The conversation about cannabis has taken a leap forward: today it's not enough to talk about effects, we also look at the genes that modulate the organism's response and the metabolic pathways that transform cannabinoids. Understanding both pieces of the puzzle helps explain why some people are more vulnerable to cannabis use disorder, why THC "hits" some people more than others, and how it is detected in blood, saliva, urine, or hair after different periods of time.
In addition, alongside clinical science, there are communities and outreach spaces where advances in areas as varied as astronomy, biology, medicine, physics, and social sciences are shared—an ecosystem that accelerates the exchange of findings and brings current research to the publicOn this fertile ground, evidence about the endocannabinoid system, genetics, and cannabis metabolism continues to grow.
Genetics and susceptibility: from the nicotinic receptor to the endocannabinoid system
The heritability of cannabis use disorders is significant: twin studies estimate that genetics explains a substantial part of the vulnerability to developing dependence. Among the markers that have gained prominence are CHRNA2, a gene linked to the nicotinic receptor, whose association with cannabis use disorder was identified in a large Danish sample and replicated in an Icelandic cohort of thousands of cases and hundreds of thousands of controls.
The relevance of CHRNA2 is not anecdotal: between 70% and 90% of those who have problems with cannabis also smoke cigarettes, suggesting a biological intersection between nicotine and cannabisRisk variants in this gene have also been linked to a higher likelihood of psychosis, bipolar disorder, anxiety, and lower cognitive performance.
The endocannabinoid system also comes into play. Variations in CNR1 (CB1 receiver) and in FAAH (an enzyme that degrades endocannabinoids such as anandamide) can modulate both the response to the plant's cannabinoids and the likelihood of dependence. In practice, small differences in these genes can translate into changes in the intensity of the effect, tolerance, and the likelihood of developing a problematic pattern of use.
The genetic component doesn't act in isolation; it interacts with the environment. Age of onset, access to high-potency products, stress, social support, and tobacco use all shape the final risk. In other words, an inherited predisposition can be amplified or mitigated depending on the context, and this interaction... gene-environment explains a large part of individual variability.
Endocannabinoid system: what links genetics, metabolism and effect
The endocannabinoid system (ECS) is the architecture upon which cannabis acts: CB1 and CB2 receptors, endogenous ligands such as anandamide (AEA) and 2-AGand enzymes such as FAAH and MAGL that synthesize and degrade these messengers. Their distribution is wide: brain, peripheral tissues, immune system, digestive system, pancreas, adipose tissue, and liver, among many others.
CB1 receptors, which are very abundant in the brain, modulate neurotransmitter release by inhibiting adenylate cyclase, thereby reducing neuronal excitability. In parallel, CB2 receptors are more common in immune cells and peripheral tissues. This network participates in processes ranging from metabolism and appetite regulation to mood, inflammatory response, sleep, or body temperature.
Hence, the endocannabinoid system (ECS) is also relevant to weight and energy balance. Activation of CB1 receptors in hypothalamic and mesolimbic circuits promotes appetite, while blocking it reduces it. And regarding CBD: despite the internet trend, any weight loss associated with cannabidiol is... indirect and modulated by multiple factorsnot a simple or guaranteed consequence of its use.
THC metabolism and company: from the liver to the urine test
After absorption, THC is primarily metabolized in the liver by cytochrome P450, with particular emphasis on CYP2C9This enzyme converts THC into 11-hydroxy-THC (11-OH-THC), an active and highly psychoactive metabolite, which is then transformed into the inactive 11-nor-9-carboxy-THC (THC-COOH). Because THC-COOH is lipophilic and accumulates in tissues, it persists and can be detected in urine for days or weeks, especially in frequent users.
Interactions between cannabinoids also play a role. CBD can influence THC metabolism, affecting its conversion to 11-OH-THC and, consequently, modulating the intensity of the psychoactive effects and its duration. These interactions are one of the reasons why different THC:CBD ratios change the effect profile and tolerability.
The route of administration affects bioavailability and the onset of effects. When inhaled, THC reaches the bloodstream and brain quickly; when taken orally, it undergoes first-pass metabolism, delaying the peak and the exposure to 11-OH-THC It is usually higher, which explains the longer and sometimes less predictable effects in edibles.
Preparation methods and consumption routes
The market and traditional uses offer many presentations, with significant differences in potency and duration. In short, these are the most common, each with an effect profile that depends on the THC concentration, terpene content, and the proportion of other cannabinoids such as CBD: The choice of form and dosage is crucial..
- Dried marijuana: cured inflorescences and aerial parts.
- Hashish: pressed resin rich in trichomes.
- Oils and resins: concentrated extracts with high potency.
- Edibles and dyes: slower and longer effects via the oral route.
- Less common routes: sublingual, buccal, rectal; different absorption profile.
In recent decades, genetic selection and cultivation techniques have led to varieties with significantly higher THC content. This increases the risk of adverse effects, especially in users with no tolerance or with predisposition to psychotic or anxiety disorders.
Effects, risks, and modulating factors
In the short term, cannabis can cause tachycardia, red eyes, dry mouth/pharynx, altered time perception, euphoria or anxiety, and impaired working memory and attention. At high doses or with very potent products, there are also motor incoordination and slowed reaction time, risk factors in driving or operating machinery.
Prolonged and frequent use can lead to subtle cognitive problems, impaired coordination, and in some individuals, cannabinoid hyperemesis syndrome (recurrent episodes of nausea and vomiting). Combining it with alcohol increases these risks, as does driving under the influence of THC. increases the probability of an accident.
On the cardiovascular front, THC can initially raise heart rate and blood pressure, followed by vasodilation and orthostatic hypotension. In individuals with uncontrolled heart disease, arrhythmias, myocarditis, and even myocardial infarction have been reported; therefore Clinical caution is mandatory if there is a history of coronary events.
Neurologically and psychiatrically, CB1 activation can alter memory, perception, and movement, with relatively frequent anxiety reactions. At high doses, and especially with a predisposition or family history, episodes of paranoid ideation, hallucinations, and other symptoms have been documented. self-limiting psychotic episodesIntense and early exposure in adolescents is associated with a higher risk of psychotic disorders.
Individual genetic variation adds layers to this picture: variants in CNR1 or FAAH can modulate the threshold for adverse effects, and the presence of the risk allele in CHRNA2, combined with nicotine use and environmental stressors, contributes to differentiated risk trajectories between individuals.
Therapeutic uses and medicines based on cannabinoids
The Spanish regulatory framework under discussion stipulates that cannabis preparations for medical purposes will be limited to compounded medications in hospital pharmacy and specific indications (e.g., spasticity in multiple sclerosis, refractory epilepsy, chemotherapy-induced nausea, or resistant chronic pain). The regulatory agency would maintain a register of standardized preparations, guaranteeing quality and traceability.
There are drugs approved in different countries: dronabinol and nabilone (THC analogues) for chemotherapy-induced nausea and HIV/AIDS-associated anorexia; purified cannabidiol (Epidiolex) for specific epileptic syndromes; and nabiximols (Sativex)A fixed-ratio THC:CBD product is used for spasticity due to multiple sclerosis in several jurisdictions. Availability varies by country, and its use requires individualized evaluation.
Clinical evidence is heterogeneous. A large report by US scientific academies concluded that there is strong evidence for spasticity in MS, chemotherapy-induced nausea, and chronic pain in adults, while the IASP questions its usefulness in neuropathic pain. The AAN endorses its use in MS for spasticity/pain, and a BMJ guideline recommends cannabis/non-inhaled cannabinoids as a third-line treatment when standard therapies fail. prudent titration of CBD (e.g., 5 mg twice daily) and gradual adjustment of THC depending on response and tolerance.
In chronic non-cancer pain, osteoarticular pain, or fibromyalgia, the results are mixed, and better-designed trials with longer follow-up are needed. As a potential advantage, in selected contexts, the use of medicinal cannabis has been associated with opioid dose reduction in some patients, although it is not a universal finding.
Screening tests, medical and forensic scenarios
When and why is it analyzed? In emergency medicine, pregnancy and peripartum, initiation of complex treatments (e.g., chronic pain or cancer), rehabilitation programs, disability assessment, traffic accidents, and job screening or pre-employmentIt is also used to monitor compliance with prescribed cannabinoid treatments.
The most common sample is urine; saliva (increasingly used in work or traffic settings), blood, and hair can also be used. In newborns, umbilical cord blood or meconium are used. For saliva samples, it is recommended not to eat or use mouthwash for 10 minutes beforehand; and in all cases, this is key. Reporting medication or medicinal cannabis to interpret results.
Cutoff values ​​are applied in urine (usually 50 ng/mL for THC-COOH). Rapid screening provides a preliminary result; if positive, it is confirmed with GC-MS or LC-MS/MSHighly specific techniques that minimize false positives. A confirmed positive indicates the presence of THC or metabolites at the time of ingestion, but does not allow inference of the dose consumed, the exact time of use, or the degree of functional impairment.
- Quick tests: strips or immunoassays with presumptive value.
- Confirmatory: GC-MS or LC-MS/MS as reference standard.
False positives in screening are now infrequent with modern methods; drugs like ibuprofen, once problematic, are no longer problematic in confirmatory tests. Chronic use prolongs the detection window (weeks in urine), while in occasional users it is usually limited to several days after the last consumptionThe tests do not differentiate between recreational and medicinal cannabis, nor do they distinguish between natural THC and synthetic pharmaceutical forms (e.g., dronabinol).
In forensic and occupational contexts, collection is carried out with a "chain of custody": sample sealing, documentation, and legal traceability. To prevent substitutions or adulteration, in some cases, further action is required. direct observation of urinationIf a sample is found to be adulterated or diluted, it is reported as invalid.
In roadside checks, saliva testing has become the preferred method due to its speed and less invasive nature, although the actual effect of THC on cognitive and motor skills varies between individuals. Passive exposure to smoke in very enclosed and poorly ventilated spaces could cause sporadic positive results, although the risk under normal conditions is low with adequate ventilation.
Important: Illicit synthetic cannabinoids (K2, Spice) are not THC and are not detected by specific tests for THC/THC-COOH; they require special panels. Furthermore, they exhibit more severe toxicity profiles (seizures, arrhythmias, encephalopathy), therefore its consumption entails particular risks.
Policies, product power and regulatory context
In the EU, products with very low THC (0,2%-0,3%) are marketed under regulated conditions for specific purposes, although regulations vary by country. The cultivation of industrial hemp (textiles, food, cosmetics) is subsidized, but the framework for human use requires... strict controls and standardsNational differences create regulatory mosaics and security challenges.
Spain registers high consumption among young people, which increases the risk of mental disorders in adolescentsPossession or consumption in public spaces carries administrative penalties and fines depend on the substance, quantity and circumstances (e.g., sale to minors). The National Strategy on Addictions 2017-2024 It prioritizes delaying the age of onset, reducing availability and harm, with a focus on educational prevention and access to evidence-based treatments.
As a regional benchmark, Colombia has defined licenses and processes for the medicinal cannabis industry, with regulatory progress but a need to consolidate implementation, healthcare training, and clinical acceptance. The sector's development requires alignment between regulator, academia and industry to guarantee safety, quality and access.
Where to find information and what to keep in mind
The quality of the evidence varies. Many trials have been short, with small sample sizes, or biased; better and longer studies are needed to refine efficacy and safety by indication. Reliable resources from health and scientific agencies (ministries of health, national institutes of health, regulatory agencies, toxicology societies) provide updated information on therapeutic uses and risksBeware of unregulated oils or extracts: they may have varying potency, traces of THC, and contaminants (pesticides, molds, bacteria) if they do not undergo controls.
The relationship between genetics and cannabis metabolism is complex but clear in its main points: there are genetic variants (CHRNA2, CNR1, FAAH, among others) that determine vulnerability and response; the endocannabinoid system (ECS) explains how cannabinoids act; and the liver, via CYP2C9, transforms THC into metabolites with varying activity that determine the duration of the effect and the detection window. Adjusting expectations, using with caution in vulnerable populations, and relying on evidence and regulation are crucial. It makes the difference between safer use and high-risk use..
