ABSTRACT

As cannabis/marijuana is one of the most consumed psychoactive substances in the world, knowing the composition and type of cannabis sold in urban environments is a necessary input for the design of public health policies based on scientific evidence. This study characterized the main phytocannabinoids of marijuana samples (cigarettes or buds) obtained in urban and rural areas of the city of Medellín in October 2021. Non-probabilistic convenience sampling was carried out in which 87 marijuana samples donated by consumers were collected at different collection points throughout the city, and gas chromatography-mass spectrometry and flame ionization techniques were employed for the characterization of phytocannabinoids. Tetrahydrocannabinol (THC) was found to be the main constituent of circulating marijuana in Medellín, where 67.8% of the samples had a high or higher toxicological range for THC; the foregoing in a context where the deregulated market in practice limits the possibility that consumers have to calibrate or decide the concentration of cannabinoids in their doses.

KEY WORDS:
Cannabis; Cannabinoids; Tetrahydrocannabinol; Cannabidiol; Colombia

INTRODUCTION

Cannabis Sativa L, also known as cannabis or marijuana, is an ancient plant that is today cultivated all around the world. It has been widely used for both medicinal and recreational purposes. As per the United States Code, the term cannabis or marijuana refers to all parts of the Cannabis L. plant, whether growing or not, including the seeds, resin extracted from any part of the plant, and any compound, manufacture, salt, derivative, mixture, or preparation of the plant, its seeds, or resin.¹1. United States Government Publishing Office. United States Code, 1994 Edition, Supplement 5, Title 21 - Food and drugs [Internet]. 2000 [citado 3 dic 2022]. Disponible en: Disponible en: https://tinyurl.com/49vvrnsr .
https://tinyurl.com/49vvrnsr... This plant belongs to the Cannabaceae family, and according to the most recent classifications, it is known to have around 170 species.²2. McPartland JM. Cannabis systematics at the levels of family, genus, and species. Cannabis and Cannabinoid Research. 2018;3(1):203-212. doi: 10.1089/can.2018.0039.
https://doi.org/10.1089/can.2018.0039.... The Cannabis species is the most well-known, capable of synthesizing approximately 565 substances, 120 of which are molecules with a terpenophenolic skeleton consisting of 21 carbon atoms called phytocannabinoids. The cannabinoid found in the highest proportion in the plant is delta 9-tetrahydrocannabinol (Δ9-THC or THC) and it is responsible for the majority of the psychoactive effects of cannabis. Other phytocannabinoids that also exhibit psychotropic activity but are present in lower proportions in the plant material include cannabivarin (THCV) and CBN, the latter being evaluated in this study as a marker of THC oxidation. There are also other cannabinoids found in the plant, such as cannabidiol (CBD), cannabichromene (CBC), and cannabigerol (CBG), which do not have psychoactive effects and can be found in varying concentrations depending on the strain.³3. Rock EM, Parker LA. Constituents of Cannabis Sativa. En: Murillo-Rodriguez E, Pandi-Perumal SR, Monti JM, eds. Cannabinoids and neuropsychiatric disorders. Cham: Springer International Publishing; 2021 p. 1-13.^,44. ElSohly MA, Radwan MM, Gul W, Chandra S, Galal A. Phytochemistry of Cannabis sativa L. En: Kinghorn AD, Falk H, Gibbons S, Kobayashi J, eds. Phytocannabinoids. Cham: Springer International Publishing; 2017. p. 1-36.

Cannabis is native to tropical environments in central and eastern Asia and has been used by humans since ancient times, adapting to different climatic conditions. Today it is a crop that spans a large part of the world.⁵5. Rocha ED, Silva VE, Pereira FC, Jean VM, Souza FLC, Baratto LC, et al. Qualitative terpene profiling of Cannabis varieties cultivated for medical purposes. Rodriguésia. 2020;71:e01192019. doi: 10.1590/2175-7860202071040.
https://doi.org/10.1590/2175-78602020710... When cannabis is consumed, it activates the receptor system and neurotransmitters within the body called the endocannabinoid system (ECS). The THC cannabinoid binds to CB1 and CB2 receptors, generating a wide range of effects, some more desirable than others. For example, THC can help reduce pain and improve appetite; however, it can also cause paranoia and anxiety. On the other hand, CBD reduces the signaling of endocannabinoids, a response that in turn depends on the dose as it binds to the allosteric site of the CB1 receptor, altering the potency of other primary ligands and producing opposite effects.⁶6. Lu H-C, Mackie K. An Introduction to the Endogenous Cannabinoid System. Biological Psychiatry. 2016;79:516-525. doi: 10.1016/j.biopsych.2015.07.028.
https://doi.org/10.1016/j.biopsych.2015.... ^,77. Chye Y, Christensen E, Solowij N, Yücel M. The endocannabinoid system and cannabidiol’s promise for the treatment of substance use disorder. Frontiers in Psychiatry. 2019;10:63. doi: 10.3389/fpsyt.2019.00063.
https://doi.org/10.3389/fpsyt.2019.00063...

The most notable psychotropic effects reported by recreational users of THC include pleasure, relaxation, happiness, and increased sensory perception, among others.⁸8. Gonzalez R. Acute and non-acute effects of cannabis on brain functioning and neuropsychological performance. Neuropsychology Review. 2007;17:347-361. doi: 10.1007/s11065-007-9036-8.
https://doi.org/10.1007/s11065-007-9036-... However, these effects are accompanied by undesirable effects on the central nervous, respiratory, and cardiovascular systems and certain psychiatric conditions such as depression, sedation, psychotic symptoms, increased cardiovascular activity, exacerbation of preexisting mental illnesses, and symptoms of dependence.⁹9. Cohen K, Weizman A, Weinstein A. Positive and negative effects of cannabis and cannabinoids on health. Clinical Pharmacology and Therapeutics. 2019;105(5):1139-1147. doi: 10.1002/cpt.1381.
https://doi.org/10.1002/cpt.1381....

The amount of THC in cannabis samples may decrease through interconversion to cannabinol (CBN), a cannabinoid that is not naturally present in the plant and with very low psychoactive potency, generated through heating or oxidation of the plant material. High concentrations of CBN in cannabis samples may indicate prolonged storage or mishandling of the sample.¹⁰10. Meija J, McRae G, Miles CO, Melanson JE. Thermal stability of cannabinoids in dried cannabis: a kinetic study. Analytical and Bioanalytical Chemistry. 2022;414:377-384. doi: 10.1007/s00216-020-03098-2.
https://doi.org/10.1007/s00216-020-03098...

Regarding the cannabinoid CBD, plant extracts and derivatives rich in this cannabinoid have been used in therapies for chronic pain, respiratory diseases, certain types of cancer, and cardiometabolic risk, among other conditions.¹¹11. Abrams DI. The therapeutic effects of Cannabis and cannabinoids: An update from the National Academies of Sciences, Engineering and Medicine report. European Journal of Internal Medicine. 2018;49:7-11. doi: 10.1016/j.ejim.2018.01.003.
https://doi.org/10.1016/j.ejim.2018.01.0... The variation in effects depends on the quantity and concentration of cannabinoids present in the plant material and its derivatives utilized by users.

Traditionally, and depending on the quantity of these components, Cannabis sativa can be classified into three chemotypes. Chemotype I is rich in the psychotropic cannabinoid THC; the majority of modern cultivars belong to this category. These plants are highly appreciated by recreational consumers seeking a “high” and by those using marijuana for holistic purposes. Chemotype II offers a balanced proportion of THC and CBD. Cultivars with this balance are gaining popularity among both recreational and holistic consumers. It produces a strong psychotropic effect, but a similar amount of CBD attenuates the influence of THC and may reduce its harmful psychotropic effects. Chemotype III is rich in CBD and has low THC content. As a result, these varieties produce minimal psychotropic effects; for some recreational and holistic consumers, this lucid effect is highly useful and functional.⁴4. ElSohly MA, Radwan MM, Gul W, Chandra S, Galal A. Phytochemistry of Cannabis sativa L. En: Kinghorn AD, Falk H, Gibbons S, Kobayashi J, eds. Phytocannabinoids. Cham: Springer International Publishing; 2017. p. 1-36. Although this classification is not valid from a taxonomic standpoint of the seed, it is practical from an analytical, pharmacological, and legal perspective (in the case of Colombia) as it quickly allows for the identification of the type of sample based on its concentration and its association with toxicological and legal risks. In Colombia, material is considered psychoactive when the THC concentration exceeds 1%.¹²12. República de Colombia, Ministerio de Salud y Protección Social. Decreto 613 de 2017 [Internet]. 2017 [citado 3 dic 2022]. Disponible en: Disponible en: https://tinyurl.com/4mk8vxj6 .
https://tinyurl.com/4mk8vxj6...

The psychotropic effects of cannabinoids present in marijuana make it one of the most widely consumed psychoactive substances worldwide, whether its consumption is legal or prohibited. Evidence indicates that the prevalence of marijuana consumption has been increasing over the past decades, with higher rates of use among young people and young adults; indeed, use of the substance continues to occur in different regions, regardless of the regulatory framework with respect to its use.¹³13. Lachance A, Bélanger RE, Riva M, Ross NA. A systematic review and narrative synthesis of the evolution of adolescent and young adult cannabis consumption before and after legalization. Journal of Adolescent Health. 2022;70(6):848-863.^,1414. Shao H, Du H, Gan Q, Ye D, Chen Z, Zhu Y, et al. Trends of the global burden of disease attributable to cannabis use disorder in 204 countries and territories, 1990-2019: Results from the Disease Burden Study 2019. International Journal of Mental Health and Addiction. 2023. doi: 10.1007/s11469-022-00999-4.
https://doi.org/10.1007/s11469-022-00999...

Something similar can be seen in the American continent. The most recent information reveals that marijuana consumption has increased in eight out of the eleven countries that reported data; according to reports from the Organization of American States (OAS), consumption is occurring at increasingly younger ages, and the overall perception of risk associated with consumption has decreased, with changes in habits and forms of consumption.¹⁵15. Organización de los Estados Americanos, Comisión Interamericana para el Control del Abuso de Drogas. Informe sobre el consumo de drogas en las américas 2019 [Internet]. 2019 [citado 3 dic 2022]. Disponible en: Disponible en: https://tinyurl.com/4unknrzv .
https://tinyurl.com/4unknrzv...

In Colombia, the latest National Survey on the Consumption of Psychoactive Substances conducted in 2019 by the National Administrative Department of Statistics [Departamento Nacional de Estadística] (DANE) revealed - in line with global and continental trends - that the highest lifetime prevalence of consumption of illicit substances was found for marijuana, at 8%. It is important to note that Colombian youth, consistent with age trends in the continent, also report an increasingly early onset of marijuana use and a visible inclination to experiment with a perceived mild level of risk.¹⁶16. Caceres D, Salazar I, Varela M, Tovar J. Consumo de drogas en jóvenes universitarios y su relación de riesgo y protección con los factores psicosociales. Universitas Psychologica. 2006;5(3):521-534. Similarly, the evidence unambiguously indicates an increase in the consumption of substances classified as illegal (marijuana) and a decrease in the consumption of legal substances (tobacco) among the Colombian population.¹⁵15. Organización de los Estados Americanos, Comisión Interamericana para el Control del Abuso de Drogas. Informe sobre el consumo de drogas en las américas 2019 [Internet]. 2019 [citado 3 dic 2022]. Disponible en: Disponible en: https://tinyurl.com/4unknrzv .
https://tinyurl.com/4unknrzv... ^,1717. Acosta A, Sierra W, Rincón J. Consumo de drogas en Colombia: análisis del enfoque de salud pública para su abordaje. Revista Academia & Derecho. 2019;10:365-387. doi: 10.18041/2215-8944/academia.18.6006.
https://doi.org/10.18041/2215-8944/acade... The supply reduction approach that has for years been implemented by the Colombian State has not reduced consumption; research on this matter establishes consistently, over three decades of study, that Colombians perceive there to be almost no barriers to accessing substances such as marijuana.¹⁸18. Departamento Administrativo Nacional de Estadística. Encuesta Nacional de Consumo de Sustancias Psicoactivas (ENCSPA) [Internet]. Bogotá: Ministerio de Justicia; 2020 [citado 3 dic 2022]. Disponible en: Disponible en: https://tinyurl.com/2p92338.
https://tinyurl.com/2p92338....

In addition, scientific literature highlights that, since 1992 and up to the latest national survey in 2019, the city of Medellín presents a higher prevalence of psychoactive substance than the national average.¹⁸18. Departamento Administrativo Nacional de Estadística. Encuesta Nacional de Consumo de Sustancias Psicoactivas (ENCSPA) [Internet]. Bogotá: Ministerio de Justicia; 2020 [citado 3 dic 2022]. Disponible en: Disponible en: https://tinyurl.com/2p92338.
https://tinyurl.com/2p92338.... This result is corroborated by local studies such as the “El Análisis de la Situación de Salud 2005-2015” [Health Situation Analysis 2005-2015] published by the city government, which states: “The municipality of Medellín has a higher lifetime prevalence than the country as a whole in the consumption of alcohol, tobacco, marijuana, cocaine, basuco [cocaine base paste], tranquilizers, stimulants, heroin, ecstasy, and in general, any legal, illegal, or illicit substance.” Additionally, young people in the city have a higher lifetime prevalence of marijuana use compared to population groups in other age ranges.¹⁹19. Torres Y, Castaño G, Sierra G, Salas C, Bareño J. Estudio de Salud Mental Medellín 2019 [Internet]. Medellín: Universidad CES; 2019 [citado 3 dic 2022]. Disponible en: Disponible en: https://tinyurl.com/2p8w3pu3 .
https://tinyurl.com/2p8w3pu3... ^,2020. Alcaldía de Medellín. Profundización del análisis de la situación de salud, Medellín 2005 - 2018 [Internet]. Medellín: Secretaría de Salud; 2020 [citado 3 dic 2022]. Disponible en: Disponible en: https://tinyurl.com/5b464fnf .
https://tinyurl.com/5b464fnf...

As can be inferred from the above, the actions of national and municipal institutions to affect the demand and use of psychoactive substances, in general, and marijuana, in particular, have not generated significant changes in consumption patterns. Additionally, the different studies on cannabis abuse mainly focus on the frequency of use,²¹21. Casajuana C, López-Pelayo H, Balcells-Olivero M, Colom J, Gual A. Constituyentes psicoactivos del cannabis y sus implicaciones clínicas: Una revisión sistemática. Adicciones 2016;30:140-151. doi: 10.20882/adicciones.858.
https://doi.org/10.20882/adicciones.858.... neglecting the composition and concentration of cannabinoids that different samples may have. This situation is concerning considering that the toxicological risk definitely changes according to the concentration of the plant’s main psychoactive component. Debates surrounding the legalization of recreational marijuana use and its medicinal use continue to shape the political agendas in Colombia and different countries in the region, which could indicate a transition from a prohibitionist paradigm towards strategies based on preventive medicine, public health, and harm reduction.²²22. Riveros D, Portilla E. Regulación actual del cannabis visto desde los beneficios terapéuticos de los cannabinoides. Revista La Propiedad Inmaterial. 2021;(31):195-208.

Identifying the types of cannabinoids present in marijuana samples circulating in urban environments is essential for developing comprehensive care strategies in public health and specialized medicine that can guide preventive interventions regarding the issues associated with the consumption of psychoactive substances. Such an analysis simultaneously provides the opportunity to strengthen or redefine the approach of promotion and prevention programs in addressing risk behaviors, basing their design and implementation on scientific evidence.

In Colombia, through Act 1787 of 2016, a regulatory framework was created to allow safe and informed access for the medical and scientific use of cannabis and its derivatives. In this regard, according to Decree 613 of 2017 issued by the Ministry of Health and Social Protection, cannabis material is considered psychoactive if the THC concentration is greater than 1% in dry weight. This indicates that for cannabis derivatives, at minimum it is necessary to quantify the cannabinoids THC as the psychoactive component, CBD as the medicinal component, and CBN as an indicator of THC degradation. Based on this regulation, the main objective of this study was to determine the concentration of THC, CBD, and CBN in cannabis samples (plant material) collected voluntarily in six comunas [urban subdivisions] and two corregimientos [rural subdivisions] of the district of Medellin. This study also aimed to provide a general sociodemographic characterization of recreational cannabis consumption.

MATERIALS AND METHODS

A cross-sectional study with prospective data collection and an analytical scope was carried out; non-probabilistic sampling was used to capture cannabis users in the city of Medellin who voluntarily agreed to donate they substance they consume as a sample for analysis. This research presented no risks to the participants, as established by Resolution 8430 of 1993, and complied with the relevant bioethical code in the data collection process. Each participant was asked to complete a survey-like form in order to collect sociodemographic information and consumption frequencies, which did not identify participants nor inquire about sensitive aspects of their behavior. Participants answered without providing their signature but did give verbal consent, an approach that took into account the fear among substance users of being identified, stigmatized, or possibly facing legal consequences. The collection and subsequent handling of the samples was approved by the International Center for Strategic Studies against Narcotrafficking [Centro Internacional de Estudios Estratégicos contra el Narcotráfico] (CIENA) of the National Police and by the National Narcotics Fund [Fondo Nacional de Estupefacientes]. To fully preserve the anonymity of the study participants, neither entity had direct or indirect contact with participants, as any practices that could be perceived as identification or tracing were avoided.

Sample collection

The collection of samples was carried out by the company Consultoría Especializada en Drogas, Salud & Sociedad (CEDSS), contracted by the Universidad Nacional de Colombia, Bogotá Campus. All samples were collected in the district of Medellin during the month of October 2021, through 22 interventions at different social events targeting youth, in which a booth was set up to encourage cannabis users to approach of their own accord and voluntarily donate the substance they consume. Detailed protocols were followed at the time of each collection to ensure standardization and quality in the collection process. Each user was asked to optionally fill out an form that allowed for the collection of information regarding the sample and general sociodemographic data. Each participant was provided with information about the research, its objectives, and the use of the resulting information for strictly academic and research purposes, then asked for their verbal consent to complete the form and voluntarily donate the sample. During the different collection sessions, four types of sampling were conducted: snowball sampling, convenience sampling, quota sampling, and voluntary or self-selected participant sampling. Once all the samples were collected, they were transported by officials from the CIENA to the Pharmaceutical Instrumental Analysis Laboratory of the Department of Pharmacy at the Universidad Nacional de Colombia, where the respective chromatographic analyses were carried out.

Types of samples and preparation for analysis

As a selection criterion for sample collection, it was determined that only plant material would be included. Other forms of cannabis were excluded from this study. The samples were collected in the comunas of Laureles-Estadio, La Candelaria, Poblado, San Javier, Guayabal, Robledo, and the corregimientos of San Antonio de Prado and Santa Elena in the district of Medellin during the month of October 2021.

Each of the cannabis plant material samples was macerated until a homogeneous particle size was achieved. A portion (50 mg) of the macerate was used for cannabinoid extraction by suspending it in 1.5 mL of ethanol in an Eppendorf vial, followed by three minutes of vortexing, five minutes of sonication, and five minutes of centrifugation at 9,000 rpm. The supernatant was filtered into a chromatography vial using a 0.45 µm membrane, and 1 µL was injected into each of the gas chromatographs.

Chemical anaylsis technique

For the identification of the different cannabinoids, gas chromatography with mass spectrometry and electron impact (GC-MS/EI) was used for all samples, while gas chromatography with flame ionization detection (FID) was employed for quantification. Both analytical methodologies were validated following the validation guidelines of the United Nations Office on Drugs and Crime (UNODC).²³23. United Nations Office on Drugs and Crime. Guidance for the validation of analytical methodology and calibration of equipment used for testing of illicit drugs in seized materials and biological specimens [Internet]. UNODC; 2009 [citado 3 dic 2022]. Disponible en: Disponible en: https://tinyurl.com/bdd5cm23 .
https://tinyurl.com/bdd5cm23...

The parameters for the identification of different cannabinoids using the GC-MS/EI analytical methodology were taken from the UNODC document “Recommended Methods for the Identification and Analysis of Cannabis and Cannabis Products.”²⁴24. Oficina de las Naciones Unidas contra la Droga y el Delito. Métodos recomendados para la identificación y el análisis del cannabis y los productos del cannabis [Internet]. UNODC; 2010 [citado 3 dic 2022]. Disponible en: Disponible en: https://tinyurl.com/mvtzvhrb .
https://tinyurl.com/mvtzvhrb...

GC-MS/EI. The system used for the identification of different phytocannabinoids employed a Thermo TRACE 1300 gas chromatograph with an ISQ QD detector and a TR-5MS analytical capillary column (30 m x 0.25 mm i.d x 0.25 µm). The injector, detector, and transfer line temperatures were set at 290°C, 230°C, and 280°C, respectively. The injection was performed in a split 20:1 mode, and the oven was programmed to start at 240°C for one minute, with a ramp of 12°C/min up to 270°C for five minutes. The Chromeleon® software with the NIST 2007 Mass Spectral Library was used for data evaluation.

GC-FID. The quantification of phytocannabinoids in the plant material was performed using a Shimadzu GC-2010 Plus gas chromatograph equipped with a Shimadzu AOC-20i autosampler and an analytical capillary column (30 m x 0.25 mm x 0.25 µm, Restek, Bellefonte, Pennsylvania, US). The detector and injector temperatures were maintained at 290 °C and 300 °C, respectively. A 1 µL aliquot of the cannabis extract dissolved in 99% ethanol was injected in a split 10:1 mode. The oven was programmed to start at 200 °C for two minutes with a ramp of 10 °C/min up to 260 °C for seven minutes, resulting in a total run time of 15 minutes. Quantification was performed for THC, CBD, and CBN using tetracosane as an internal standard at a concentration of 100 ppm. The LabSolutions VR 5.52 software from Shimadzu was used for data evaluation.

Chemical and reactive substances

The reference material was “THC cannabinoids mixture-3” with delta-9-tetrahydrocannabinol (Δ9-THC), cannabinol (CBN), and cannabidiol (CBD) at a concentration of 1 mg/mL from Cerilliant Corporation (Round Rock, TX) and tetracosane of 99% purity from Sigma/Merck (Colombia) as well as analytical-grade ethanol at 99% purity from PanReac. The working solution of cannabinoids was prepared at a concentration of 100 µg/mL.

Statistical analysis

The analysis of the information was conducted using the open-source statistical software Jamovi 2.3.21. Categorical variables were analyzed by calculating absolute and relative frequencies. Descriptive statistics including measures of central tendency (mean and median) and measures of dispersion (standard deviation and interquartile range) were used for quantitative variables.

RESULTS

A total of 87 cannabis samples were collected, each corresponding to plant material, along with an equal number of survey responses. The average amount donated for this material was 282.8 mg, with a range of 29.1 to 1,037.4 mg.

Regarding the sociodemographic characteristics of the sample donors, as shown in Table 1, it can be observed that 22 were female and 63 were male, while 2 individuals did not respond to the sex category. The majority of the sample donors had a professional or postgraduate education level and fell within the age range of 29 to 59 years. It is also worth highlighting that 70% of the sample donors belonged to the middle or high socioeconomic level (stratum 3-4 or stratum 5-6), according to the system of socioeconomic stratification defined in Colombia.²⁵25. Gobierno de Colombia. Ley 142 de 1994 [Internet]. 1994 [citado 3 dic 2022]. Disponible en: Disponible en: https://tinyurl.com/46496yfk .
https://tinyurl.com/46496yfk... Furthermore, 80.5% of the consumers had been using the substance for more than 5 years.

Chromatographic analysis

The 87 samples collected within the framework of the Youth Public Health Program of the Secretary of Youth in Medellin were obtained in six of the sixteen comunas of the urban area of the city, as well as two of the five corregimientos that make up the rural zone. According to Table 2, the urban territories contributed 83.9% (73) of the samples, while the rural zone contributed 16.1% (14).

Of the six comunas from which samples were collected, the comunas located on the western side (Laureles, Guayabal, Robledo, and San Javier) contributed 58.9% of the samples. The comunas located in the eastern part of the city (La Candelaria and Poblado) contributed 41.1%. The corregimiento of San Antonio de Prado provided 42.8% of the samples from the rural zone. The number of gathered samples and their spatial dispersion allowed for a comprehensive overview of the cannabinoids present in the marijuana consumed in the city of Medellín.

Analysis of the samples

GC-MS/EI

The qualitative analysis by GC-MS/EI allowed for the detection of seven phytocannabinoids, ordered according to their incidence in the different samples (Table 3): tetrahydrocannabinol (THC), cannabigerol (CBG), cannabinol (CBN), cannabichromene (CBC), delta-9-tetrahydrocannabivarin, cannabidiol (CBD) and cannabidivarin (CBDV).

The structure and composition of each of the phytocannabinoids can be observed in Table 4. The presence of THC in 100% of the samples and CBG in 78 of them is logical, considering that THC is the largest component of cannabinoids in plant material, and CBG is derived from CBG acid, the first phytocannabinoid biosynthesized after the formation of olivetolic acid, serving as a precursor to other cannabinoids in the plant.²⁶26. Jin D, Dai K, Xie Z, Chen J. Secondary Metabolites Profiled in Cannabis Inflorescences, Leaves, Stem Barks, and Roots for Medicinal Purposes. Scientific Reports. 2020;10:3309. doi: 10.1038/s41598-020-60172-6.
https://doi.org/10.1038/s41598-020-60172... However, despite THC having an average composition of 89.4% of the total cannabinoids in the 87 samples, the therapeutic non-psychoactive cannabinoid CBD had an average composition of 37.1%, which is a significant percentage in the total composition of the 13 samples in which it was present. The average presence of other cannabinoids (CBG, CBN, CBC, CBDV, and delta-9-tetrahydrocannabivarin) was less than 2.3%.

Regarding their psychotropic activity,²⁷27. Arango J, Bedoya V. Cannabinoides no psicoactivos en cáncer: estudios in vivo. Hechos Microbiológicos. 2020;11:61-71. doi: 10.17533/udea.hm.v11n1a04.
https://doi.org/10.17533/udea.hm.v11n1a0... this study found THC and CBN (low activity) as psychoactive cannabinoids, while CBG, CBC, CBD, and CBDV were identified as non-psychoactive components. In comparison to other cannabinoids, THC made up a significantly higher percentage of the composition. Therefore, when studying the composition of cannabis in the city of Medellín, THC should be considered as the main contributor to the type of effect that consumers expect from the substance. CBN, another less psychoactive component of cannabis - ten times less potent than THC²⁸28. Inzunza G, Peña A. From cannabis to cannabinoids a medical-scientific perspective. Revista Médica de la Universidad Autónoma de Sinaloa. 2019;9(2):96-114. doi: 10.28960/revmeduas.2007-8013.v9.n2.006.
https://doi.org/10.28960/revmeduas.2007-... - was present in 77.0% of the samples (Table 3). However, its concentration in the samples did not exceed 1%, indicating that all 87 analyzed samples corresponded to fresh plant material with minimal manipulation.

Regarding non-psychoactive cannabinoids, CBD was identified in 13 samples with a significant percentage compared to other cannabinoids (37.1%). CBD structurally differs from THC by the presence of a carbon double bond and a hydroxyl group, which prevents the deleterious effects of high doses of THC, moderating its psychoactive effects while exhibiting medicinal properties.²⁹29. National Academies of Sciences, Engineering, and Medicine. The health effects of cannabis and cannabinoids: the current state of evidence and recommendations for research. Washington DC: NASEM; 2017. doi: 10.17226/24625.
https://doi.org/10.17226/24625.... Additionally, CBG was identified in 78 samples with an average presence of 2.3% (Table 4). These two cannabinoids, acting through a mechanism different from THC, potentially have certain anti-inflammatory, analgesic, antipsychotic, anti-ischemic, antiepileptic, and anxiolytic effects that are being widely studied.³⁰30. Duran M, Hereu D. Uso terapéutico de los cannabinoides. Adicciones. 2004;16:143-152. doi: 10.20882/adicciones.412.
https://doi.org/10.20882/adicciones.412.... ^,3131. Rivera-Olmos V, Parra-Bernal M. Cannabis: efectos en el sistema nervioso central: Consecuencias terapéuticas, sociales y legales. Revista Médica del Instituto Mexicano del Seguro Social. 2016;54:626-634.

Table 5 reports the chemotype and average concentration of THC, while Table 6 shows the percentage of each of the three most relevant cannabinoids in this study.

*Range of THC Concentration - Toxicological Risk³²32. Santos-Álvarez I, Pérez-Lloret P, González-Soriano J, Pérez-Moreno M. Aproximación a la evaluación de la potencia de la resina de cannabis en Madrid: ¿un riesgo para la salud? Adicciones. 2021. doi: 10.20882/adicciones.1630.
https://doi.org/10.20882/adicciones.1630... : low: THC content between 1.0%-5.0%; moderate: THC content between 5.0% - 10.0%; high: THC content between 10.0% - 15.0%; very high: THC content between 15.0% - 20.0%; extremely high: THC content between 20.0% - 25.0%.

According to current Colombian legislation, all quantified samples would be classified as psychoactive material because the concentration of THC exceeds 1% w/w (Table 5). The vast majority of the quantified samples (90.8%) correspond to chemotype I, rich in the cannabinoid THC, indicating that they primarily have psychotropic effects. Another 9.2%, corresponding to 8 samples, exhibited chemotype II, rich in CBD (higher CBD content than THC), suggesting that these samples may have fewer psychotropic effects on the body due to the counteractive effects of high concentrations of the medicinal cannabinoid. Specifically, the 8 CBD-rich samples reported CBD contents in the range of 4.7% to 9.6% w/w. The neighborhoods where the highest number of cannabis plant material samples were collected were Laureles-Estadio, La Candelaria, and Poblado. Overall, the majority of the samples (44.8%) present high toxicological risks in relation to the concentration of THC present.

As shown in Table 6, the average concentrations (% w/w) of THC were found to be in the range of 6.1-14.7% with a mean of 11.5%. The concentrations of CBD ranged from 0.2-4.4% with a mean of 0.8%, and the concentrations of CBN ranged from 0.0-0.3% with a mean of 0.1%. The average concentration of the total sum of these three mentioned cannabinoids was 12.4%.

DISCUSSION

Despite scientific evidence showing that acute cannabis consumption increases inflammation in the respiratory pathways and damages lung tissue, as well as studies that show that chronic cannabis use is associated with a higher risk of chronic diseases such as bronchitis, emphysema, chronic respiratory inflammation, and impaired respiratory function,³³33. Sachs J, McGlade E, Yurgelun-Todd D. Safety and Toxicology of Cannabinoids. Neurotherapeutics. 2015;12:735-746. doi: 10.1007/s13311-015-0380-8.
https://doi.org/10.1007/s13311-015-0380-... marijuana smoking continues to be a growing practice in Medellín and different cities in the region.¹⁸18. Departamento Administrativo Nacional de Estadística. Encuesta Nacional de Consumo de Sustancias Psicoactivas (ENCSPA) [Internet]. Bogotá: Ministerio de Justicia; 2020 [citado 3 dic 2022]. Disponible en: Disponible en: https://tinyurl.com/2p92338.
https://tinyurl.com/2p92338.... ^,3434. Ministerio de la Protección Social, Dirección Nacional de Estupefacientes. Estudio Nacional de consumo de sustancias psicoactivas en Colombia [Internet]. 2008 [citado 3 dic 2022]. Disponible en: Disponible en: https://tinyurl.com/299t54bx .
https://tinyurl.com/299t54bx... ^,3535. Ministerio de Justicia y del Derecho, Observatorio de Drogas de Colombia. Estudio Nacional de Consumo de Sustancias Psicoactivas en Población Escolar Colombia - 2011 [Internet]. 2011 [citado 3 dic 2022]. Disponible en: Disponible en: https://tinyurl.com/t8unvjaa .
https://tinyurl.com/t8unvjaa... ^,3636. Ministerio de Justicia y del Derecho, Observatorio de Drogas de Colombia, Ministerio de Salud y Protección Social. Estudio Nacional de consumo de sustancias psicoactivas en Colombia 2013 [Internet]. 2013 [citado 3 dic 2022]. Disponible en: Disponible en: https://tinyurl.com/ytsm3anf .
https://tinyurl.com/ytsm3anf... ^,3737. Ministerio de Justicia y del Derecho, Observatorio de Drogas de Colombia, Ministerio de Educación Nacional, Ministerio de Salud y Protección Social. Estudio nacional de consumo de sustancias psicoactivas en población escolar Colombia 2016 [Internet]. 2016 [citado 3 dic 2022]. Disponible en: Disponible en: https://tinyurl.com/3hemb5a6 .
https://tinyurl.com/3hemb5a6... All the adverse effects observed in the respiratory pathways and lung tissue are closely related to the primary method of marijuana consumption. When marijuana is consumed via inhalation, THC reaches peak blood concentrations between seven and ten minutes after consumption, with maximum effects occurring within 20 to 30 minutes, and lasting up to three to four hours, subject to interindividual variability.³⁸38. Téllez Mosquera J, (ed). Marihuana cannabis: aspectos toxicológicos, clínicos, sociales y potenciales usos terapéuticos. Bogotá: Ministerio de Justicia y del Derecho; 2016.

Several relevant findings can be highlighted in this characterization of the components of the obtained marijuana samples. Firstly, the cannabinoid content is not consistent across all samples, indicating that the supply of cannabis in the Medellín District is dynamic. The recreational cannabis samples could originate from different varieties of cannabis cultivated in different thermal floors and regions of the Colombian topography, or from hydroponic crops or the use of seeds belonging to different varieties or strains, among other factors. Secondly, synthetic cannabinoids (molecules designed in a laboratory that produce THC-like effects by binding to the CB1 and CB2 receptors of the endocannabinoid system), such as new psychoactive substances (NPS), were not found in this study. This result is relevant because these types of synthetic molecules are not regulated by the 1961 or 1971 drug control conventions³⁹39. Banister SD, Connor M. The chemistry and pharmacology of synthetic cannabinoid receptor agonist new psychoactive substances: evolution. En: Maurer HH, Brandt SD, (eds). New psychoactive substances. Cham: Springer International Publishing; 2018. p. 191-226. and therefore lack safety and efficacy studies, posing a significant public health risk as they can be even more toxic than cannabis used for recreational purposes. Thirdly, THC was found in different concentrations in all analyzed samples, which is unquestionably associated with varied toxicological risks that can be exacerbated depending on the frequency of use by each user.³²32. Santos-Álvarez I, Pérez-Lloret P, González-Soriano J, Pérez-Moreno M. Aproximación a la evaluación de la potencia de la resina de cannabis en Madrid: ¿un riesgo para la salud? Adicciones. 2021. doi: 10.20882/adicciones.1630.
https://doi.org/10.20882/adicciones.1630... Thanks to the combined effects of THC as a psychoactive and central nervous system depressant, this molecule causes relaxation, alterations in perception, and a sense of well-being, which is sought after by social consumers of this type of drug.⁴⁰40. Dos Santos RG, Hallak JEC, Crippa JAS. Neuropharmacological effects of the main phytocannabinoids: A narrative review. En: Murillo-Rodriguez E, Pandi-Perumal SR, Monti JM, (eds). Cannabinoids and neuropsychiatric disorders. Cham: Springer International Publishing; 2021. p. 29-45. Lastly, as a fourth aspect worth highlighting, in 8 out of the 87 analyzed samples, CBD was found in concentrations similar to or higher than that of THC, and were therefore classified as chemotype II. This finding is noteworthy considering that CBD is non-psychoactive and mitigates the adverse effects of THC.⁴¹41. Baron EP. Medicinal properties of cannabinoids, terpenes, and flavonoids in cannabis, and benefits in migraine, headache, and pain: An update on current evidence and cannabis science. Headache: The Journal of Head and Face Pain. 2018;58(7):1139-1186. doi: 10.1111/head.13345.
https://doi.org/10.1111/head.13345.... These types of samples may come from crops intended for the medicinal use of cannabis with subsequent treatment of extracts to minimize THC concentration, from the creation of strains with modified CBD content, or from other cultivation and production dynamics aiming to provide cannabis with higher CBD concentrations for both recreational and therapeutic use.

To date, there is one study in Colombia similar to the present investigation. In 2009, Florian et al. quantified cannabinoids in samples of fresh marijuana material cultivated in four regions of Colombia: Llanos Orientales, Santa Marta, Cauca, and Eje Cafetero.⁴²42. Florian RNM, Parada AF, Garzon MWF. Estudio del contenido de cannabinoides en muestras de marihuana (cannabis sativa l.) cultivadas en varias regiones de Colombia. Vitae. 2009;16(2):237-244. In all four regions, the main cannabinoid found was THC, with higher concentrations in samples from Llanos Orientales (up to 17.6%) and Cauca (up to 15.5%). This suggests that over the years, and in comparison with the present study, enhanced varieties of Cannabis are being cultivated in Colombia, as the maximum THC content found in the plant material samples from the city of Medellín reach concentrations of up to 21.3%, whereas worldwide, the THC content without genetic manipulation does not exceed 7%.⁴³43. Di Marzo V. A brief history of cannabinoid and endocannabinoid pharmacology as inspired by the work of British scientists. Trends in Pharmacological Sciences. 2006;27:134-140. doi: 10.1016/j.tips.2006.01.010.
https://doi.org/10.1016/j.tips.2006.01.0... This finding is corroborated by a study conducted by the Ministry of Justice and Law, the Drug Policy Directorate, and the Drug Observatory of Colombia in 2013, which states that “tetrahydrocannabinol (THC) is the most abundant cannabinoid among plant cannabinoids in Colombia.”³⁸38. Téllez Mosquera J, (ed). Marihuana cannabis: aspectos toxicológicos, clínicos, sociales y potenciales usos terapéuticos. Bogotá: Ministerio de Justicia y del Derecho; 2016. Regarding CBD, Florian’s study found maximum concentrations of 4.9%, which did not surpass the concentrations of THC in any of the quantified samples. In this study, the maximum CBD concentration (% w/w) found was 9.5%, and in some cases, the values were higher than the concentrations for THC. This suggests recreational use of enhanced varieties rich in CBD, which could be an indication of a change in consumption dynamics within the city, creating more favorable toxicological conditions in comparison to when cannabis with high THC content is consumed without CBD. CBD, due to its lack of psychotropic activity, has neuroprotective, anti-inflammatory, and anxiolytic effects. Additionally, studies indicate that it could attenuate some of the neurocognitive and behavioral effects of THC.⁴⁴44. Englund A, Morrison PD, Nottage J, Hague D, Kane F, Bonaccorso S, et al. Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment. Journal of Psychopharmacology. 2012; 27(1):19-27. doi: 10.1177/0269881112460109.
https://doi.org/10.1177/0269881112460109... ^,4545. Moltke J, Hindocha C. Reasons for cannabidiol use: a cross-sectional study of CBD users, focusing on self-perceived stress, anxiety, and sleep problems. Journal of Cannabis Research. 2021;3:5. doi: 10.1186/s42238-021-00061-5.
https://doi.org/10.1186/s42238-021-00061... ^,4646. Bartoli F, Riboldi I, Bachi B, Calabrese A, Moretti F, Crocamo C, et al. Efficacy of cannabidiol for Δ-9-tetrahydrocannabinol-induced psychotic symptoms, schizophrenia, and cannabis use disorders: A narrative review. Journal of Clinical Medicine. 2021;10(6):1303. doi: 10.3390/jcm10061303.
https://doi.org/10.3390/jcm10061303.... Although the evidence of interaction between both components is inconclusive due to the existence of contradictory studies,⁴⁷47. Lichenstein SD. THC, CBD, and Anxiety: a review of recent findings on the anxiolytic and anxiogenic effects of cannabis’ primary cannabinoids. Current Addiction Reports. 2022; 9(4):473-485. doi: 10.1007/s40429-022-00450-7.
https://doi.org/10.1007/s40429-022-00450... ^,4848. Zamarripa CA, Spindle TR, Surujunarain R, Weerts EM, Bansal S, Unadkat JD, et al. Assessment of orally administered Δ9-tetrahydrocannabinol when coadministered with cannabidiol on Δ9-tetrahydrocannabinol pharmacokinetics and pharmacodynamics in healthy adults: A randomized clinical trial. JAMA Network Open. 2023;6(2):e2254752. doi: 10.1001/jamanetworkopen.2022.54752.
https://doi.org/10.1001/jamanetworkopen.... the presence of CBD in recreational cannabis is emerging as a possible factor to control in order to reduce the toxicological risks associated with consumption.⁴¹41. Baron EP. Medicinal properties of cannabinoids, terpenes, and flavonoids in cannabis, and benefits in migraine, headache, and pain: An update on current evidence and cannabis science. Headache: The Journal of Head and Face Pain. 2018;58(7):1139-1186. doi: 10.1111/head.13345.
https://doi.org/10.1111/head.13345.... ^,4949. Crocq MA. History of cannabis and the endocannabinoid system. Dialogues in Clinical Neuroscience. 2020;22(3):223-228. doi: 10.31887/DCNS.2020.22.3/mcrocq.
https://doi.org/10.31887/DCNS.2020.22.3/... Along these lines, it has been observed that in clinical trials conducted with cannabis users, CBD-based pharmacotherapies (cannabis with 0.4% THC and 9% CBD) have reduced cannabis consumption frequency, cravings, and withdrawal symptoms.⁵⁰50. Batalla A, Janssen H, Gangadin SS, Bossong MG. The potential of cannabidiol as a treatment for psychosis and addiction: Who benefits most? A systematic review. Journal of Clinical Medicine. 2019;8(7):1058. doi: 10.3390/jcm8071058.
https://doi.org/10.3390/jcm8071058.... Thus, CBD-rich material is considered an alternative for mitigating risks and adverse outcomes in cannabis consumption, even among users of other illicit drugs and alcohol, and in reducing opioid addiction.⁵¹51. Lau N, Sales P, Averill S, Murphy F, Sato S-O, Murphy S. A safer alternative: Cannabis substitution as harm reduction: Cannabis substitution as harm reduction. Drug and Alcohol Review. 2015;34:654-659. doi: 10.1111/dar.12275.
https://doi.org/10.1111/dar.12275....

Looking internationally, a study⁵²52. Stempfer M, Reinstadler V, Lang A, Oberacher H. Analysis of cannabis seizures by non-targeted liquid chromatography-tandem mass spectrometry. Journal of Pharmaceutical and Biomedical Analysis. 2021;205:114313. Doi: 10.1016/j.jpba.2021.114313.
https://doi.org/10.1016/j.jpba.2021.1143... conducted in Innsbruck, Austria in 2021 using 93 confiscated marijuana samples revealed that all samples contained THC. However, 45% of them exhibited higher concentrations of CBD (ranging from 2.5% to 14%) compared to THC. This highlights the use of CBD-rich marijuana samples for recreational purposes, which, according to the results of the present study, is a practice beginning to be employed in the city of Medellín. Additionally, the Austrian study detected one synthetic cannabinoid and 15 pesticides. In the present study, as mentioned previously, no synthetic cannabinoids or volatile pesticides were detected, at least in high concentrations.

Considering the concentrations of THC found in the different samples analyzed and based on existing academic evidence, the predominant varieties of marijuana circulating in the city with high THC contents (in the double digits) can be classified as “creepy,” a term that has emerged to distinguish them from conventional varieties. “Creepy” marijuana has a higher THC percentage (between 10% and 25%) compared to regular varieties and allows for two or more harvests per year, which increases its profitability. The higher THC content is attributed to genetic modifications.⁵³53. Pérez Correa C, Ruiz A, Youngers C. Cultivo de cannabis en América Latina: su erradicación y efectos [Internet]México: CEDD; 2019 [citado 3 dic 2022]. Disponible en: Disponible en: https://tinyurl.com/mry5y8de .
https://tinyurl.com/mry5y8de... This phenomenon has to do with continental trends to increase the THC level in marijuana in producing countries such as Paraguay, Uruguay, Mexico, Costa Rica, and Colombia.⁵³53. Pérez Correa C, Ruiz A, Youngers C. Cultivo de cannabis en América Latina: su erradicación y efectos [Internet]México: CEDD; 2019 [citado 3 dic 2022]. Disponible en: Disponible en: https://tinyurl.com/mry5y8de .
https://tinyurl.com/mry5y8de...

Marijuana with a high THC composition produces high potency doses that take effect with one or two “hits” when smoked, increasing the speed at which the effects appear.⁵⁴54. Ramos-Guerrero L, Montalvo G, Cosmi M, García-Ruiz C, Ortega-Ojeda FE. Classification of various marijuana varieties by Raman Microscopy and Chemometrics. Toxics. 2022;10(3):1-13. Doi: 10.3390/toxics10030115.
https://doi.org/10.3390/toxics10030115.... The problem lies in the fact that more potent marijuana poses a greater risk of intoxication, and a deregulated market limits consumers’ ability to calibrate or choose their THC dosage in practice.

Smoking marijuana with the described THC levels is not a harmless practice. Additionally, smokers inhale deeply and hold their breath to maximize THC absorption, thereby increasing the risks of mild, severe, or acute intoxication.⁵⁵55. Olano Espinosa E, Lozano Polo A, Grifell Guàrdia M, Pinet Ogué MC, Isorna Folgar M, Moreno Arnedillo JJ. ¿Por qué y cómo tener en cuenta al cannabis en nuestros pacientes fumadores? Atención Primaria. 2020;52:47-53. Doi: 10.1016/j.aprim.2018.05.014.
https://doi.org/10.1016/j.aprim.2018.05....

THC, as the main component of the marijuana circulating in Medellín, aligns with the preferences of producers and consumers at a continental level. The academic literature and the research findings demonstrate a convergence between genetically modified (“creepy”) strains aimed at achieving higher THC levels and an increased propensity in the population for greater consumption. In other words, this convergence of supply and demand shows a preference for stronger depressant effects on the nervous system of consumers through more potent doses.⁵³53. Pérez Correa C, Ruiz A, Youngers C. Cultivo de cannabis en América Latina: su erradicación y efectos [Internet]México: CEDD; 2019 [citado 3 dic 2022]. Disponible en: Disponible en: https://tinyurl.com/mry5y8de .
https://tinyurl.com/mry5y8de... ^,5656. Rose Achá G. Stock de cannabis en América Latina: radiografía del microtráfico y la venta al menudeo [Internet]. México: CEDD; 2019 [citado 3 dic 2022]. Disponible en: Disponible en: https://tinyurl.com/2s4eexb7 .
https://tinyurl.com/2s4eexb7...

The risk of this confluence is that the probability of intoxication increases, leading to higher levels of morbidity for consumers who are unable to make decisions within an illegal market that prevents control over the desired THC levels. A technically and scientifically structured regulation of the cannabis market in the region could allow for control over available chemotypes, enabling consumption dynamics that reduce the toxicological risk of the substance and its impact on public health.

It is necessary to continue the characterization and chemical analysis of circulating marijuana in a continuous and permanent manner, and to do the same with other illicit substances. Such actions would contribute scientific evidence for the redefinition of the normative, evaluative, and theoretical frameworks on which the conventional approach to the issue of psychoactive substance use and antidrug policies is based in cities and countries in the region.

ACKNOWLEDGEMENTS

We would like to express our gratitude to the Secretaría de la Juventud de Medellín [Secretary of Youth of Medellín] and the Programa de Salud Pública Juvenil [Youth Public Health Program] for their comprehensive understanding of the issue of psychoactive substance use and their commitment to contributing research that strengthens and supports approaches with a predominant focus on public health. We also thank the Universidad Nacional de Colombia for guiding and carrying out the research project in the city of Bogotá.

References

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History