinoid system is mediated by 3 parts: the cannabinoids, the cannabinoid receptors, and the enzymes. The receptors are of 2 types, CB1 which is found primarily in the nervous system especially in the areas that subserve pain modulation, memory and movement. The CB2 receptor is more peripherally found specifically in the immune system. The CB2 receptor is found to a lesser extent in other organs including tissues of reproduction, pituitary, heart, lungs, adrenal and gastrointestinal systems.  Cannabinoids also react with the TRPV receptor or the transient receptor cation channel subfamily V. They can also act on G receptors including GPR55 thought to be significant in controlling seizures. Other receptors include GPR12, GPR18, and GPR119 (2).

Tetrahydrocannabinol and cannabidiol and their effect on receptors

THC and CBD are the most well-known and well-studied. THC has psychoactive properties and works as a partial agonist on the CB1 receptor and the CB2 receptor. Cannabidiol which has no psychoactive properties works as an antagonist on CB1/CB2 receptor and an agonist on the CB1 and CB2 receptor. Rather than decreasing the effects of THC, it works in a synergistic manner in combination with THC. It potentiates the THC effects by increasing the CB1 densities. CBD increases vanilloid pain receptors, reduces metabolism and reduces re-uptake of anandamide, THC’s mimetic component. Other studies suggest CBD acts as an indirect agonist by interacting with the CB1 receptor so there are less psychoactive symptoms from THC when the two are combined.

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Pharmacokinetics of tetrahydrocannabinol

Regardless of the way of taking it, the protein binding and the and volume of distribution are not affected by the route of taking it. Pharmacokinetics of creams and vaporizers are unclear. Smoking THC appears to exert an effect within minutes of intake and bioavailability is variable depending upon the extent of inhalation ranging between 2-69%. The effect is within minutes. Half-life increases with each inhalation at 2 puffs inhaled for THC it is 1.9 hours and 5.3 hours in CBD at 8 inhalations it is 5.2 hours in THC and 9.4 hours in CBD at a dosage of 5.4mgTHC/5.0mg CBD and 21.5mg THC/20 mg CBD respectively.

Oral routes may seem to be safer but have more adverse effects including GI symptoms such as nausea, vomiting, and diarrhea. Oral mucosal absorption is rapid within 15 minutes to 60 minutes. Oral tablets are lower in the rate of absorption at about 0.6 to 2.5 hours. The rate of elimination, when taken orally, is biphasic, initially occurring at 4 hours then 24-38 hours after ingestion.

In summary

There is much research ongoing on the mechanisms underlying the medical value of medical marijuana. It is now thought that cannabigerolic acid may have medicinal properties as well. So far, the most well-known and well studied are delta-9-tetrahydrocannabinol and cannabidiol. Most likely as research continues, greater value will likely be attributed towards the phytocannabinoids.

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About

References

  1. Wang, et al, “Quantitative Determination of delta 9-tetrahydrocannabinol, CBG, CBD, their acid precursors and five other neutral cannabinoids by UHPLC-UV-MS,” Planta. Med, 2019, mar., 84 (4):260-266.
  2.  Landa, et al, “Medical cannabis in the treatment of cancer pain and spastic conditions and options of drug delivery in clinical practice,”Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech Repub., 2018, Mar; 162(1):18-25.
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Epilepsy, Glaucoma, pain, Peripheral neuropathy, Tumor

Medical Marijuana: why the huge disconnect between physicians, laws, policies, and patients?

Virginia Thornley, M.D., Neurologist, Epileptologist

March 11, 2018

Introduction

A patient comes to you asking “Doc, my seizures are getting worse, I really hate the side effects of my medications, I really want to go a different route. Have you heard about medical marijuana?” You start sweating profusely, fidgeting in your seat, thinking of every single reason why not to recommend it and come up with  the standard response, “uh, well, I’m not qualified to recommend it and it’s not FDA approved, plus we don’t really know much about it there could be so many side effects.” And then we have the oldie but goodie response, “there’s not enough large randomized control trials to recommend it.” This scene plays 100,000 times over if not a million times over in physician offices across the country. Patients who are disillusioned with adverse effects of medications are looking towards alternative therapy. As surprising as it sounds, patients with chronic pain do not want to get intoxicated by opioids. In fact, some want to be tapered off of them or refuse them all together. Patients with end-stage cancer at the terminal stage of their lives wish to live a comfortable and humane existence without the need for more chemotherapeutic medications or pain medications that consistently make them feel like a zombie. While other patients with epilepsy may be on 4 different anti-epileptic agents and can no longer function or have a good quality of life because of side effects. There are two sides to every coin.

Why you should be educated on cannabidiol and THC use in medical conditions

If patients do not get their answers from their trusted physicians who they trust with their well-being, their health, the temples of their souls, they will go to great lengths in procuring this knowledge. This is via various sites on the internet some of the dubious nature others are from high quality companies that have been in business even before this seeming treatment fad started. Or, the information may be obtained from their brother-in-law’s friend’s hair stylist who is now pain-free after going through a long course of pain medications including ablative treatments, physical therapy, and acupuncture and has a physician who does recommend it. Like it or not, cannabidiol and tetrahydrocannabinol are alternative treatment options and are gaining more and more traction. To ignore it is to be complacent with the changing direction and landscape of medicine. As patients become more and more disillusioned by the limitation of conventional treatments, attention is directed towards alternative regimens. It is not just for the yoga-practicing patient looking for more natural methods, one sees the sweet 83-year-old gentleman who must be someone’s grandfather with the chronic hip pain of 50 years who have failed opioids and is simply looking for pain relief.

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Is there any evidence that it works?

The endocannabinoid pathway is found naturally in the system. It is responsible for the runner’s sense of wellbeing one gets after a 5-mile run and the pleasant mood you get after a 1-hour work-out with Zumba. There are 2 receptors in the system CB1 receptor which has the highest number of brain cells and the CB2 receptor which is found predominantly in the immune system. There are 2 common cannabinoids cannabidiol and tetrahydrocannabinol which exert various medical effects. Cannabidiol (CBD) has a weak affinity for the CB1 receptor and one needs 100 times the amount to get the same euphoria that one gets from tetrahydrocannabinol, the bane of every ER physician. Unfortunately, the side effects of euphoria of THC have preceded its popularity as a medical product. Little do we know it was once used for hundreds of years as a medication before the psychoactive properties were exploited for recreational purposes. In urologic culture cell lines, it is found that cannabinoids may reduce proliferation of cancer cells and reduce the pro-inflammatory microenvironment that is necessary for metastatic conditions (1). Human studies are still needed to determine a reduction in tumor loads. THC receptors are found in retinal cells and may be found to reduce intraocular pressure in glaucoma (5, 6). Cannabidiol is found to bind to the 5HT1 receptor which reduces anxiety. THC has been well-established in the mouse model to promote the inhibitory control of excitatory pathways in the hippocampus, where seizures commonly arise (8). There is an increase in CB1 receptors after prolonged seizures suggesting a compensatory response.  It has been used in combination and found in several randomized control trials to reduce the frequency of seizures by as much as 36% in medically refractory patients (2). It is well-established that cannabinoids reduce pain refractory to conventional medications (3). It has been found in bench research to be an antioxidant and have anti-inflammatory properties (4, 7). Some studies cite side effects of somnolence, nausea, dysphoria, however, it is not clear what was the quality of cannabinoids or dosages were used. At high doses, while THC can reduce pain it may also result in side effects, which is why it is usually used in combination with CBD which ameliorates the side effects of THC.  In addition, cannabidiol by itself has no euphoria and it takes 100 times the amount to achieve intoxication seen with THC use. Synthetic products will have more side effects than products that are organic meaning only of natural materials.

Given the huge amount of evidence in several different medical conditions (3), the results should overwhelmingly be towards a push in using cannabinoids more frequently. However, because of the cynicism of the public, physicians even of patients, who have been exposed more frequently to the harmful psychoactive side effects, the benefits are far overshadowed. More clinical randomized controlled trials are needed. Most literature cites small numbers of patients enrolled in studies or review multiple medical centers where the conditions are not uniform. In addition, some of the patients that would benefit the most are the least in numbers such as those with rare neurological conditions such as Dravet syndrome or Lennox-Gastuat syndrome.

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In conclusion

As it still stands, many states still do not recognize the medicinal value of cannabidiol or tetrahydrocannabinol. In some states, medical physicians are not allowed to recommend it and put themselves at risk for FBI questioning in even suggesting its use. It is not uncommon for patients to move states or order from other states or countries to procure this liquid gold that is supposed to work wonders. Only time will tell if this is a passing fad and if there are long-standing side effects, however, as of current standing, medical marijuana is here to stay. As far as the literature goes, there are beneficial results but it is a cautionary tale as more studies in large human trials are still needed. As with any new preclinical data, the preclinical status may get ahead of itself and human trials do not replicate the desired results. But from the small clinical trials in seizures, pain, nausea, anxiety, and loss of appetite, the results are promising while more research is needed for anti-tumor effects in humans.

As with any medication, there will be clear-cut side effects just as with any other medication which is why more studies are needed to determine the least amount with the least amount of side effects. In some studies,  amounts upwards of 50mg/kg (2) is used the high amounts likely responsible for causing side effects, which is far higher than that cautioned by medical marijuana dispensaries. It will take patients time to wrap their heads around taking guidance from a fresh-faced 20-year-old millennial at the spa-like dispensary which is currently the norm at most dispensaries, who likely knows much more than even most medical professionals. It seems it will take even longer in Congress to understand the potential benefit of cannabinoids from a medical standpoint especially with the present opioid epidemic. Countries in Europe have far surpassed the United States when it comes to cutting-edge treatments. Perhaps, it will take even longer for the medical community to see the medical potential with their exposure to the sinister side of tetrahydrocannabinol seen in patients in the ER for non-medical reasons, which may be one of the most challenging stumbling blocks.

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Introduction/Disclaimer

References:

  1. Ghandhi, et al, “Systemic review of the potential role of cannabinoids as anti-proliferative agents for urological cancer,” Can. Urol. Assoc. J., 2017, May,-April., 11(3-4):E138-E142.
  2. Devinsky, et al, “Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial,” Lancet Neurology, 2016, Mar., 15(3):270-280.
  3. Petzke, et al, “Efficacy, tolerability, and safety of cannabinoids for chronic neuropathic pain: a systemic review of randomized controlled studies,” Schmerz, 2016, Feb., 30(1):62-88.
  4. Rajan. et al, “Gingival stromal cells as an in vitro model: cannabidiol modulates genes linked with amyotrophic lateral sclerosis,” Journal of Cellular Biochemistry, 2017, Apr., 118(4):819-828.
  5. ElSohly, et al, “Cannabinoids in glaucoma II: the effect of different cannabinoids on intraocular pressure on rabbits,”Current Eye Research, 1984, Jun., 3(6):841-50.
  6. Jarvinen, T., “Cannabinoids in the treatment of glaucoma,” Pharmacology and Therapeutics, 2002, Aug., 95(2):203-20.
  7. Carroll, et al, “9-Tetrahydrocannabinol exerts a direct neuroprotective effect in human cell culture model of Parkinson’s disease,” Neuropathology and Applied Neuropharmacology, 2012, Oct., 38(6):3535-547.
  8. Kaplan, et al, “Cannabidiol attenuates seizures and social deficits in a mouse model in Dravet syndrome,” Proceedings of the National Academy of Science, 2017, Oct.
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Parkinson's disease

Parkinson’s disease: cannabidiol, tetrahydrocannabinol, CB1 and CB2 receptors and anti-oxidant properties in neuroprotection 

Virginia Thornley, M.D., Neurologist, Epileptologist

March 2, 2018

Introduction

Cannabinoids are compounds part of the endocannabinoid pathways found inherent to the brain comprising of endocannabinoids, transporters and receptors. Cannabidiol is a mimetic for 2-2-arachidonyl (2-AG) and tetrahydrocannabinol is a mimetic for Anandamide (AEA). 2 receptors for cannabidiol are found in the brain CB1 mainly seen in the basal ganglia and limbic system and CB2 found in the immune system. The receptors are G-coupled and suppress adenylate.

With Parkinson’s disease, there is reduced production of dopamine in the substantia nigra which means there is less inhibitory effect on the basal ganglia resulting in increased acetylcholine from the basal ganglia which results in tremors. Cannabinoids appear to influence the neurotransmitter system within the brain and have found to be beneficial in movement disorders in the animal model.

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Mechanisms of cannabidiol and THC in Parkinson’s disease animal model

There are more CB1 receptors in brains with Parkinson’s disease and the MPTP model, likely a result of less inhibition from the dopaminergic substances and a compensatory mechanism in the brain. There are more CB1 receptors possibly as a response to the reduced dopaminergic effect (2). It was postulated that CB1 agonists may exert a neuroprotective effect against 3 toxins paraquat, MPP+, and lactasyn. However, using experimental techniques, the neuroprotection from 9THC is likely not related to the CB1 receptor. Evidence supports that the neuroprotection afforded by THC may be related to its antioxidant properties. This may be through the effects of PPARy or the peroxisome proliferator-activated receptor gamma.

Other studies propose that the neuroprotective effects of cannabidiol and THC are independent of the CB1 receptor and related to the antioxidant effects. It was found that CB2 receptor activation may slow the progression of neurodegeneration on Parkinson’s disease. CB2 receptors are found naturally in the cells but appear upregulated in diseased cells such as in Parkinson’s disease, suggesting an endogenous protective effect. It may exert effects by reducing proinflammatory responses. Activation of CB2 receptors may represent a promising role of CB2 receptors in the treatment of Parkinson’s disease (3).

Cannabidiol and clinical studies in Parkinson’s disease

In one study of 119 patients, cannabidiol was given at 75mg/day or 300mg/day. Patients were assessed using variables of motor symptoms according to the UPDRS, well-being and life quality (PDQ-39) and neuroprotective effects.

One week before the trial and in the last week of treatment participants were assessed in respect to (i) motor and general symptoms score (UPDRS); (ii) well-being and quality of life (PDQ-39); and (iii) possible neuroprotective effects (BDNF and H(1)-MRS). They found no difference in motor assessment and neuroprotection but the quality of life seemed to improve in the group taking 300mg compared with placebo(1).

 

Medical marijuana has been demonstrated to be effective in bradykinesia, tremors seen in the Parkinson’s disease. Cannabinoids have been found effective in psychosis and sleep disorders seen in Parkinson’s disease(4).

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Introduction/Disclaimer

About

References

  1. Chagas, et al, “Effects of cannabidiol in the treatment of patients with Parkinson’s disease: an exploratory double-blind trial,” Journal of Psychopharmacology, 2014, Nov., 28(110):1088-1098.
  2.  Carroll, et al, “9-Tetrahydrocannabinol exerts a direct neuroprotective effect in human cell culture model of Parkinson’s disease,” Neuropathology and Applied Neuropharmacology, 2012, Oct., 38(6):3535-547.
  3. Fernandez-Ruiz, et al, “Prospects of cannabinoid therapies in basal ganglia disorder,” British Journal of Pharmacology, 2011, Aug., 163 (7):1365-1378.
  4. Babyeva, et al, “Marijuana compounds: a non-conventional approach to Parkinson’s disease therapy,” Parkinson’s Disease, 2016:1279042.
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Glaucoma, Uncategorized

9Tetrahydrocannabinol and novel mechanisms in reducing intraocular pressure in glaucoma

Virginia Thornley, M.D.,  Neurologist, Epileptologist

February 28, 2018

Introduction

The endocannabinoid system is composed of 3 systems: (the cannabinoid receptors, (2) endocannabinoid transportation system and (3) enzymes that break down the ligands. Two endocannabinoids anandamide (AEA) and 2-arachidonyl glycerol (2-AG) are elevated in response to a wide variety of pathological events. This suggests a compensatory response of endocannabinoids in response to damage or pathology within the system (3). Activation of the endocannabinoid system appears to correlate with cell repair and survival. The G-receptors discovered called CB1 and CB2 trigger transducer signal cascades and influence peripheral central cell functions.

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Cannabidiol in glaucoma

Cannabidiol is becoming a topic of hot debate in pain, anti-tumor effects, epilepsy and in glaucoma.  Glaucoma can result in increased intraocular pressure resulting in damage to the optic nerve at the retinal attachment. There is the narrowing of the visual field and eventual blindness through retinal damage. Cannabinoid receptors have been found in the ocular cells leading to speculation of benefits of cannabinoids in glaucoma.

Mechanism for treating glaucoma

One possible mechanism in ameliorating intraocular pressure is by suppressing N-methyl D-aspartate or NMDA receptor excitability, increasing neural vasculature circulation, suppressing apoptosis and damaging free radicals. Separation of the novels effects appears possible from the toxic side effect through novel technique (2).

Involvement of cannabinoid and their receptors in retinal cells have been well documented in fish cells to primates and more recently in neurodegeneration and neuroprotection. There is a fine balance of biosynthetic and degrading enzymes that influence endocannabinoids and exert neuroprotection during trauma, inflammation, ischemia, and neurotoxicity found in brain damage (4).

THC studies and glaucoma

In a rabbit model, 9THC showed improved penetration to the anterior chamber with reduction of intraocular pressure using a prodrug. THC is an established neuroprotectant and has the possibility of being an effective IOP lowering agent. THC and THC-Val-HS reached the retina choroid(5).

 

In one study of 32 different types of cannabinoids, it was found that certain derivatives of delta 9THC and delta 8THC were more effective at lowering intraocular pressure in glaucoma than the parent derivative cannabidiol (1).

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Introduction/Disclaimer

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About

 

References

  1. ElSohly, et al, “Cannabinoids in glaucoma II: the effect of different cannabinoids on intraocular pressure on rabbits,”Current Eye Research, 1984, Jun., 3(6):841-50.
  2. Jarvinen, T., “Cannabinoids in treatment of glaucoma,” 2002, Aug., 95(2):203-20.
  3.  Karanian, et al, “Cannabinoid drugs and enhancement of endocannabinoid responses: strategies for a wide array of disease states,” Current Molecular Med., 2006, Sep., 6(6):677-84.
  4.  Rapino, et al, “Neuroprotection by endocannabinoids in glaucoma and retinal neurodegenerative diseases,” Current Neuropharmacology, 2017, Jul., doi:10.2174 (Epub ahead of print)
  5.  Goutham, et al, ” Development of a 9tetrahydrocannabidiol amino acid dicarboxylate prodrug with improved ocular bioavailablity,” Investigative Ophthalmology and Visual Science, 2017, Apr., 58(4):2167-2179.

 

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