[DRAFT] The Endocannabinoid System – Ch 2: ADHD & The ECS

Introduction

Attention deficit hyperactivity disorder (ADHD) is a common, heritable, neuropsychiatric disorder affecting 2.5%–5% of adults. It is described as a neurodevelopmental syndrome that emerges in childhood or early adolescence; in 60%–70% of cases, it persists into adulthood. It is characterized by symptoms of inattention or hyperactivity, and impulsivity, or both. These core symptoms typically manifest as restlessness, mind-wandering, emotional instability, and an inability to relax or concentrate. Psychiatric conditions such as depression, anxiety, substance abuse disorder, and antisocial disorders are common psychiatric comorbidities in ADHD. Further, ADHD is a multifaceted disorder involving multiple genes as well as neurobiological and environmental factors in its age-related development and treatment. Genetic and neurobiological studies have shown that multiple risk genes are responsible for the underlying liability to ADHD, with estimates of heritability at 76%. In addition to strong neurobiological and genetic underpinnings, environmental elements are also shown in both the etiology of ADHD and its related impairment.

The management of ADHD typically includes psychostimulant medications (methylphenidate and amphetamine derivatives), non-stimulant medications (e.g. atomoxetine), and extended-release clonidine and guanfacine. Multiple other medications are used “off-label,” with less efficacy and tolerability. Nonetheless, methylphenidate remains the most prescribed, efficacious, and tolerated medication for ADHD. The non-serious adverse effects (AEs) of these medications include insomnia, decreased appetite, anxiety, increased systolic and diastolic blood pressure, nausea, dry mouth, fatigue, headache, urinary hesitation, erectile dysfunction, infection, and nervousness. Increasingly, there is a recognition that medical cannabis (MC) may offer an alternative treatment option for adult ADHD. Observational studies have shown that medical cannabis patients in general use cannabinoids as a substitution for alcohol, illicit drugs, and/or commonly used prescription drugs for better symptom management, as well as to experience fewer side effects.

Recently increased attention has been given to the role of the ECS in ADHD. Traditionally, ADHD pathology has been associated with the dopaminergic system. Cannabinoid 1 (CB1) receptors, which interact with the dopaminergic system, have been suggested as possible pharmacological targets to reduce hyperimpulsivity and distractibility. Therefore, exocannabinoids, such as Δ9-THC, hold potential as pharmacological therapy, as they have been demonstrated to induce dopamine release in the human striatum. It has been suggested that the brain regions where the modulation of endocannabinoids might lead to action restraint and the regulation of impulsive action are the medial prefrontal cortex and the ventral tegmental area. In addition to dopamine, the role of glutamate, GABA, and other neurotransmitter systems need consideration, as well as N-methyl-D-aspartate and cannabinoid 2 (CB2) receptors, which have been suggested to modulate, for instance, impulsivity in interaction with endocannabinoids. Therefore, further preclinical and clinical studies are warranted to map the complex interactions involved with the ECS in various pathophysiologies.

Literature

A cross-sectional questionnaire-based study published by Technion-Israel Institute of Technology in Israel aimed to identify associations between the doses of cannabinoids and terpenes administered, and symptoms of attention deficit hyperactivity disorder (ADHD). Participants were adult patients licensed for medical cannabis (MC) treatment who also reported a diagnosis of ADHD by a physician. Notably, most patients (n=47, 89%)  consumed inflorescences, either by smoking, vaporizing, or both. Five patients (9%) combined oil extracts and inflorescences, and one patient (2%) consumed only oil extracts. Medical cannabis treatment duration of our sample ranged from 1 to 16 years. These findings reveal that the higher-dose consumption of MC components (phytocannabinoids and terpenes) is associated with ADHD medication reduction. In addition, a high dosage of CBN was associated with a lower ASRS score. Moreover, there was an association between a lower ASRS score subgroup and lower anxiety scores. In addition, we found an association between lower ASRS score and consumption of high doses of cannabinol (CBN), but not with ∆-9-tetrahydrocannabinol (THC). Notably, anxiety scores, sleep quality, sleep latency, and sleep duration did not vary significantly between the MC dose subgroups. Medical cannabis-related AEs were reported by a total of 28% (n=15) of the sample; AEs were not significantly different between the MC dose subgroups (P>0.05). Reports of AEs included central nervous system (n=7, 13%), gastrointestinal (n=7, 13%), psychological (n=6, 11%), cardiovascular (n=3, 6%), ophthalmic (n= 3, 6%), musculoskeletal (n=2, 4%), and auditory (n=2, 4%) AEs.

Furthermore, a case report published by the University of Tampere in Finland presented a detailed patient case report of a male patient who was diagnosed in adulthood (aged 33) with attention deficit hyperactivity disorder (ADHD) and treated initially with immediate-release methylphenidate (Ritalin® 10 mg twice daily). After experiencing adverse effects from prolonged use of this medication and afterward other medications that were prescribed as alternatives, the patient started using cannabinoid therapeutics. Subsequently, he was evaluated by a physician in Germany (June 2010) who prescribed cannabinoid therapeutics (Bedrocan®, Bediol®). A Finnish neurologist later confirmed the two prescribed medicines (Bedrocan®, October 2010; Bediol®, May 2011) in the patient’s own country of permanent residence (Finland). During a 5-year period of access, Bedrocan®, which mainly contains Δ9-tetrahydrocannabinol (Δ9-THC), was found to help alleviate the patient’s ADHD symptoms, in particular poor tolerance to frustration, outbursts of anger, boredom, and problems related to concentration. The second cannabinoid therapeutic medication, Bediol®, which contains both Δ9-THC and the phytocannabinoid cannabidiol, was found to neutralize the excessive dronabinol effects of Bedrocan® as well as to offer other medical benefits (e.g., improved sleep).

Finally, a study published by the University of Tabriz and the Maragheh University in Iran investigated the association of FAAH (the degrading enzyme of the endocannabinoids) rs2295633 polymorphism with ADHD. A total of 100 healthy subjects and 110 patients with ADHD were included in the study from which 72.7% of cases were male and 27.3% were female. Among the 100 controls, 55% were male and 45% were female. There was a significant difference in the allele frequency and genotype distribution of the FAAH rs2295633 between ADHD cases and controls. The ADHD children appeared to have less TT genotype and T allele. Thus, these data suggest that the FAAH rs2295633 SNP could serve as a possible marker for increased ADHD risk in Iranian children; future studies are warranted to explore the clinical utility of this marker.

Limitations

The studies had a few limitations. Firstly, the small sample size could have biased their results. Secondly, in regards to the self-report articles, bias could have occurred. Thirdly, in the cross-sectional questionnaire-based study published by Technion-Israel Institute of Technology in Israel due to their study design, they did not have access to patients’ data before initiation of MC treatment, making it impossible to draw causal conclusions.

Conclusion

In summary, ADHD is a common psychiatric disorder in the adult population that is frequently unrecognized, under-diagnosed, and under-treated. It is often comorbid with other psychiatric disorders. ADHD is associated with poorer academic performance and fewer friends during schooling years. ADHD continues through adulthood in 60–70% of cases (4–5% of adults) and causes significant functional disabilities including antisocial behavior, high rates of criminality, low job performance, and substance abuse. Although medical cannabinoids are not directly indicated for ADHD, low ADHD symptom frequency and ADHD medication-sparing effects were found to be associated with medical cannabinoids treatment. The neurobiology of ADHD is reported as being similar to other psychiatric conditions, such as bipolar disorder. Similar regions and circuitry in the brain are involved in both ADHD and other psychiatric disorders, notably the limbic–cortical–striatal– pallidal–thalamic (LCSPT) circuit. Neuronal activity within the LCSPT circuits is principally glutamatergic and is modulated by the gamma-aminobutyric acid (GABA) system. This LCSPT circuitry is additionally modulated by a variety of other neuromodulators, including endocannabinoids. How the endocannabinoid system may modulate the circuitry involved in both ADHD and comorbid psychiatric conditions remains to be elucidated. More preclinical and clinical research is warranted to establish the optimal levels of cannabinoids, terpenes, and dosing regimens, which vary between different ADHD patients.

Ahmadalipour A, Mehdizadeh Fanid L, Zeinalzadeh N, et al. The first evidence of an association between a polymorphism in the endocannabinoid-degrading enzyme FAAH (FAAH rs2295633) with attention deficit hyperactivity disorder. Genomics. 2020;112(2):1330‐1334. doi:10.1016/j.ygeno.2019.07.024

Hergenrather JY, Aviram J, Vysotski Y, Campisi-Pinto S, Lewitus GM, Meiri D. Cannabinoid and Terpenoid Doses are Associated with Adult ADHD Status of Medical Cannabis Patients. Rambam Maimonides Med J. 2020;11(1):e0001. Published 2020 Jan 30. doi:10.5041/RMMJ.10384

Hupli A, M, M: Medical Cannabis for Adult Attention Deficit Hyperactivity Disorder: Sociological Patient Case Report of Cannabinoid Therapeutics in Finland. Med Cannabis Cannabinoids 2018;1:112-118. doi: 10.1159/000495307