Cannabis: Drug of Abuse and Therapeutic Agent, Two Sides of the Same Coin

ABSTRACT The consumption of Cannabis sativa plant, known as marijuana in the Western world, for different purposes (therapeutic, intoxicating, and spiritual) due to its psychoactive effects, can be traced back to ancient times. Cannabis is the most used illicit drug worldwide; however, its legal status is changing rapidly. Cannabis regulation will allow a better understanding of its effects as a misused drug, including new challenges, such as the availability of highly potent Cannabis extracts. Furthermore, scientific research is making significant efforts to take advantage of the potential therapeutic uses of Cannabis active compounds. The science of Cannabis derivatives started with the identification of the phytocannabinoids Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), allowing the formal study of the complex set of effects triggered by Cannabis consumption and the deciphering of its pharmacology. Δ9-THC is recognized as the compound responsible for the psychoactive and intoxicating effects of Cannabis. Its study led to the discovery of the endocannabinoid system, a neuromodulatory system widespread in the human body. CBD does not induce intoxication and for that reason, it is the focus of the search for cannabinoid potential clinical applications. This review examines the current state of knowledge about contrasting perspectives on the effects of Cannabis, Δ9-THC, and CBD: their abuse liability and potential therapeutic use; two sides of the same coin.

Indications for the use of cannabinoids / Indicação do uso de canabinoides

ABSTRACT BACKGROUND AND OBJECTIVES: The increasingly widespread use of cannabinoids in the management of acute and chronic pain generates an urgent need to study how cannabinoids act on CB1 and CB2 receptors and what their effects are on the organism. It is important to understand the difference in action between natural cannabinoids (cannabidiol, delta 9-tetrahydrocannabinol, cannabigerol, cannabinoil, terpenes) and synthetic ones, so that the appropriate choice is made in each case, and depending on the pathophysiology of pain, one or the other active is more indicated. CONTENTS: Studies collected in the Pubmed, Cochrane Library and Web of Science databases were analyzed. These studies focus were on natural cannabinoids (cannabidiol, delta 9-tetrahydrocannabinol, cannabigerol, cannabinoil, terpenes) and synthetic cannabinoids in the use for the treatment of chronic pain, their action on the endocannabinoid system through the activation of the CB1 and CB2 receptor and their effect after activating this receptor, aiming to compile which cannabinoid is more indicated in the treatment of pain pathology. CONCLUSION: The subject still requires much study and new articles are being published daily. The analysis of the studies must be carried out with criteria to evaluate their seriousness. The endocannabinoid system is closely linked to the treatment of chronic pain and some cannabinoids such as: cannabidiol, delta 9-tetrahydrocannabinol, cannabigerol, cannabinoil, as well as some terpenes are already considered important in the treatment of chronic pain inferring sparing effect of opioids, anticonvulsants, antidepressants among others.

RESUMO JUSTIFICATIVA E OBJETIVOS: O uso cada vez mais disseminado dos canabinoides no controle da dor aguda e crônica gera uma necessidade urgente do estudo de como os canabinoides agem nos receptores CB1 e CB2 e quais seus efeitos no organismo. É importante entender a diferença de ação entre os canabinoides naturais (canabidiol, delta 9-tetrahidrocanabinol, canabigerol, canabinol, terpenos) e os sintéticos, para que a escolha adequada seja realizada em cada caso, sendo que dependendo da fisiopatologia da dor é mais indicado um ou outro ativo. CONTEÚDO: Foram analisados estudos coletados na Pubmed, Cochrane Library e Web of Science. Os estudos se concentram em canabinoides naturais (canabidiol, delta 9-tetrahidrocanabinol, canabigerol, canabinoil, terpenos) e canabinoides sintéticos no uso para o tratamento da dor crônica, sua ação no sistema endocanabinoide através da ativação do receptor CB1 e CB2 e seu efeito após ativar esse receptor, visando compilar qual canabinoide é mais indicado no tratamento da patologia álgica. CONCLUSÃO: O assunto ainda requer muito estudo e diariamente novos artigos vem sendo publicados. A análise dos estudos deve ser realizada com critério para avaliar sua seriedade. O sistema endocanabinoide está intimamente ligado ao tratamento da dor crônica e alguns canabinoides como: canabidiol, delta 9-tetrahidrocanabinol, canabigerol, canabinoil, assim como alguns terpenos já são considerados importantes no tratamento da dor crônica inferindo efeito poupador de opioides, anticonvulsivantes, antidepressivos entre outros.

New targeted compounds-biosynthesis of phytocannabinoids / 生物工程学报

Phytocannabinoids are bioactive terpenoids that are exclusive to Cannabis sativa L. The main pharmacologically active phytocannabinoids are Δ9-tetrahydrocannabinol and cannabidiol, both target endogenous cannabinoid receptors. Δ9-tetrahydrocannabinol and cannabidiol have extensive therapeutic potential due to their participation in many physiological and pathological processes in human body by activating the endocannabinoid system. At present, Δ9-tetrahydrocannabinol, cannabidiol and their analogues or combination preparations are used to treat epilepsy, vomiting in patients with cancer chemotherapy, spasticity in multiple sclerosis and relieve neuropathic pain and pain in patients with advanced cancer. With the further exploration of the application value of Δ9-tetrahydrocannabinol and cannabidiol as well as the increasing demand for standardization of pharmaceutical preparations, it is imminent to achieve large-scale production of Δ9-tetrahydrocannabinol and cannabidiol in the pharmaceutical industry. In this article, pharmacological research progress of phytocannabinoids in recent years, biosynthetic pathways of phytocannabinoids and the mechanism of key enzymes as well as various product development strategies of cannabinoids in pharmaceutical industry are reviewed. By exploring the potential of synthetic biology as an alternative strategy for the source of phytocannabinoids, it will provide a theoretical basis for the research and development of microbial engineering for cannabinoids synthesis, and promote the large-scale production of medicinal cannabinoids.

Chemical Characteristics, Therapeutic Uses, and Legal Aspects of the Cannabinoids of Cannabis sativa: A Review

Abstract Marijuana (Cannabis sativa) is an important annual medicinal plant that belongs to the Cannabaceae family. It contains 421 substances of 18 chemical types-the most significant compound is δ-9-tetrahydrocannabinol, which causes several effects, both in the Central Nervous System and in several peripheral locations in the organism. The objectives of this scientific review are to mention the anatomical distribution, chemical characteristics and biosynthesis of cannabinoids, as well as its actions mechanisms. The endogenous cannabinoid system, the therapeutic properties of C. sativa and its action on the nociceptive control are described. Finally, the modulators of the cannabinoid system in clinical use are indicated, together with marijuana legalization benefits.

Determinación y comparación cualitativa de cannabinoides presentes en productos naturales comerciales del departamento del Cauca, Colombia / Determination and qualitative comparison of cannabinoids present in commercial natural products of the Cauca Department-Colombia

RESUMEN Actualmente, hay un creciente interés por el estudio de Cannabis sativa y sus componentes ya que se le atribuye propiedades terapéuticas en el tratamiento de enfermedades. En Colombia y específicamente en el departamento del Cauca se comercializan productos de cannabis tanto para fines no medicinales como terapéuticos. En consecuencia, es necesario el análisis de estos productos de manera que se pueda conocer la composición de los mismos y el posible efecto que pueda tener sobre la salud. El análisis de los componentes de estos productos se llevó a cabo empleando la cromatografía líquida de alta resolución (CLAR) y espectrometría de masas (EM), de tal manera que permitieron la identificación de las principales especies cannabinoides; Δ9-tetra hidrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG). La separación de los analitos se llevó a cabo mediante la implementación de una columna analítica C18 de fase reversa, elución isocrática 1 mL/ min, presión del sistema 800 PSI, una mezcla de acetonitrilo ACN y buffer fosfato (KHPO4) en relación 65/35 como fase móvil, volumen de inyección de 10 µL, un tiempo de análisis de 15 min, y detección a 220 nm.

SUMMARY Cannabis sativa has now experienced an increasing interest in the study of its components since it is attributed therapeutic properties in the treatment of diseases. In Colombia and specifically in the Cauca Department, Cannabis products are marketed both for non-medicinal and therapeutic purposes. Consequently, it is necessary to analyze these products in such a way that the composition of the products and their possible effect on health can be known. The analysis ofthe components of these products was carried out using high performance liquid chromatog-raphy (HPLC) and mass spectrometry (MS), in such a way that they allowed the identification of the main cannabinoid species; Δ9-tetra hydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG). The separation of the analytes was carried out by means of the implementation of a reverse phase C18 analytical column, isocratic elution 1 mL/min, system pressure 800 PSI, a mixture of acetonitrile ACN and phosphate buffer (KHPO4) in relation 65/35 as mobile phase, injection volume of10 µL, analysis time of15 min, and detection at 220 nm.

Action of ketamine and endocannabinoid system in rapid anti-depression therapy / 上海交通大学学报（医学版）

Major depression disorder (MDD) is a common but serious affective disorder in modern society. Suicide idea and suicide behaviour induced by MDD during its later stage put a heavy burden on society and family. Anti-depression drugs lack efficiency in treating a portion of MDD patients. This is referred to as treatment resistant depression (TRD). A study reported the rapid onset and long lasting anti-depression effect of ketamine, which also come into effect in TRD patients. Δ9-Tetrahydrocannabinol is the active substance of marijuana, which also exerts rapid anti-depression effect via targeting at brain cannabinoid receptors. The two central nerve system stimulants belonging to the tightly controlled psychoactive substances have obvious adverse effects. This article summarizes the action of ketamine and endocannabinoid system in rapid anti-depression therapy in recent researches.

Action of ketamine and endocannabinoid system in rapid anti-depression therapy / 上海交通大学学报（医学版）

Major depression disorder (MDD) is a common but serious affective disorder in modern society. Suicide idea and suicide behaviour induced by MDD during its later stage put a heavy burden on society and family. Anti-depression drugs lack efficiency in treating a portion of MDD patients. This is referred to as treatment resistant depression (TRD). A study reported the rapid onset and long lasting anti-depression effect of ketamine, which also come into effect in TRD patients. △9-Tetrahydrocannabinol is the active substance of marijuana, which also exerts rapid anti-depression effect via targeting at brain cannabinoid receptors. The two central nerve system stimulants belonging to the tightly controlled psychoactive substances have obvious adverse effects. This article summarizes the action of ketamine and endocannabinoid system in rapid anti-depression therapy in recent researches.

The dimerization of -tetrahydrocannabinolic acid A (THCA-A)

The renewed interest in dimeric salicylates as broad-spectrum anti-inflammatory and anti-diabetic agents provided a rationale to investigate the dimerization of the substituted salicylate -tetrahydrocannabinolic acid (THCA-A, ) as a strategy to solve its instability to decarboxylation and to generate analogues and/or pro-drugs of this native pre-cannabinoid. Activation of the carboxylic group with the DCC-HOBt-DMAP protocol afforded a high yield of the OBt ester , that was next converted into the highly crystalline di-depsidic dimer upon treatment with DMAP. The mono-depsidic dimer was also formed when the reaction was carried out with partially decarboxylated THCA-A samples. The structure of the depsidic dimers was established by spectroscopic methods and by aminolysis of into the pre-cannabinoid amide . Both dimers showed excellent shelf stability and did not generate significant amounts of -THC upon heating. However, only the didepsidic dimer activated PPAR-, the major target of pre-cannabinoids, but strong binding to serum proteins abolished this activity, also shielding it from the action of esterases.

Development and validation of reverse phase high performance liquid chromatography method for the determination of delta-9-tetrahydrocannabinol and cannabidiol in oromucosal spray from cannabis extract

ABSTRACT A simple, fast, precise, accurate and responsive high performance liquid chromatography method was developed and validated carefully for determining an amount of delta-9-tetrahydrocannabinol and cannabidiol. A reverse phase Zorbax C-18 column 4.6 mm × 100 mm, 3.5 µm was eluted by using a mixture (85:15) of methanol and water as the mobile phase in an isocratic system with a flow rate of 1.0 ml/min and the injection volume was 10 µl, at a wavelength of 220 nm. The method was developed and validated through linearity, accuracy, precision and detection and quantitation limits studies. A good linear relationship (R2) of delta-9-tetrahydrocannabinol and cannabidiol were 0.9998 and 0.9995, respectively. The obtained % recoveries were found to be 98.3% and 96.5%. The relative standard deviations values of peak areas were found to range from 0.20% to 2.55% and 0.30% to 3.28% for delta-9-tetrahydrocannabinol and cannabidiol, respectively. Delta-9-tetrahydrocannabinol and cannabidiol presented limits of detection of 0.12, 0.23 µg/ml and limits of quantitation of 0.40, 0.76 µg/ml. The developed method could be employed for quantitative analysis of cannabis extract and oromucosal spray formulation.

Determination of Three Kinds of Cannabinoids in Cannabis UsingUltra-high Performance Liquid Chromatography-Tandem MassSpectrometry and Analysis of Phenotype of Cannabis / 分析化学

An analytical method of ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC/PDA-QDa) for the qualitative and quantitative analysis of Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD), and cannabinol (CBN) in confiscated cannabis was developed.The seized cannabis was extracted in methanol by sonication.The binary mobile phase consisted of methanol (containing 0.1% formic acid) and water.After centrifugation, the supernatant was separated on Waters UPLC BEH C18 column (50 mm×2.1 mm, 1.7 μm) with isocratic elution at a flow rate of 0.2 mL/min.The three cannabinoids were analyzed by photodiode array (PDA) detector at 220 nm and confirmed by mass spectrometer QDa.The correlation coefficient of standard curve for the three cannabinoids in linearity range was not less than 0.999, as well as the recoveries were 82%-102% with the relative standard deviations (RSD) of 0.36%-4.12% at three spiked levels.The method is specific, easy, quick and suitable for confirmation of the cannabinoids in seized cannabis.Cannabis plants in different areas were classified by their chemical phenotype as drug-type or fiber-type plants, taking into account the phenotypic index Δ9-THC, (Δ9-THC+CBN)/CBD, or the Δ9-THC/CBD and the (Δ9-THC+CBN)/CBD ratios.The analysis of the original composition of plant material is necessary for the detection and the quality control of cannabis plants.

Validación de un método para cuantificar ácido-11-nor-9-carboxi-delta 9-tetrahidrocannabinol en orina por cromatografía gaseosa-espectrometría de masas previa extracción en fase sólida / Validation of a method for quantify 11-nor-9-carboxy-delta 9-tetrahydrocannabinol in human urine using solid phase extraction and gas chromatography-mass spectrometry

El cannabis es una de las drogas ilegales más usadas a nivel mundial. Su consumo se relaciona con diferentes hechos en el ámbito forense, laboral, deportivo y clínico. Para su detección se utilizan métodos con diferentes fundamentos y alcances (inmunológicos, cromatográficos). En este trabajo se describe un método preciso, reproducible y validado, para la cuantificación del principal metabolito urinario del Δ9-tetrahidrocannabinol, el ácido-11-nor-9-carboxi- Δ 9-tetrahidrocannabinol (THC-COOH), por cromatografía gaseosa-espectrometría de masas (GC-MS). Se efectuó una extracción en fase sólida (SPE) a partir de la orina, previa hidrólisis alcalina. Se utilizó el análogo deuterado (THC-COOH D3) como estándar interno. El análisis por GC-MS se realizó en modo SIM. La curva de calibración fue lineal en el rango de trabajo (10-100 ng/ml, r > 0,999) y el límite de cuantificación fue de 10 ng/ml. La recuperación absoluta estuvo comprendida entre el 91,0 y 99,0 %. La precisión intra e inter ensayo fue de 1,06 a 1,26 y 3,59 a 9,80 %, respectivamente. El método fue aplicado a muestras reales, positivas por test inmunológico, resultando ser muy útil y fiable en el análisis de rutina de THC-COOH en orina humana con fines toxicológicos.

Cannabis is one of the most widely used illegal drug in the world. Its consumption is related to different forensic, work, sports and clinical events. In order to determinate the presence of cannabis, different methods with distinct fundamentals and scopes (immunoassay and chromatography) are applied. This report described an accurate, reproducible, and validated gas chromatography-mass spectrometry (GC-MS) method for the quantitation of 11-nor-9-carboxy- Δ9-tetrahydrocannabinol (THCCOOH), the major metabolite of Δ9-tetrahydrocannabinol in urine. A solid phase extraction (SPE), previous alkaline hydrolysis, was performed on the urine sample. Its deuterated analog (THC-COOH D3) was used as internal standard. The GC-MS analysis made by selected ion monitoring (SIM). Calibration curve was linear over the specified range (10 -100 ng/ml; r > 0.999) and limit of quantitation was 10 ng/ml. Absolute recoveries ranged from 91.0 to 99.0. Intra-assay and inter assay precision ranged from 1.06 to 1.26 and 3.59 to 9.80 %, respectively. The method has been applied to real samples, positive to immunological screening test, resulting to be very useful and reliable in routine analysis of THC-COOH in human urine for toxicological purposes.

Dependence Potential of the Synthetic Cannabinoids JWH-073, JWH-081, and JWH-210: In Vivo and In Vitro Approaches

Synthetic cannabinoids (CBs) such as the JWH series have caused social problems concerning their abuse liability. Because the JWH series produces euphoric and hallucinogenic effects, they have been distributed illegally under street names such as "Spice" and "Smoke". Many countries including Korea have started to schedule some of the JWH series compounds as controlled substances, but there are a number of JWH series chemicals that remain uncontrolled by law. In this study, three synthetic CBs with different binding affinities to the CB1 receptor (JWH-073, 081, and 210) and Delta9-tetrahydrocannabinol (Delta9-THC) were evaluated for their potential for psychological dependence. The conditioned place preference test (unbiased method) and self-administration test (fixed ratio of 1) using rodents were conducted. Ki values of the three synthetic cannabinoids were calculated as supplementary data using a receptor binding assay and overexpressed CB1 protein membranes to compare dependence potential with CB1 receptor binding affinity. All mice administered JWH-073, 081, or 210 showed significantly increased time spent at unpreferred space in a dose-dependence manner in the conditioned place preference test. In contrast, all tested substances except Delta9-THC showed aversion phenomenon at high doses in the conditioned place preference test. The order of affinity to the CB1 receptor in the receptor binding assay was JWH-210 > JWH-081 >> JWH-073, which was in agreement with the results from the conditioned place preference test. However, no change in self-administration was observed. These findings suggest the possibility to predict dependence potential of synthetic CBs through a receptor binding assay at the screening level.

Effect of (-)- Δ9 -tetrahydrocannabinoid on the hepatic redox state of mice

(-)-∆9-Tetrahydrocannabinol (∆9-THC), a psychoactive component of marijuana, has been reported to induce oxidative damage in vivo and in vitro. In this study, we administered (∆9-THC to healthy C57BL/6J mice aged 15 weeks in order to determine its effect on hepatic redox state. Mice were divided into 3 groups: (∆9-THC (N = 10), treated with 10 mg/kg body weight (∆9-THC daily; VCtrl (N = 10), treated with vehicle [1:1:18, cremophor EL® (polyoxyl 35 castor oil)/ethanol/saline]; Ctrl (N = 10), treated with saline. Animals were injected ip twice a day with 5 mg/kg body weight for 10 days. Lipid peroxidation, protein carbonylation and DNA oxidation were used as biomarkers of oxidative stress. The endogenous antioxidant defenses analyzed were glutathione (GSH) levels as well as enzyme activities of superoxide dismutase, catalase, glutathione S-transferase, glutathione reductase, and glutathione peroxidase (GPx) in liver homogenates. The levels of mRNA of the cannabinoid receptors CB1 and CB2 were also monitored. Treatment with ∆9-THC did not produce significant changes in oxidative stress markers or in mRNA levels of CB1 and CB2 receptors in the liver of mice, but attenuated the increase in the selenium-dependent GPx activity (∆9-THC: 8 percent; VCtrl: 23 percent increase) and the GSH/oxidized GSH ratio (∆9-THC: 61 percent; VCtrl: 96 percent increase), caused by treatment with the vehicle. ∆9-THC administration did not show any harmful effects on lipid peroxidation, protein carboxylation or DNA oxidation in the healthy liver of mice but attenuated unexpected effects produced by the vehicle containing ethanol/cremophor EL®.

Determination of ?~9-tetrahydrocannabinol Content in Hemp by GC-MS / 中国药房

OBJECTIVE:To determine the content of ?9-tetrahydrocannabinol (THC) in hemp by GC-MS. METHODS: HP-5 quartz capillary column was used. The temperature programming was as follows: the initial temperature was kept at 200 ℃ for 1 min, then raised to 270 ℃ at the rate of 3 ℃?min-1 and kept for 10 min; the injector temperature was 280 ℃and the detector temperature was 290 ℃. RESULTS: The good linearity between peak area and concentration was obtained over the range of 5.0 ～45.0 ?g?mL-1 (r=0.998 7). The lowest detectable limit was 1.0 ?g?mL-1(S/N=5).The average recovery rate was 81.1% (RSD=3.8%,n=9). CONCLUSION: The procedure is simple, accurate and reproducible, and suitable for the quality control of hemp preparation.

Delta-9-tetrahydrocannabinol and human spermatozoa.

The in vitro effect of Δ9-tetrahydrocannabinol on adenosine triphosphatase and phosphodiesterase activities as well as on the cyclic-AMP content of human spermatozoa has been studied. At a concentration of 1·0 μg, sperm metabolism may be increased as shown by increased cyclic AMP and adenosine-triphosphatase activity while at a higher concentration (10 μg tetrahydrocannabinol), it may be reversed.