While ADHD affects many children and adolescents, 15% of them still meet full DSM-5 diagnostic criteria in adulthood.1 Untreated or under-treated ADHD can result in impaired quality of life, relationships, the ability to achieve or maintain employment, and driving safety. The disorder also puts individuals at increased risk of depression, anxiety, accidental death, and suicide.2,3

These concerns have led many patients and caregivers to seek out other means of symptom control, including cannabidiol (CBD) and/or cannabis. Here’s what recommending clinicians need to know.

 

Is CBD or Cannabis a Wise Choice for ADHD Treatment?

Current Medication Gaps

Since the 1930s, stimulants have remained the first-line pharmacotherapy for managing ADHD symptoms in both children and adults. Poor adherence to treatment, however, is an ongoing issue, often due to tolerance, stigma, and patient-specific barriers.1 Adverse effects (AE) of stimulants include insomnia, reduced appetite, nervousness, increased blood pressure, dry mouth, difficulty urinating, nausea, drowsiness, erectile dysfunction, and headache.2,3 Long-term stimulant use is associated with growth suppression, misuse/abuse potential, and sudden cardiac death. Alternative or new agents with increased tolerability, improved patient satisfaction, and long-term efficacy are desirable.1 CBD is one such proposed option.

CBD’s Therapeutic Properties & Risks

Preclinical studies have proposed that CBD possesses numerous potential therapeutic properties: anti-inflammatory, neuroprotective, analgesic, anticonvulsant, antioxidant, and more. Yet, research remains inadequate regarding the use of CBD to treat a range of psychiatric and neurologic conditions, ADHD included.

Pharmacokinetic and pharmacodynamic data illustrate the complexity of studying CBD given its variability in form and concentration – not to mention its lack of federal regulation which impacts quality and safety of the product across the country. For instance, the bioavailability of oral CBD is between 11% and 13%, while inhalational CBD has a 31% mean bioavailability. The half-life of oromucosal CBD ranges 1.4 to 10.9 hours but may last up to 5 days following chronic oral administration.4

In March 2020, an official FDA statement highlighted the intricacy of researching, regulating, and marketing CBD products.5

Potential harms associated with CBD include hepatotoxicity, damaged male fertility (per animal studies), altered cognition and mood, and gastrointestinal distress.5 Pediatric CBD trials most commonly report diarrhea, somnolence, and decreased appetite as adverse effects, although this data is poorly quantified.6

Caution should be taken with concurrent administration of CBD and medications that affect (or are affected by) CYP3A4, 2C19, and 2C9 enzymes.4 However, in vivo evidence to corroborate these metabolic drug-drug interactions is minimal.7 When considering CBD as an adjunctive ADHD therapy, clinicians should consider the potential drug-drug interaction with amphetamine, as in vitro data suggests one or more amphetamine metabolites act as mild CYP3A4 inhibitors.8

 

TABLE I: DRUG-DRUG INTERACTIONS INVOLVING CBD.7

P450 Enzyme Example Medications Effects
CYP3A4 substrate Benzodiazepines, z-hypnotics, opioids, certain antidepressants, antipsychotics Increased risk of substrate-mediated AEs
CYP3A4 inhibitor Protease inhibitors, ketoconazole, loperamide Increased risk of CBD-mediated AEs
CYP3A4 inducer Phenytoin, phenobarbital, carbamazepine, topiramate Decrease in therapeutic effects of CBD
CYP2C19 substrate Certain antidepressants, warfarin, antiepileptics, propranolol Increased risk of substrate-mediated AEs
CYP2C19 inhibitor Fluvoxamine, fluoxetine Increased risk of CBD-mediated AEs
CYP2C19 inducer Carbamazepine, phenobarbital, phenytoin, St. John’s wort Decrease in therapeutic effects of CBD
CYP2C9 substrate Buprenorphine, montelukast, naproxen, phenobarbital, phenytoin, warfarin Increased risk of substrate-mediated AEs

 

Cannabis’s Therapeutic Properties & Risks

Federally recognized as a Schedule I drug, cannabis is defined as any product containing greater than 0.3% THC (delta-9-tetrahydrocannabinol) according to the 2018 Agriculture Improvement Act. Oral or buccal spray cannabis is used as an analgesic and a treatment for rheumatoid arthritis or multiple sclerosis symptoms. Despite a lack of high-quality safety and efficacy data, medicinal cannabis is smoked for nausea, glaucoma, appetite stimulation, epilepsy, anxiety, Crohn’s, Lou Gehrig’s disease, and many other indications.9

Like CBD, the pharmacokinetics of cannabis are complicated by the variety of available forms. Vaporized THC is absorbed more rapidly than smoked. Absorption from any inhalational route ranges from 2% to 56% and peak plasma levels are achieved just 10 to 30 minutes after use. However, orally, peak plasma levels occur 1 to 6 hours after ingestion.9

The most common AEs of inhalational cannabis include headache, dizziness, drowsiness, fatigue, xerostomia, nausea, paranoia, and dissociation. Cannabis intoxication may result in impaired motor coordination and reaction time, blurry vision, panic, hallucinations, and emotional disturbances. Long-term cannabis use is associated with cognitive impairment, decreased memory, and increased risk of developing psychosis, seizures, cardiac arrhythmias, or myocardial infarction.9

The same CYP interactions presented above for CBD are also present for THC. Again, evidence for these interactions is limited (either anecdotal, theoretical based on pharmacology, or based solely on animal/in vitro studies).9

 

Evidence for CBD as an ADHD Treatment

Across all ages, a lack of evidence exists for assessing CBD or cannabis as a treatment for ADHD symptoms.  However, a few CBD trials have offered ADHD-related secondary outcomes or studied cannabis use in relation to ADHD. While causal relationships can therefore not be drawn between CBD or cannabis and behavioral, social, educational, or psychological changes seen (or not seen) in patients with ADHD patients, the following studies may be used for hypothesis-generating purposes.

Recreational Use: A late 1990s retrospective survey study investigated the influence of recreational inhalational cannabis on patients living with Tourette’s Syndrome (TS). Sixty-four patients were interviewed, seventeen (27%) self-reported past marijuana use. Most participants were male (n = 15) and smoked occasionally (n = 15), with a mean age of 30.5 years. Ten patients had comorbid ADHD, only one of whom reported a marked reduction in attention difficulties. This patient smoked three to four marijuana cigarettes/day on a regular basis. No patients reported worsening symptoms in response to smoking. Due to the use of DSM-III criteria, the waxing and waning disease course of TS, the lack of statistical data analyses, a very small sample size, and recruitment from a single European mood disorder clinic, generalizability is extremely limited.10

Medical cannabis and stimulants: In another study, adult Israeli patients with ADHD and an active medical cannabis (MC) license were surveyed regarding MC use, cannabis-related adverse effects, and comorbid psychiatric conditions. Multiple validated questionnaires, including the five-point ADHD self-report scale (ASRS), were used. Fifty-three patients completed the surveys and provided their MC monthly dose. Most smoked or vaped MC, and there was a wide duration of use. Sixteen (30%) participants used prescription stimulants as ADHD treatment. The high MC use subgroup self-reported greater incidence of ADHD pharmacotherapy discontinuation compared to those with low use (OR 5.8, 95% CI 1 to 60). When dividing the study sample into low ASRS score (score < 3.17, n = 30) and high (score > 3.18, n = 29), independent of high versus low use, the low score subgroup discontinued all ADHD medication at a greater rate (OR 0.22, 95% CI 0.04 to 0.84).3

MC-related adverse effects were reported by 15 participants and did not differ between high and low use subgroups. Adverse effects were documented by affected system: CNS (n = 7), gastrointestinal (n = 7), psychological (n = 6), cardiovascular (n = 3), ophthalmic (n = 3), musculoskeletal (n = 2), and auditory (n = 2). However, a list of specific AEs would have been most useful. Investigators concluded that an ADHD medication-sparing effect was associated with MC use in the study population.3

Oromucosal THC:CBD spray: Sativex oromucosal spray contains a 1:1 ratio of THC to CBD and was the focus of a double-blind, placebo-controlled RCT conducted at King’s College in London.9 Sativex is not FDA-approved for any indication, despite gaining approval in many countries in 2011 – 2012 as an adjunctive therapy for multiple sclerosis-associated neuropathic pain/spasticity and moderate to severe advanced cancer pain.7 The primary outcome was mean Quantitative Behavior Test (QbTest) score, a validated tool for analyzing cognitive performance in ADHD. Eligible adult participants attended baseline and 6-week follow-up evaluations. Patients stopped their prescribed stimulants one week prior to, and for the duration of, the study period. Participants using a non-stimulant ADHD medication were excluded. Also excluded where individuals with: a current or past diagnosis of manic depressive disorder, panic or anxiety disorders, bipolar I disorder, any psychotic disorder, obsessive compulsive disorder (OCD), TS, intellectual disability, known/suspected alcohol or substance use disorder, or a history of cardiovascular disease, renal disease, or hepatic dysfunction.11

The randomized patients (n = 30) were instructed to “spread doses throughout the day as best suited them.”  On average, patients in the treatment group used 4.7 sprays/day (range 1–13). There was no statistically significant difference between the Sativex and placebo groups in QbTest performance. One patient per arm suffered a serious adverse effect (muscle spasm/seizure in Sativex arm, tachycardia/chest tightness in control arm). Three Sativex-treated participants suffered mild adverse effects: lightheadedness (n = 2) and diarrhea (n = 1, resulting in therapy discontinuation for 4 days).11

Due to the small study sample, ADHD symptoms not being evaluated as the primary outcome, and most patients being able to correctly guess if they were on active treatment vs. placebo (93% and 85% respectively), this pilot trial has many weaknesses. A larger study that elucidates a proper dosing regimen should be pursued.11

CBD oil in adolescents: A randomized, controlled, double-blind, parallel-design pilot study evaluated the effects of CBD in patients age 8 to 16 with intellectual disability and severe behavioral problems. Eight participants received either oral placebo or 98% cannabidiol oil for 8 weeks. Dose titration occurred over 9 days to a target 20 mg/kg/day in two divided doses (max dose 500 mg). Three of four participants in the treatment arm and four of four participants in the control arm had an ADHD diagnosis.6

One participant in the placebo group used methylphenidate, one in the CBD group used guanfacine, and one per arm used clonidine. Notably, the aim was to assess feasibility of a large-scale version of this trial. All other outcomes were simply preliminary findings and not adequately powered to assess efficacy.6

Results did, however, indicate a greater reduction in baseline Aberrant Behavior Checklist Subscale (ABC-I) hyperactivity/non-compliance score in the treatment arm (mean reduction of 17 points) compared to placebo (mean reduction of 4.3 points). A clinically significant reduction was defined as a mean reduction of 7.9 points. No dose reductions were required in response to adverse events, nor were there any study withdrawals, serious adverse effects, or clinically significant abnormal lab values. Medication and study appointment adherence were 100% and all parents reported that they would recommend the study to families with children facing similar challenges.6

 

Bottom Line: No Clear Answer on Use for ADHD

An easily accessible, product-rich marketplace of over-the-counter CBD is at the fingertips of patients living with ADHD, and regulations regarding medical/recreational cannabis use have loosened across many states. Yet, there is little supportive evidence regarding safe and efficacious use of these substances for ADHD management. In the pool of outcome data presented herein, no adults and just seven pediatric patients with ADHD have undergone an experimental CBD study,­ making a well-informed risk versus benefit comparison nearly impossible. Similarly, THC is not well-studied in patients with ADHD.

Clinicians may do well to consider other options for the management of ADHD symptoms in adolescents and adults, but should be prepared to discuss the limitations of CBD and cannabis with inquiring patients or caregivers.

 

Related Articles

More on the risks of marijuana use in patients with schizophrenia, and on the external factors associated with ADHD assessments.

Psychosis and CannabisADHD Assessments
References
Last Updated: Oct 28, 2020