Virginia Thornley, M.D., Neurologist, Epileptologist
May 6, 2018
Medical cannabis is being more and more commonly used in medical conditions specifically neurological. The CB1 receptor is found predominantly within the nervous system and in a few other organs on a lesser basis. The CB2 receptor is mainly in the immune system and found in other organs to a lesser extent.
Recent arguments have arisen promoting medical cannabis in children particularly in those with autism and attention deficit hyperactivity disorder. It has already been well-established in patients with epilepsy. However, the effects on the developing brains of children have not yet been well-documented as it is not yet widely used or studied in the pediatric population. There are many animal models but this does not always correspond to translate into similar human findings.
Effect in autism in animal models and clinical studies
A current topic of debate is not only using THC in pediatric patients but those with autism. Autism is part of the pervasive developmental disorder consisting of social inhibition and isolation including poor eye contact, delayed language skills, aggressive behavior and may be characterized as having stereotypies such as flapping of the arms. Self-injury, eating and sleep disorders may occur. The etiology may be related to genetic, neurobiochemical or environmental and the exact cause is unclear.
In one animal model study, mice with induced Dravet syndrome-like symptoms was noted to improve in autistic-like social interactions with the addition of low dose cannabidiol (2) of 10mg/kg. At low doses, the DS mice interacted more with stranger mice. At higher doses, this was not noted. Dravet syndrome is a type of epileptic syndrome affecting the SCN1A gene causing medically refractory seizures combined with autism. However, this was an animal model. Scientific studies do not necessarily translate into positive human clinical results.
There was one case report of a six-year-old boy with early autism. Dronabinol (delta-9-THC) was administered at 3.62mg a day and followed for 6 months. Using the ABC scale (aberrant behavior checklist), the patient improved in terms of stereotypies which were less, lethargy was reduced, hyperactivity improved, and inappropriate speech improved (4).
Endocannabinoid system and mechanisms in relation to autism
There are several lines of thinking regarding the role of the endocannabinoid and autism. It is thought that the endocannabinoid system plays a role in neurological development, but can also be modulated by outside cannabinoids. Another line of thinking is that autism spectrum disorders may be related to disrupted pathways that have been affected by the endocannabinoid pathway (5). In one animal study, it was found that the oxytocin peptide may be responsible for disrupting normal signaling pathways giving rise to autism spectrum disorders. Oxytocin appears to be crucial in mediating social reward which is impaired in autistic patients. Anandamide seems to play a role in the signaling pathways for oxytocin which is responsible for the social reward. Social reward is aberrant in those with autism and this pathway thought to play a key role in causing its pathogenesis. By increasing anandamide at the CB1 receptor, ASD and social impairment is improved (5).
Effect on a fetus
Tetrahydrocannabinol is lipophilic and crosses the blood-brain barrier. It can get stored in the fatty stores which are likely the reason it may have a long-lasting effect. Cannabinoids have been found to cross the placenta and affect the fetus. It may result in hyperactivity and impulsivity in babies with cannabinoid exposure in utero.
Effect on early cerebral development
It was found that in adolescents who used cannabis, there is a reduction in the IQ by the age of 38. It was found that cannabinoid receptors influence axonal migrations as well as subcortical projections within the cerebrum. This affects synaptic connections during childhood and adolescence(3).
The adolescent brain is still not fully matured and likely still subject to neuronal plasticity and changes. It may be affected by substances. One study showed that the frontal lobe is vulnerable to cannabis in adolescents who used it heavily and that cannabis use may impact working memory. (1)
During adolescence, when cannabis is initiated it may affect the neuronal circuitry developing in the immature brain. The richest regions in the brain with cannabinoid receptors are the prefrontal cortex, medial temporal lobes, striatum, white matter connections, and cerebellum. When cannabis is introduced during this neurocritically important time of development, these regions can become dysfunctional although some functional studies have shown altered, weakened, strengthened or combination of changes (6).
Some of the most common adverse effects
At high doses in chronic users, it was found to induce anxiety, panic attacks. It can increase blood pressure. However, clinically, it may control seizures
There is a small body of evidence from a scientific standpoint that cannabis may work to help alleviate autism-like symptoms based on the animal models. There is a not enough evidence from a clinical evidence standpoint in human studies to support its use in pediatric patients, with one case report that it helped with impulsivity, reduced lethargy, and inattention. Randomized placebo-controlled clinical trials are needed.
Research has found that cannabinoids may help oxytocin and disrupted signaling pathways that play a role in social reward which is impaired in autism. At present, there is evidence that cannabis may affect neurocognitive development but these are studies in pregnant mothers who used it heavily recreationally and adolescents who used it heavily. It is unclear if there may be a similar impact when used in the pediatric population at a medical dosage and administration as there are not enough studies to expound on this.
- Jager, et al, “Cannabis use and memory brain function in adolescent boys: a cross-sectional multicenter fMRI study,” J. Am. Acad. Child Adolesc. Psychiatry, 2010, Jun., 49(6):561-572.
- 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.. 114 (42):11229-11234.
- Scott, et al, “Medical marijuana: a review of the science and implications for developmental-behavioral pediatric practice,” J. Dev. Behav. Ped., 2016, Feb., 36 (2):115-123.
- Kurz, et al, “Use of dronabinol (delta-9-THC) in autism: a prospective single-case study with early infantile autistic child,” Cannabinoids, 2010, 5 (4):4-6.
- Wei, et al, “Enhancement of anandamide-mediated endocannabinoid signaling corrects autism-related social impairment,” Cannabis Cannabinoid Research, 2016, 1(1):81-89
- Kelly, et al, “Distinct effects of childhood ADHD and cannabis use on brain functional architecture in young adults, Neuroimage Clin., 2017, 13:188-200.
Virginia Thornley, M.D., Neurologist, Epileptologist
April 28, 2018
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.
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.
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.
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.
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.
- 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.
- 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.
Virginia Thornley, M.D., Neurologist, Epileptologist
March 11, 2018
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.
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.
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.
- 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.
- Devinsky, et al, “Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial,” Lancet Neurology, 2016, Mar., 15(3):270-280.
- 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.
- 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.
- 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.
- Jarvinen, T., “Cannabinoids in the treatment of glaucoma,” Pharmacology and Therapeutics, 2002, Aug., 95(2):203-20.
- 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.
- 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.