Bridging THC Knowledge Gaps for Safer Roads: A Call for Action

Abstract

The rising cases of cannabis‐impaired driving present a looming public safety concern that's currently addressed through varying state regulations. However, these regulations are yet validated and lack scientific robustness. One of the roadblocking factors is our insufficient understanding of THC's pharmacokinetics (PK) and pharmacodynamics (PD) due to limited clinical data. Therefore, we call for joint efforts among researchers and policymakers to conduct more comprehensive cannabis PK/PD studies to improve and validate existing cannabis driving regulations.

A pattern throughout human history is our tendency to discover and use psychoactive substances for their effects, whether medicinal, ritualistic, or recreational, well before we understand their underlying mechanisms. Cannabis stands as a classic example of this historical pattern.

First appearing in the Chinese pharmacopeia Pen Ts'ao in 2700 B.C., cannabis was initially recognized for its therapeutic applications like pain relief and appetite stimulation, long before its psychoactive effects were extensively documented. But times change, and so has cannabis use. The 20th century brought major cultural and social shifts, especially in Western societies, where cannabis gradually moved from the medicine shelf to recreational use. Yet, despite humans having used cannabis for millennia, we still lack sufficient pharmacokinetics (PK) and pharmacodynamics (PD) data to fully characterize its main psychoactive compound, Δ‐9‐tetrahydrocannabinol (THC).

But this knowledge gap hasn't slowed the cannabis policy evolution in the United States. By 2024, 24 states have fully legalized cannabis use, reflecting increased recreational consumption. The policy changes have outpaced our scientific understanding of THC, especially in the context of cannabis‐impaired driving. Although findings on crash risk post‐legalization remain mixed, cannabis‐involved traffic incidents have increased. ¹ This trend highlights the pressing need for evidence‐based policies to address this public safety concern.

Current approaches to cannabis‐impaired driving vary considerably across states and fall into three categories: effect‐based laws, zero‐tolerance policies, and per se limits. Most states use effect‐based laws that depend on observable signs of impairment. Other states enforce either zero‐tolerance policies that prohibit any detectable THC or per se laws that establish specific blood concentration limits (1–5 ng/mL) for THC and its metabolites, with exceeding these limits constituting driving under the influence (DUI). While per se limits mirror alcohol‐related driving laws, they overlook THC's complex PK/PD properties. Unlike alcohol, where blood concentrations reliably predict impairment, THC's effects on driving ability are more complicated and not yet fully understood.

In our recently published work, ² our group tried to apply pharmacometrics modeling to bridge this THC PK/PD knowledge gap. We built a semi‐mechanistic population PK model using THC and its metabolites' PK data from published literature and conducted large‐scale Monte Carlo simulations to assess current per se limits. ² While our model was robust, we couldn't draw definitive conclusions about the 2 and 5 ng/mL per se limits due to limited data linking PD effects with PK profiles.

This work revealed something important: we have the right tools to solve the remaining puzzles of THC PK/PD – what we lack is sufficient data. This realization drives our call for more comprehensive cannabis research. Building a broader database would accelerate our understanding of how THC affects driving ability and help refine current laws to make roads safer.

CHALLENGES IN CANNABIS‐IMPAIRED DRIVING ASSESSMENT

THC route‐dependent PK

Cannabis administration routes greatly influence how THC affects the body. Inhalation and oral consumption, the two most common routes, produce different PK profiles. ³ Inhaled THC demonstrates rapid absorption, reaching peak blood concentrations within 3–10 minutes. ³ This creates a sharp THC concentration spike followed by rapid distribution and decline. In contrast, orally consumed THC is absorbed slower, with peak blood concentrations reached in 1.5–3 hours. ⁴ It undergoes extensive first‐pass metabolism, which generates large quantities of 11‐hydroxy‐Δ9‐tetrahydrocannabinol (11‐OH‐THC), a psychoactive metabolite that also contributes to impairment. ³ Studies have shown that oral administration can produce an 11‐OH‐THC/THC ratio as high as 1.5. ³

These route‐dependent differences complicate impairment assessment. For example, at equal doses, oral users may have lower THC blood concentrations than smokers due to the first‐pass metabolism. But that does not mean oral users are less intoxicated, as they present slower absorption time and higher 11‐OH‐THC levels.

THC usage‐pattern‐dependent PK

THC's lipophilicity creates complex distribution patterns that vary with usage frequency. Following ingestion, THC rapidly distributes into adipose tissue, creating a depot for long‐term storage and gradual release. ³ While this may not largely affect occasional users, studies reported that frequent users have a terminal half‐life of 4 days, with THC levels detectable up to 30 days after cessation. ⁵ Hence, regular cannabis users often maintain baseline blood THC concentrations even during abstinence periods, potentially exceeding per se limits without active use or acute impairment.

THC PK‐PD disconnect

The relationship between blood THC concentrations and functional impairment presents another challenge to current assessment methods. THC exhibits hysteresis relationships between blood concentrations and effects. This disconnect is particularly relevant since THC's main target, the endocannabinoid receptors in the central nervous system, mediate THC's psychoactive effects on cognitive function and motor control. Forensic study has found that brain tissue THC concentrations remained elevated even after blood concentrations became undetectable. ⁶ This disconnect creates scenarios where individuals may be impaired despite blood THC concentrations below per se limits, or conversely, exceed limits despite minimal functional impairment.

Real‐world cannabis product challenge

Cannabis products in today's market, whether homemade, illicit, or even legal full‐spectrum products, often lack consistent quality control and standardization, which introduces additional challenges for impairment assessment. These unregulated products usually contain varying concentrations of different cannabinoids and terpenoids that interact with THC through what's known as the “entourage effect”, which could affect impairment differently than THC alone. Many users don't know exactly what's in their cannabis products, which sometimes leads to unexpected levels of impairment. When cannabis products contain varying amounts of these compounds, it becomes challenging to create consistent standards for measuring driving impairment.

CURRENT REGULATORY APPROACHES AND THEIR LIMITATIONS

Effect‐based Laws

Most states assess cannabis‐impaired driving through effect‐based laws, where officers often use field sobriety tests (FSTs) to look for visible signs of impairment. While FSTs have proven useful in identifying psychomotor impairments, they were initially validated for alcohol detection, not cannabis. Although some signs of impairment overlap between alcohol and cannabis, cannabis affects the body in more complex ways that FSTs might miss. Recent research has found that FSTs alone may be insufficient in detecting cannabis impairment. ⁷ Without validated roadside tests, officers have to rely on their training and experience rather than objective measures to ensure consistent enforcement.

Zero‐tolerance policies

Some states have adopted zero‐tolerance laws that make it illegal to drive with any detectable THC or its metabolites in a driver's system. While straightforward to enforce, these laws overlook a critical issue: THC's extended detection window after the effects wear off due to its adipose disposition. Studies reported that frequent users can have detectable blood THC levels for up to 30 days after abstinence. ⁵ This creates false‐positive challenges, particularly for frequent users who might test positive under zero‐tolerance rules days or even weeks after use, despite being capable of driving safely. By focusing on presence rather than impairment, zero‐tolerance may unfairly penalize drivers who are no longer under the influence.

Per se limits

Several states (Illinois, Montana, Nevada, Ohio, Pennsylvania, and Washington) employ per se limits that set blood THC thresholds at 1, 2, or 5 ng/mL to define impairment. While this mirrors the approach used for alcohol, this method is not fully validated and has faced criticism for its inaccuracy. Our recently published work evaluating these limits in oral cannabis users found that the 1 ng/mL threshold was particularly ineffective, while the effectiveness of the 2 and 5 ng/mL thresholds remains unclear due to insufficient data linking blood levels to actual impairment. ²

Also, as previously discussed, THC blood concentrations correlate poorly with impairment for several PK/PD factors. First, consumption methods affect THC PK: oral users produce higher levels of the psychoactive metabolite 11‐OH‐THC while showing lower THC levels compared to smokers, ³ potentially causing false negatives for oral users under per se limits. Second, frequent users maintain detectable THC blood levels for up to 30 days, ⁵ creating a high risk of false positives. Third, the disconnect between blood concentrations and cognitive effects makes it challenging to establish appropriate per se thresholds to accurately capture acute impairment. Therefore, using blood THC levels alone as evidence for cannabis DUI may not provide a fair basis for conviction.

Sampling and testing limitations

While alcohol can be reliably measured through roadside breath testing, the current gold standard for THC assessment is a blood test. The time delay between a traffic stop and blood collection could affect THC blood concentration. Depending on the route of administration and formulation type, THC's rapid distribution and disconnect between PK and PD mean that the blood concentrations at testing might not accurately reflect the degree of impairment at the time of the traffic stop.

MOVING FORWARD: SCIENCE TO POTENTIAL SOLUTIONS

Advancing cannabis research

Comprehensive pharmacological studies are essential to better characterize THC's effects on driving impairment. These studies should look at THC and its metabolites across multiple biological matrices to establish clear relationships between drug concentrations and impairment. As we have already known that no single measurement tells the whole story. Future studies should prioritize the variations of PK and PD between smokers and oral users, regular users and occasional users, and among a wide range of doses.

Researchers are pursuing several promising approaches. Some studies measure standard deviation of lateral position (SDLP) using advanced driving simulator after cannabis use to directly assess driving performance, while others apply SDLP metrics in on‐the‐road studies to capture real‐world impairment. ⁸ , ⁹ Others use functional near‐infrared spectroscopy (fNIRS) to observe brain activity changes that might not be visible in behavior. ¹⁰ When combined with PK data including doses, routes, and population demographics, these PD measurements become especially insightful for pharmacometrics modeling to predict impairment probabilities. Also, large‐scale simulations could explore scenarios across diverse populations and usage patterns. These researches together could result in pooled data that are particularly valuable given the practical and ethical constraints of large‐scale THC research, and eventually pave the path to tailored insights into THC's impact on driving ability.

Improving impairment detection methods

Current impairment detection methods fall short of what we need. Looking ahead, instead of focusing on THC and its metabolites concentrations, the future detection methods could potentially combine real‐time roadside detection of THC and its metabolites with measures of cognitive function. For example, AI‐driven analysis of eye movements is a promising technology. Though rigorous validations are warranted, the development of next‐generation detection tools would represent a groundbreaking step forward in identifying drivers who are genuinely impaired by cannabis use.

Standardizing cannabis products

Product inconsistency remains a major hurdle in assessing cannabis impairment. We need standardized products with reliable doses, and detailed cannabinoid and cannabidiol profiles. A good first step would be agreeing on a standard THC unit, where researchers suggest 5 mg as a reference point. ¹¹ This conservative recommendation makes sense given that studies show 10 mg THC typically causes minimal impairment, making 5 mg a safer baseline. ⁴

The path forward will require innovative and targeted collaboration between researchers, policymakers, and law enforcement. Cannabis laws and use are changing fast, and we need to act quickly to keep our roads safe. We call on researchers worldwide to conduct comprehensive PK/PD studies across diverse cannabis user populations, product types, and dosing regimens. By pooling these findings in a global database, we could leverage data from a wide range of scenarios to better understand cannabis impairment. This would strengthen evidence‐based regulations and help refine existing cannabis‐impaired driving laws.

CONFLICT OF INTEREST

The authors declared no competing interests for this work.