What are the long-term effects of Cannabidiol (CBD) and Tetrahydrocannabinol (THC) on brain health and cognitive function, particularly in older adults or individuals with pre-existing neurological conditions?

Long-Term Effects of CBD and THC on Brain, Cognition, and Functionality

Chronic cannabis use, particularly THC, carries significant long-term psychiatric risks including increased risk of depressive disorders, cannabis use disorder (10% of chronic users), and cognitive impairment, while CBD appears to have a more favorable safety profile with potential neuroprotective effects, though evidence for cognitive enhancement remains limited to preclinical studies. 1

THC: Established Long-Term Risks

Cognitive and Neurological Effects

• THC induces documented neurotoxicity with cell death, neuronal shrinkage, and DNA fragmentation specifically in the hippocampus, a critical region for memory formation 2
• Cognitive deficiencies persist after withdrawal, indicating potentially lasting damage 2
• Memory impairment and difficulties with concentration are hallmark effects that may not fully resolve 2
• The average THC concentration has nearly doubled from 9% in 2008 to 17% in 2017, substantially elevating risk profiles 3

Psychiatric Consequences

• Chronic cannabis use is strongly associated with increased risk of developing depressive disorders and may exacerbate psychiatric conditions in vulnerable individuals 1
• Early onset of cannabis use, especially weekly or daily use, strongly predicts future dependence 1
• Ten percent of adults with chronic cannabis use develop cannabis use disorder, characterized by using more than intended and difficulty cutting back 1
• A randomized trial found participants receiving medical cannabis cards had nearly twice the incidence of cannabis use disorder (17% vs 9%) within 12 weeks compared to controls 1

Withdrawal and Dependence

• Long-term daily cannabis users experience withdrawal symptoms after cessation including irritability, restlessness, anxiety, sleep disturbances, appetite changes, and abdominal pain 1
• Symptoms typically occur within 3 days of cessation and may last up to 14 days 1

Other Long-Term Risks

• Cardiovascular effects may include arrhythmias and orthostatic hypotension, though no evidence links cumulative lifetime use with higher cardiovascular disease incidence or mortality 1
• Respiratory effects remain unclear due to conflicting data, often confounded by concomitant nicotine use; association with impaired lung function, asthma, COPD, and pneumonia risks is uncertain 1
• Oncologic risk: No clear evidence demonstrates cannabis inhalation increases lung cancer risk, though a possible link with testicular cancer exists 1
• Cannabinoid hyperemesis syndrome develops after long-standing use (>4 times per week for over a year), characterized by cyclical emetic episodes 1

CBD: More Favorable but Limited Evidence

Safety Profile

• CBD demonstrates a favorable safety and abuse liability profile with no acute psychotropic effects 4, 5
• Hepatotoxicity risk is negligible at doses below 300 mg/day with no reported cases 6
• Common side effects at therapeutic doses include dizziness, confusion, dry mouth, and fatigue 6

Cognitive Effects: Preclinical Promise vs Clinical Reality

• Preclinical studies show evidence for improved cognitive performance with CBD, but clinical studies have not replicated these findings 4
• A 4-week randomized controlled trial of 200-800 mg daily CBD in cannabis users found no effect on delayed verbal memory (primary outcome) 7
• The same trial showed 800 mg CBD may improve working memory manipulation (backwards digit span), but no broad cognitive effects were observed 7
• An open-label 10-week trial of 200 mg daily CBD in regular cannabis users showed improvements in attentional switching, verbal learning, and memory, with reduced depressive and psychotic-like symptoms 8
• However, the open-label trial lacked placebo control, limiting interpretation 8

Potential Therapeutic Applications

• CBD has demonstrated analgesic, anxiolytic, anti-inflammatory, antipsychotic, and anticonvulsant effects in animal and limited human studies 4
• Growing evidence supports CBD use for neurological disorders including epilepsy, multiple sclerosis, Parkinson's disease, and Alzheimer's disease 4, 5
• Only pharmaceutical-grade CBD (Epidiolex) is FDA-approved for seizure disorders, not THC-containing products 3

Critical Drug Interaction Concerns

Both CBD and THC

• CBD inhibits multiple cytochrome P450 enzymes (CYP3A4, CYP2C9, CYP2C19), leading to significant drug interactions 6
• Very high-risk interaction with warfarin; high-risk interactions with buprenorphine and tacrolimus 6
• Studies describe a small risk of significant drug interactions with drugs metabolized by P-450 systems 1
• No contraindications exist for perioperative use with NSAIDs, opioids, local anesthetics, ketamine, gabapentinoids, dexmedetomidine, or acetaminophen 1

Population-Specific Risks

Adolescents and Young Adults

• Adolescents face elevated risks including neurodevelopmental decline and should avoid cannabis use entirely 3
• Age of first use is critical, with early onset strongly predicting dependence and cognitive impairment 1

Driving Safety

• Cannabis users are more than twice as likely to be involved in motor vehicle crashes 1
• Fatal motor vehicle accidents involving cannabis alone increased from 9.0% in 2000 to 21.5% in 2018 1
• Higher blood levels of cannabis are associated with increased risk of fatal accidents, especially when co-involving alcohol 1

Clinical Pitfalls to Avoid

• Unregulated cannabis products lack standardization, making risk profiles unpredictable 3
• Cannabis concentrates with THC levels up to 70% pose substantially higher risks than traditional plant material 3
• Medical marijuana has NOT been FDA-approved for any indication despite state-level legalization 3
• Patients may be reticent to discuss cannabis use due to stigma in healthcare settings 1
• The delayed onset of oral CBD (≥1 hour) can lead to "stacking doses" before the first dose takes effect, causing excessive side effects 6