- Meehan-Atrash, J., Luo. W., McWhirter, K.J., Strongin, R.M. Aerosol gas-phase components from cannabis e-cigarettes and dabbing: mechanistic insight and quantitative risk analysis. ACS Omega. 2019, Sep. 16,;4(14):6111-16120
- Hughes, B., Herron, C.E., Cannabidiol reverses deficits in hippocampal LTP in a model of Alzheimer’s disease. Neurochem. Res. 2019, Mar. 44(3):703-713
This is medical information not medical advice. Please consult with your physician.
July 18, 2018
This looks into the role cannabinoids may play in the treatment of gliomas under which glioblastoma multiforme is categorized. Every mechanism is key in providing valuable information in targeting various mechanisms to assist with treatment.
Cannabinoid system and evidence of a role in gliomas
Phytocannabinoids have been identified from the plant cannabis sativa including delta-9-tetraydrocannabinol and cannabidiol. There are 2 significant receptors CB1 receptor and CB2 receptors. Within the endocannabinoid system there are 2 well-studied endocannabinoids, 2-arachidonoylglycerol (2-AG) and anandamide (AEA) and G-related proteins (1). delta-9-tetrahydrocannabinol is a pharmacomimetic of anandamide while cannabidiol is a mimetic of 2-AG. Anandamide is metabolized by fatty acid amide hydrolase or FAAH while 2-AG is metabolized through monoacylglycerol lipase (MAGL).
The receptors are of 2 types. The CB1 receptor is found predominantly in the nervous system in areas subserving pain modulation, memory, and movement. The CB2 receptor is peripherally found in the immune system. The CB2 receptor is found to a lesser extent in other organ systems including adrenal, cardiac, endocrine, pulmonary, gastrointestinal and gynecological organs. Cannabinoids react with the TRPV receptor or the transient receptor cation channel subfamily V. They can act on G receptors including GPR55 which is thought to influence inhibition of seizures. Other receptors include GPR12, GPR18, and GPR119 (2).
In glioblastoma multiforme, degrading enzymes of anandamide were found to be reduced with 60% reduction of fatty acid amide hydrolase (FAAH). Anandamide was found to be significantly increased compared to non-tumor tissue. In meningiomas, 2-AG were found to be significantly increased. This points towards elevation of levels of endogenous cannabinoids in the presence of tumor cells which may possibly signal an anti-tumor process by modulating cannabinoid receptor mechanisms (3).
There are various mechanisms by which cannabinoid can modulate the pathogenesis in tumors including proliferation, invasion, cell survival. Cannabinoids are thought to be involved mechanistically in the anti-proliferative, anti-migration and apoptotic effects of tumor cells in gliomas.
Cannabinoids may make tumor cells in gliomas more susceptible to radiation
One study found that cannabinoids may make tumor cells in gliomas more strongly susceptible to irradiation. When heat shock proteins were treated with CBD, they were upregulated. This did not occur in the setting of THC. Heat shock proteins are important in degradation, assembly, and transcription factor regulation. They are important in cell survival in the setting of abnormal pH, temperature and inflammation which may be caused by abnormal stability in the cell related to hypoxia, oxidative stress and temperature. Heat shock proteins are associated with resistance of tumor cells to treatment and a poorer prognosis (5). Heat shock proteins can inadvertently promote cancer cell survival, hence, their presence may correlate with a poorer prognosis. Cannabinoids were found to increase reactive oxidative stress leading to an alteration in the expression of HSP’s by increasing it. Increased HSP’s may alter the cytotoxicity of CBD towards cancer cells. By using an HSP inhibitor in conjunction with CBD, there may be better impact of irradiation of tumor cells. In summary, CBD along with HSP inhibitors may make tumor cells in gliomas more vulnerable to tumor irradiation (6).
Cannabinoids causes tumor cell death through apoptotic mechanisms
In one study, cannabinoids were found to have an anti-proliferative effect on tumors. Apoptosis is reduced by mechanisms where cannabinoids stimulate the pro-apoptotic ceramide which subsequently has impact on cell proliferation, differentiation and apoptosis in tumors (7).
In another study, there is supportive evidence that sphingolipid metabolism changes. This causes tetrahydrocannabinol to change the sphingolipid content in the endoplasmic reticulum, autolysosomes and autophagosomes. This contributes towards cell death promotion by autolysosomes which are stimulated by the cannabinoids (8).
Another study confirms that arachidonoylethanolamide (AEA) or anandamide which is the most potent endogenous cannabinoid works through anomalously expressed vanilloid receptor-1 (VR-1) in activating apoptosis in glioma cell lines through this receptor (9). THC is a mimetic of anandamide and may induce apoptosis through this mechanism. This may represent a potential specific molecular mechanism where therapeutic agents may be developed.
Cannabinoids reduce angiogenesis and proliferation of glioma cell lines
In the human cell glioma cell lines U-87MG and T98G, cannabidiol was found to inhibit the proliferation and cell invasion of these cancer cell lines. These results are significant since aggressive tumors have an ability for normal tissue invasion and proliferation leading to a poor outcome. The doses required for reduction of invasion was less compared to the dosage needed to prevent proliferation. Cannabidiol demonstrated the ability to inhibit different proteins necessary for cell invasion of the 2 cell lines including MMP-9, TIMP-1, TIMP-4, uPA, VEGF and SerpinE1-PAI. Their roles play a significant part in metastasis and vascular proliferation (10). Interestingly, T98G cell lines were found to be delta-9-THC resistant.
Cannabinoids reduce MMP9 which is important in tumor cell invasiveness
MMP are proteases and are increased in the presence of gliomas signaling the invasiveness of the tumor. Cannabinoid inhibition of MMP9 may be the way by which invasiveness of the tumor is reduced. Inhibition of TIMP was also noted in the presence of cannabinoids, which is demonstrated in clinically aggressive gliomas (10).
Cannabinoids inhibits HIF-1 which allows tumor cells to thrive in hypoxic settings
Another significant concept produced by the research is cannabidiol inhibition of HIF1-alpha (or hypoxia induced factor) which is a transcription factor serving a regulatory role in the setting of hypoxia. Hypoxia occurs in fast-growing tumors when the demands for oxygen are outpaced and hypoxia results. In the setting of hypoxia, HIF1-alpha allows tumor cells to thrive in hypoxic conditions through migration, survival and vascular proliferation allowing these tumors to be resistant to chemotherapy (10).
Cannabinoids can modulate mechanistic properties of tumor cells in gliomas
One study demonstrated that cell “stiffness” correlates with the aggressiveness of invasion from tumor cell lines and may represent a mechanistic cell marker to signal invasiveness of a tumor. Cannabinoids can modulate the mechanistic properties of tumors and may be a potential anti-tumor therapeutic target in glioma cell lines(11).
In summary, cannabinoids are demonstrated to have a role in significant mechanisms involved in tumor activities including anti-proliferation, anti-migration, anti-angiogenesis and anti-survival. Cannabidiol inhibit conditions where transcription factors cause cancer cells to thrive in hypoxic environments which is crucial in the aggressive profile of malignant tumors. Cannabidiol reduces MMP9 significant in invasiveness. Cannabidiol along with HIF inhibitors can make gliomas more radiation susceptible.
The pre-clinical studies are accumulating rapidly which each discovery. Every mechanism elucidated counts towards potential therapeutic targets in gliomas. Pre-clinical studies do not always translate to human studies but the science is gaining headway.
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
Petersen, G., Moesgaard, B., Schmid, P.C., Broholm, H., Kosteljanetz, M., Hansen, H.S. Endocannaboinoid metabolism in human glioblastomas and meningiomas compared to human non-tumour brain tissue. J. Neurochem. 2005, Apr., 93 (2):299-309
- Sredni, S.T., Huang, C.C., Suzuki, M., Chou, P., Tomita, T. Spontaneous involution of pediatric low-grade gliomas: high expression of cannabinoid receptor 1 (CNR1) at the time of diagnosis may indicate involvement of the endocannabinoid system. Childs Nerv. Sys.t 2016, Nov, 32(11):2061-2067
- Calderwood, S.K., Khaleque, A., Sawyer, D.B., Ciocca, D.R., Heat shock proteins in cancer: chaperones to tumorigenesis. Trends in Biochemical Sciences. 2006, Mar. 31(3):164-172
Scott, K.A., Dennis, J.L., Dalgeish, A.G., Liu, W.M. Inhibiting heat shock proteins can potentiate the cyototoxic effect of cannabidiol in human glioma cells. Anticancer Research. 2015, Nov., 35 (11):5827-583
Ellert-Miklaszewska, A., Ciechomska, I., Kaminska, B. Cannabinoid signaling in glioma cells. Adv. Exp. Med. Biol. 2013, 986:209-220
Hernandez-Tiedra, s., Fabrias, G., Davila, D., Salanueva, I.J., Casas, J., Montes, L.R., Anton, Z., Garcia-Taboada, E., Salazar-Roa, M., Lorente, M., Nylandsted, J., Armstrong, J., Lopez-Valero, I., McKee, C.S., Serrano-Puebla, A., Garcia-Lopez, R., Gonzale-Martinez, J., Abad, J.L.,, Hanada, K., Boya, P., Goni, F., Guzman, M., Lovat, P., Jaatela, M., Alonso, A., Velasco, G. Dihydroceramide accumulation mediates cytotoxic autophagy of cancer cells via autolysosome destabilization. Autophagy, 2016, Nov. 12 (11):2213-2229
Contassot, E., Wilmotte, R., Tenan, M., Belkouch, M.C., Schuriger, V., de Tribolet, N., Burkhardt, K., Dietrich, P.Y. Arachidonoylethanolamide induces apoptosis of human glioma cells through vanilloid receptor-1. J. Neuropathol. Exp. Neurol. 2004 Sep, 63(9):956-63
Solinas, M., Massi, P., Cinquina, V., Valenti, M., Bolognini, D., Gariboldi, M., Monti, E., Rubino, T., Parolaro, D. Cannabidiol, a non-psychoactive cannabinoid compound, inhibits proliferation and invasion in U87-MG and T98G glioma cells through multitarget effect. PLoS One 2013, 8(10):e76918
Hohmann, T., Grabiec, U., Ghadban, C., Feese, K., Dehghani, F. The influence of biomechanical properties and cannabinoids on tumor invasion. Cell Adh Migr 2017, 11(1):54-67
Virginia Thornley, M.D., Neurologist, Epileptologist
June 25, 2018
Alzheimer’s disease is not a natural progression of senescence. It is a neurological disorder involving deposition of beta amyloid peptides in senile plaques and accumulation of amyloid precursor proteins within the cerebrum particularly in areas affecting memory and cognition. Current pharmaceutic agents at best can only slow the progression of this disorder. There is no cure. Because it not a devastating illness in that it does not decrease the longevity per se, nonetheless, it is devastating to the patient and family members around him or her.
With the advent of cannabinoids into the pharmaceutic fold, attention is turning towards medical value outside its well-known repertory including anti-inflammatory and neuroprotective properties. Can cannabinoids slow the inflammatory process that is involved in this neurodegenerative condition? This seeks to explore mechanisms by which cannabinoids may play a role in ameliorating the clinical effects seen in Alzheimer’s disease.
As an overview, the endocannabinoids system is found naturally within the body consisting of endocannabinoids, enzymes and receptors. There are 2 receptors the CB1 receptor which is concentrated in the nervous system and found to a lesser extent in other organ systems and the CB2 receptor which is found mostly in the immune system and in other systems. Anandamide is an endocannabinoid that exerts its actions on the CB1 receptor, while di-arachidonoylglycerol has a low affinity for the CB1 receptor and interacts with the TPRV or transient receptor potential channels of the vanilloid subtype and the G-coupled receptor family.
Within the cannabis sativa plant are 2 most well-studied phytocannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). The CB1 receptor is where delta-9-tetrahydrocannabinol (THC), a mimetic of Anandamide, interacts and can cause psychoactive effects. Cannabidiol is a mimetic of di-arachidonoylglyerol with a lower affinity to the CB1 receptor where 100 times the amount of CBD is required to achieve the same psychoactivity as THC. When CBD and THC are combined there are less side effects since the CBD acts as a non-competitive allosteric modulator at the CB1 receptor. When the 2 are combined there is an effect that is increased together compared to when each cannabinoid is taken alone, where the effect is significantly much different. The presence of CBD offsets side effects of THC. Common side effects include agitation, hyperactivity and paranoia.
Senile plaques are found to express CB1 and CB2 receptors within the brain in addition to microglial activation markers. The neurons are rich in CB1 receptors but seem to be greatly reduced in microglial activated areas. CB1 receptor expression and G-related coupled protein are reduced in brains with Alzheimer’s disease. Nitration of proteins are enhanced especially in CB1 and CB2 proteins in Alzheimer’s diseased brains. Adding synthetic cannabinoid WIN55-212-2 to rats caused an inhibition of microglial activation and neuron marker loss. Cannabinoids were found to ameliorate neurotoxicity caused by microglial activation (1).
Another study demonstrates the role of cannabinoids on inflammation in the mouse model using synthetic cannabinoids JWH-133 and WIN55.212-2. Cognition and inflammation were studied. FDG uptake on PET scan was used to assess areas of metabolic uptake. The amyloid precursor protein mice showed poor object recognition. After administration of the JWH compound, cognitive impairments were reversed. There was reduced FDG uptake in the hippocampal areas. No changes were seen using WIN55.212-2. Beta amyloid proteins were significantly reduced in the mice models when cannabinoids were applied. Microglia was elevated in the APP mice which was reduced after cannabinoid administration (2).
In another mouse study, CB2 receptors were at a low level found in the neurons of unmanipulated mice whereas there was a noted increase in the CB2 receptors in mice that underwent chronic inflammation in the microglia surrounding plaques. This suggests that there is an upregulation of CB2 receptors in the presence of pathological inflammation. This may be a potential target in therapeutic agents in the future (3).
These pre-clinical studies demonstrate a neuroprotective and anti-inflammatory role of cannabinoids on Alzheimer’s disease. The CB2 appears to be upregulated around activated microglial cells around plaques implying a possible therapeutic target for future treatments. While pre-clinical studies are not human trials, elucidating these mechanisms may play a role in the future therapeutic benefits of cannabinoids on Alzheimer’s disease.
Ramirez, B.G., Blazquez, C., del Pulgar, T.G., Guzman, M., de Ceballos, M.L. Prevention of Alzheimer’s disease pathologyby cannabinoids: neuroprotection mediated by blockade of microglial activation. J. Neurosci. 2005, 25:1904-13
Martín-Moreno, A.M., Brera, B., Spuch, C., Carro, E., García-García, L., Delgado, M., Pozo, M.A., Innamorato, N.G., Cuadrado, A., de Ceballos, M.L. Prolonged oral cannabinoid administration prevents neuroinflammation, lowers b-amyloid levels and improves cognitive performance in Tg APP 2576 mice. J. Neuroinflam. 2012, 9:8
Lopez, A., Aparicio, N., Pazos, M.R., Grande, M.T., Barredo-Manso, M.A., Benito-Cuesta, I., Vazquez, C., Amores, M., Ruiz-Perez, G., Garcia-Garcia, E., Beatka, M., Tolon, R.M., Dittel, B.N., Hillard, C.J., Romero, J. Cannabinoid CB2 receptors in the mouse brain: relevance for Alzheimer’s disease. J. Neuroinflam. 2018, May, 15:158
Virginia Thornley, M.D., Neurologist, Epileptologist
June 16, 2018
Obsessive-compulsive disorder infamously known to the layman as someone who is excessively interested in keeping their environment clean and orderly. It is a neuropsychiatric condition, where thoughts or actions are repetitive. Usually it involves the complex balance of neurotransmitters within the nervous system so that ideas and actions are carried out in a specific manner. When there is an alteration, repetitive loops occur resulting in repetitive thoughts or reverberating loops of motor activity without the usual negative feedback inhibition. Clinically, this results in intrusive thoughts and repetitive actions that are difficult to control.
Because there is a fine orchestration of the interplay of neurotransmitters, many psychiatric agents have been developed but success is not always complete.
Medical cannabis is emerging as a treatment option recognized as successfully treating many neuropsychiatric conditions. While large clinical randomized controlled trials are sorely lacking. Scientific research is also necessary to understand the exact science on why t might help with neuropsychiatric disorders.
Mechanisms of cannabinoids on the CB1 receptor to alleviate repetitive behavior
Anandamide and 2-AG are metabolized by FAAH or fatty acid amide hydrolase and MAGL or monoacyglycerol lipase. FAAH inhibition has been shown to increase anxiolytic effects of endocannabinoid anandamide.
One study sought to seek the effects of FAAH inhibition and MAGL inhibition on the marble burying features of mice (1). Marble burying is a research measure where marble burying is thought to be a sign of anxiety in animals and may correlate with compulsive behavior in mice to alleviate anxiety. Marble burying is an acceptable animal model to demonstrate repetitive behavior and anxiety elicited from mice demonstrating obsessive compulsive disorder (2). Marble burying is not affected by the novelty of the marble or by anxiety. Marble burying is suggested to be a repetitive perseverative type of activity related to digging movements of mice and is a valuable measure in research to evaluate repetitive responses in animals (2).
Benzodiazepines, PF-3845, an FAAH inhibitor and JZL184, a MAGL were found to reduce marble burying activity but did not affect locomotor activity. Delta-9-THC did not reduce marble burying behavior without reducing the locomotor activity (1). In essence, there was significant hypomotility with the marble burying activity.
Reduction of catabolic enyzymes of endocannabinoids may alleviate anxiety
An antogonist at the CB1 receptor negated the reduction of marble burying activity of FAAH and MAGL but not the benzodiazepine. This suggests that the CB1 receptor has anxiolytic properties. Possible treatments would include targeting of the enzymes that break down cannabinoids making the cannabinoids more available.
Cannabidiol effect on obsessive compulsive behavior in the animal model
Cannabidiol was given to mice using the marble burying test which is an animal model demonstrating compulsive behavior. At 15, 30 and 60mg/kg there was effective reduction of marble burying behavior compared to control mice. This study demonstrated that cannabidiol is effective in reducing repetitive perseverative behavior similar to the conditions in obsessive compulsive disorder (3).
While most of the preliminary data is entirely preclinical, there is scientific evidence that cannabidiol can reduce obsessive-compulsive behavior in the animal model. The mechanism appears to be at the level of the CB1 receptor. While preclinical data does not always translate into positive human results, this concept is promising. Clinical studies are needed.
- Kinsey, et al, “Inhibition of endocannabinoid catabolic enzymes elicits anxiolytic-like effects in the marble burying assay,” Pharmacol. Biochem. Behav., 2011 Mar, 98(1)21-7
- Thomas, et al, “Marble burying reflects a repetitive and perseverative behavior more than novelty-induced anxiety,” Psychopharmacology, 2010, Jun., 204(2):361-373
- Casarotto, et al, “Cannabidiol inhibitory effect on marble-burying behavior:involvement of CB1 receptor,” Behav. Pharmacol, 2010, Jul., 21(4):353-358
Virginia Thornley, M.D., Neurologist, Epileptologist
June 11, 2018
When one hears Tourette’s syndrome the glorified Hollywood impression young person who shouts obscenities comes to mind. It is composed of complex motor or vocal tics generally preceded by a premonitory urge. Vocal tics may consist of coprolalia and echolalia. Motor tics may involve complex actions including copropraxia or simple motor tics. Obsessive compulsive disorder and other neuropsychiatric conditions are often associated with it.
The underlying problem is thought to be related to an imbalance of the neurotransmitters necessary to maintain the fine coordination necessary to avoid excessive motor activity. When that balance is impaired there is less inhibition of motor loop control resulting in reverberating loops and excess movements involving motor groups including muscles controlling speech and body movements. Because the pathophysiology is not entirely clear, these may be some of the most challenging neurological disorders in terms of treatments from a neurological standpoint.
Background on Cannabinoid Mechanisms
With the advent of medical cannabis used in neurological conditions, new indications are discovered. The mechanism is at the level of the endocannabinoid system already inherent within the system. There are 2 receptors, CB1 and CB2. The CB1 receptor is found mostly within the nervous system. The CB2 receptor is mostly in the immune system but is found in other organ systems to a lesser extent. Tetrahydrocannabinol (THC) is a mimetic of Anandamide which works within the endocannabinoid system and has medical properties. THC interacts with the CB1 receptor which is responsible for psychoactive properties most people are familiar with. It is likely at the CB1 receptor where other neurological symptoms are alleviated since this most abundantly found in the nervous system and many neurological symptoms are ameliorated with medical cannabis. Cannabidiol (CBD), which is non-psychoactive, is a pharmacomimetic of 2-AG or diarachidonylglycerol. It is an non-competitive allosteric modulator of the CB1 receptor which alleviates any side effects from THC when they are combined together (1).
There is one report of a patient treated with nabiximol where there was improvement of tics. There was overall improvement in quality of life and global improvement. There was lessening of premonitory urges. Patients feel the premonitory symptoms are more bothersome. In one study anti-psychotics helped ameliorate the motor tics but did not improve the premonitory symptoms (2). Nabiximol was used in this study where 1 puff contained 2.7mg of THC and 2.5mg of CBD. Assessments included the Yale Global Tic Severity Scale (YGTSS), Tourette’s Syndrome Symptom LIst (TSSL), Modified Rush Video Tic Scale, Premonitory Urge for Tic Scale, Global Clinical Impairment, Visual Analogue Scale for satisfaction for the GTS-Quality of Life. The study showed the best results in the quality of life in terms of alleviating premonitory urges. Larger clinical trials are needed to further this study (2).
In a recent case report, THC (trademark Sativex) was used with success to treat a patient using 10.8mg THC and 10mg CBD daily. Yale Global Tic Severity Scale (YGTSS) and the Original Rush Video Tic Scale were used as measures of evaluation. The results demonstrated effective use of THC in combination with THC for treatment in medically refractory patients (5).
In one single dose, cross over study in 12 patients and a randomized trial in 24 patients spanning 6 weeks was performed (3). The study demonstrated that THC reduces tics without any disruption in cognitive function. Neuropsychological impairment was not seen (3).
In the randomized double blinded placebo-controlled clinical trial of 24 patients, THC of up to 10mg was used in the treated cohort over 6 weeks. Measures used included the Tourette’s Syndrome Clinical Global Impression Scale (TS-CGI), Shapiro Tourette Syndrome Severity Scale (STSS), the Yale Global Tic Severity Scale (YGTSS), Tourette Syndrome Symptom List (TSSL) and the videotape based rating scale. Patients were rated at visits 1 for baseline, visits 3-4 during treatment and visits 5-6 after withdrawal. There was a significant difference between both groups. There was a significant reduction in motor tics, vocal tics and obsessive compulsive disorder. No significant adverse cognitive effects were noted (4).
More randomized controlled clinical studies are necessary
While there may be a paucity of large clinical trials of the use of medical cannabis in Tourette’s syndrome, tetrahydrocannabinol is a potential therapeutic agent in a neurological disorder where treatment options are very limited and often times unsuccessful. Adverse side effects can preclude treatment using conventional pharmaceutic agents.
While large randomized controlled clinical trials are necessary in providing standard of care, tetrahydrocannabinol has emerged as a potential treatment option used by clinicians who are on the frontlines of treating this debilitating disorder.
1. Laprairie, et al, “Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor,” Br. J. Pharmacology, 2015, Oct., 172(20):4790-4805
2. Kanaan, et al, “Significant tic reduction in an otherwise treatment-resistant patient with Gilles de la Tourette syndrome following treatment with nabiximol,: Brain Science, 2017, Apr., 7 (5):47
3. Muller-Vahl,”Cannabinoids reduce symptoms of Tourette’s syndrome,” Expert Opin Pharmacother., 2003, Oct., 4(10):17-1725
4. Muller-Vahl, “Delta-9-Tetrahydrocannabinol (THC) is effective in the treatment of tics in Tourette syndrome: a 6 week randomized trial,” J. Clin Psychiatry, 2003, Apr., 64 (4):459-65
5. Trainor, “Severe motor and vocal tics controlled with Sativex®,” Australas Psychiatry, 2016, Dec, 24 (6):541-544
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
May 2, 2018
With the advent of a wide use of cannabinoids in neurological disease compared to previous times, attention hyperactivity deficit disorder has arisen as one of the possible disorders where patients may benefit. Because it starts in childhood, questions arise whether it may be applied to the pediatric patients with ADHD. If so, what are the long-term consequences on the developing brain?
Effect of cannabis in ADHD and on the brain
There is a paucity of literature on cannabis use in children with ADHD, most have been on adults. There are some recent clinical trials and its use in adult patients with ADHD. In a recent study on ADHD in adults, 30 patients were studied, 15 were in the placebo-controlled group and 15 were given Sativex oromucosal spray (combination CBD:THC). There was no statistical difference in cognitive performance although the score patterns on those on Sativex were higher. There was some improvement in attention. There was a significant improvement in emotional lability and hyperactivity (p=0.3). This implies that cannabinoids may play a role in adult ADHD (1).
In a study of 579 young adult patients with an early history of ADHD of which 129 had to be excluded, it was found that the dorsal attention network found in the parietal region was stronger in those with ADHD. The right fronto-parietal and right inferior frontal region connections were weaker in the ADHD group. The left prefrontal dorsal connections and the right prefrontal cortex connections in ADHD were reduced (2).
One of the key components of ADHD in children is motor dysregulation and weakened connections in the somatosensory region. The stronger connections in ADHD in the frontal-opercular regions suggests compensatory adaptations to maintain normal cognition. There are stronger right parietal region connections in patients with ADHD possibly suggesting maladaptive mechanisms. When patients with ADHD and cannabis use were studied it appeared that there were neuroadaptive processes. In those who used cannabis, there were stronger intrinsic connections with a superior delayed recall. There were stronger connections in the left fusiform gyrus that correlated with a) less cognitive interference, these are emotional thoughts or personality traits that can intrude and affect tasks at hand and b) better response inhibition performance, this is the ability to ignore distractions. This is consistent with other studies showing an increased task activation response (2).
Effect of cannabis on the 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 (3). There was a greater incidence of inattention and delinquency in prenatal exposure to cannabis.
Effect of medical marijuana in 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(4).
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 (5).
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 (2).
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 paucity of literature on the effects of medical marijuana on the pediatric population. It has been mostly studied in adult patients. It is difficult to correlate the results of beneficial effects on adults on children since the pediatric brain is still developing. In adult patients with ADHD, apparently exposure to cannabis results in a superior delayed recall, there were fewer thought intrusions when completing tasks and better able to ignore distractions.
When exposed in utero, there was a greater risk of developing inattention, hyperactivity, and impulsivity in children who were exposed before conception. There was a greater tendency towards delinquency. In addition, adolescents who had been chronically exposed to cannabis may have had their working memory impacted. The adolescent period is significant from a neurological standpoint in brain development. There were mixed reports on connections being strengthened, weakened or a combination of the two being reported.
It is difficult to correlate the data of chronic medical cannabis exposure of adolescents in a patient who will use it for its medicinal value since the route, amount and administration and frequency will be completely and distinctly different. In addition, most of the adolescent data has been derived from those who had used it recreationally usually by smoking it heavily, there may be a synthetic component which may be detrimental and it is not clear what other substances may have been added.
In short, there is not enough scientific and clinical data to support the use of medical cannabis in pediatric patients. Most of the data is derived from animal studies or studies in adults where there are medical benefits. In the pediatric brain even while studies showed abnormal memory in chronic use it was studied in a very different population of heavy recreational users. Therefore, it is not clear if adult findings can translate into similar pediatric success and the same dysfunctional development of chronic heavy abusers would correlate with similar findings in pediatric patients using it for distinctly different reasons and dosing and administrations. If there is some adverse effect on the pediatric brain, it is unclear if the risks outweigh the benefits in a developing brain of the pediatric population. It may be used anecdotally in some practices with some benefits. Large clinical trials are needed to support this.
1. Cooper, et al, “Cannabinoid in attention-deficit/hyperactivity disorder: a randomized controlled trial,” Eur. Neuropsychopharmacol., 2017, Aug., 27 (8):795-808
2. Kelly, et al, “Distinct effects of childhood ADHD and cannabis use on brain functional architecture in young adults, Neuroimage Clin., 2017, 13:188-200.
3. Goldschimd, et al, “Effects of prenatal marijuana exposure on child behavior problems at age 10,” Neurotoxicol. Teratol., 2000, May-Jun., 22(3):325-326.
4. 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.
5. 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.