1972-08-3

Usage

Uses

1. Medical Applications:
DELTA9-TETRAHYDROCANNABINOL is used as an antinausea agent and appetite stimulant for patients with AIDS and cancer. It is particularly effective in treating anorexia associated with AIDS and nausea and vomiting associated with cancer chemotherapy.
2. Pharmaceutical Industry:
Used in the Pharmaceutical Industry:
DELTA9-TETRAHYDROCANNABINOL is used as a controlled substance (hallucinogen) for the development of prescription drugs such as Marinol and Cesamet. These drugs are approved by the Food and Drug Administration for their antinausea and appetite-stimulating properties.
3. Forensic and Research Purposes:
DELTA9-TETRAHYDROCANNABINOL is used as a natural psychoactive compound for forensic and research purposes. It binds with high affinity to both the central CB1 receptor and the peripheral CB2 receptor, allowing for the study of its diverse effects on various physiological processes.
4. Pain Management:
In 2005, Canada was the first country to approve Sativex, a cannabis spray that relieves pain in people with multiple sclerosis. DELTA9-TETRAHYDROCANNABINOL is a key component of this spray, providing relief for patients suffering from chronic pain.
5. Cannabis Industry:
DELTA9-TETRAHYDROCANNABINOL is the principal active constituent of cannabis, making it a crucial component in the production of marijuana and hashish. It is responsible for the psychoactive effects of these substances, which are used for recreational and medicinal purposes. The THC content in these products can vary, with good quality marijuana having a THC content of approximately 10%, and good hashish and hashish oils generally having THC contents between 30% and 80%.
6. Hemp Industry:
Although not directly a use for DELTA9-TETRAHYDROCANNABINOL, the Cannabis sativa plant from which it is derived is also known as hemp. Hemp is a versatile resource, with its stem being used for the production of fiber for rope, twine, paper, and cloth. Additionally, hemp seeds are edible and high in protein, and their fatty oil can be used for food, cosmetics, medicines, and as a fuel source.

Originator

Unimed (USA)

History

THC was first isolated from hashish in 1964 by Raphael Mechoulam (1930–) and Yehiel Gaoni at the Weizmann Institute. In the early 1990s, the specific brain receptors affected by THC were identified. These receptors are activated by a cannabinoid neurotransmitter called arachidonylethanolamide, known as anandamide. Anandamide was named by Mechoulam using ananda, which is the Sanskrit word for ecstasy. Anandamide is thought to be associated with memory, pain, depression, and appetite. THC is able to attach to and activate anandamide receptors. These receptors are actually called THC receptors rather than anandamide receptors because researchers discovered that THC attaches to these receptors before anandamide was discovered. The areas of the brain with the most THC receptors are the cerebellum, the cerebral cortex, and the limbic system. This is why marijuana affects thinking, memory, sensory perception, and coordination.

Manufacturing Process

δ-9-Tetrahydrocannabinol (THC, also known as dronabinol) is the main biologically active component in the Cannabis plant extracted from the resin of Cannabis sativa (marihuana, hashish).One kg of the fine powdered marijuana plant material [average % of THC was about 5.21%] was macerated with 6 L hexanes (Hexanes GR from EM Sciences) in a percolator (9" in diameter from the top and 20" long, cone shaped) for 24 hours at room temperature and filtered. The macerate was reextracted with 5 L hexanes for another 24 hours. The hexane extracts were combined and evaporated under reduced pressure at low temperature to give 110.7 g residue (11.07% extractives). The % of THC in the hexane extract was 41.21%.Column Chromatography.The hexane extract (110.7 g) was mixed with 150 g silica gel (silica gel 60, Art.# 9385-3) and 50 ml hexane. The air dried slurry was transferred to the top of a silica gel column (800 g silica gel 60, particle size 0.04-0.063 mm, from EM Science, Art.# 9385-3). The column was eluted with hexane:ether mixtures in a manner of increasing polarities. Fractions were collected and TLC screened (analytical silica gel plates, developing system: Hexane:Ether (80:20), Visualizing agent: Fast blue). The fractions collected with hexane (3 L) and hexane-ether (95:5, 2 L) were discarded. The following fractions collected with hexane-ether (95:5, 3 L) and hexane-ether (9:1, 5 L) were combined and evaporated to yield 77.2 g of residue. GC analysis of the residue showed THC concentration to be 54.74%.Fractional DistillationA portion (30.5 g) of the residue collected above was subjected to fractional distillation under reduced pressure (0.1-0.15 mm/Hg). The temperature was slowly raised to 125°C and the materials collected were kept separate. The temperature was then raised between 140°-160°C where the major fraction was collected (14 g). GC analysis showed >96% THC. Further purification on a silica gel column gives THC with at least 98% purity. An improvement of this process includes the use of high pressure liquid chromatography (HPLC). The preparation of dronabinol and related compounds have employed acidcatalyzed electrophilic condensation of a 5-alkylresorcinol such as 5-npentylresorcinol (commonly known as olivetol) and a menthadienol, followed by cyclization; yield of desired product is about 17-22% (Petrzilka et al., Helv. Chim. Acta, 52, 1102 (1969)).

Therapeutic Function

Appetite stimulant

Air & Water Reactions

Slightly soluble in water.

Reactivity Profile

DELTA9-TETRAHYDROCANNABINOLis very unstable to light and high temperatures. DELTA9-TETRAHYDROCANNABINOL should be protected from air during all handling due to its extreme instability. . Flammable and/or toxic gases are generated by the combination of alcohols with alkali metals, nitrides, and strong reducing agents. They react with oxoacids and carboxylic acids to form esters plus water. Oxidizing agents convert them to aldehydes or ketones. Alcohols exhibit both weak acid and weak base behavior. They may initiate the polymerization of isocyanates and epoxides.

Fire Hazard

Flash point data for DELTA9-TETRAHYDROCANNABINOL are not available; however, DELTA9-TETRAHYDROCANNABINOL is probably combustible.

Biological Activity

Cannabinoid receptor agonist (K i values are 5.05 and 3.13 nM for CB 1 and CB 2 receptors respectively; EC 50 values are 6, 0.4 and 8 nM at CB 1 , CB 2 and GPR55 receptors respectively). Major psychoactive constituent of marijuana.

Clinical Use

Dronabinol (synthetic △9-THC) i s a n antinauseant approved for the treatment of nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetics. A related cannabinoid, nabilone, was introduced in Canada for his indication in 1982.

Safety Profile

Poison by intraperitoneal and intravenous routes. Moderately toxic by ingestion. Experimental reproductive effects. Questionable carcinogen with experimental tumorigenic and teratogenic data. Human mutation data reported. A hallucinatory drug. When heated to decomposition it emits acrid smoke and irritating fumes. See also CANNABIS.

InChI:InChI=1/C21H30O2/c1-5-6-7-8-15-12-18(22)20-16-11-14(2)9-10-17(16)21(3,4)23-19(20)13-15/h11-13,16-17,22H,5-10H2,1-4H3/t16-,17-/m0/s1

Upstream product

• 917-64-6 methyl magnesium iodide 
• 930597-99-2 1-(2,6-dimethoxy-4-pentylphenyl)prop-2-en-1-ol 
• 500-66-3 Olivetol 
• 5392-40-5 (E/Z)-3,7-dimethyl-2,6-octadienal 
• 874126-33-7 1-Chlor-hexahydrocannabinol 
• 20053-58-1 (1S,2S,3R,6R)-(+)-trans-car-2-ene epoxide 
• 1686-20-0 p‐mentha‐1,5‐dien‐8‐ol 
• 936-91-4 3-carene epoxide 
• 36403-68-6 D1,2-Tetrahydrocannabinol methyl ether 
• 1195-92-2 (4R)-limonene 1,2-epoxide 
• 22976-40-5 1,3-dimethoxy-5-pentylbenzene 
• 16849-50-6 tetrahydrocannabinol 
• 23978-85-0 tetrahydrocannabinolic acid 
• 20053-40-1 cis-Δ²-p-menthene-1,8-diol 

Downstream Products

• 36557-05-8 11-nor-9-carboxt-Δ-9-tetrahydrocannabinol 
• 74184-29-5 cannabitriol 
• 52855-15-9 Δ9-THC-1-O-COCH2CH2COOH 
• 1259515-25-7 10-ethoxy-6,6,9-trimethyl-3-pentyl-7,8,9,10-tetrahydro-6H-benzo[c]chromene-1,9-diol 
• 521-35-7 cannabinol 
• 36403-68-6 D1,2-Tetrahydrocannabinol methyl ether 
• 1563174-96-8 (6aR,10aR)-1-(4-chlorobenzyloxy)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene 
• 1563174-95-7 (6aR,10aR)-1-(2-chlorobenzyloxy)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene 
• 16849-50-6 tetrahydrocannabinol 
• 878210-24-3 1-O-(4-methoxycarbonyl)benzyl-Δ9-tetrahydrocannabinol 

Relevant academic research and scientific papers

Antioxidant function of phytocannabinoids: Molecular basis of their stability and cytoprotective properties under UV-irradiation

In this contribution, a comprehensive study of the redox transformation, electronic structure, stability and photoprotective properties of phytocannabinoids is presented. The non-psychotropic cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN), cannabichromene (CBC), and psychotropic tetrahydrocannabinol (THC) isomers and iso-THC were included in the study. The results show that under aqueous ambient conditions at pH 7.4, non-psychotropic cannabinoids are slight or moderate electron-donors and they are relatively stable, in the following order: CBD > CBG ≥ CBN > CBC. In contrast, psychotropic Δ9-THC degrades approximately one order of magnitude faster than CBD. The degradation (oxidation) is associated with the transformation of OH groups and changes in the double-bond system of the investigated molecules. The satisfactory stability of cannabinoids is associated with the fact that their OH groups are fully protonated at pH 7.4 (pKa is ≥ 9). The instability of CBN and CBC was accelerated after exposure to UVA radiation, with CBD (or CBG) being stable for up to 24 h. To support their topical applications, an in vitro dermatological comparative study of cytotoxic, phototoxic and UVA or UVB photoprotective effects using normal human dermal fibroblasts (NHDF) and keratinocytes (HaCaT) was done. NHDF are approx. twice as sensitive to the cannabinoids’ toxicity as HaCaT. Specifically, toxicity IC50 values for CBD after 24 h of incubation are 7.1 and 12.8 μM for NHDF and HaCaT, respectively. None of the studied cannabinoids were phototoxic. Extensive testing has shown that CBD is the most effective protectant against UVA radiation of the studied cannabinoids. For UVB radiation, CBN was the most effective. The results acquired could be used for further redox biology studies on phytocannabinoids and evaluations of their mechanism of action at the molecular level. Furthermore, the UVA and UVB photoprotectivity of phytocannabinoids could also be utilized in the development of new cannabinoid-based topical preparations.

Synthesis of Para (-)-Δ8-THC Triflate as a Building Block for the Preparation of THC Derivatives Bearing Different Side Chains

A two-step synthesis of para (-)-Δ8-THC-OTf that can be used as building block for late-stage introduction of side chains to the tetrahydrodibenzopyran core of THC by cross-coupling chemistry is presented. No protecting groups are needed, and (

Decarboxylation of Δ9-tetrahydrocannabinol: Kinetics and molecular modeling

Efficient tetrahydrocannabinol (Δ9-THC) production from cannabis is important for its medical application and as basis for the development of production routes of other drugs from plants. This work presents one of the steps of Δ9-THC production from cannabis plant material, the decarboxylation reaction, transforming the Δ9- THC-acid naturally present in the plant into the psychoactive Δ9-THC. Results of experiments showed pseudo-first order reaction kinetics, with an activation barrier of 85 kJ mol-1 and a pre-exponential factor of 3.7 × 108 s-1. Using molecular modeling, two options were identified for an acid catalyzed β-keto acid type mechanism for the decarboxylation of Δ9- THC-acid. Each of these mechanisms might play a role, depending on the actual process conditions. Formic acid proved to be a good model for a catalyst of such a reaction. Also, the computational idea of catalysis by water to catalysis by an acid, put forward by Li and Brill, and Churchev and Belbruno was extended, and a new direct keto-enol route was found. A direct keto-enol mechanism catalyzed by formic acid seems to be the best explanation for the observed activation barrier and the pre-exponential factor of the decarboxylation of Δ9-THC-acid. Evidence for this was found by performing an extraction experiment with Cannabis Flos. It revealed the presence of short chain carboxylic acids supporting this hypothesis. The presented approach is important for the development of a sustainable production of Δ9-THC from the plant.

Cannabidiol as the Substrate in Acid-Catalyzed Intramolecular Cyclization

The chemical reactivity of cannabidiol is based on its ability to undergo intramolecular cyclization driven by the addition of a phenolic group to one of its two double bonds. The main products of this cyclization are Δ9-THC (trans-Δ-9-tetrahydrocannabinol) and Δ8-THC (trans-Δ-8-tetrahydrocannabinol). These two cannabinoids are isomers, and the first one is a frequently investigated psychoactive compound and pharmaceutical agent. The isomers Δ8-iso-THC (trans-Δ-8-iso-tetrahydrocannabinol) and Δ4(8)-iso-THC (trans-Δ-4,8-iso-tetrahydrocannabinol) have been identified as additional products of intramolecular cyclization. The use of Lewis and protic acids in different solvents has been studied to investigate the possible modulation of the reactivity of CBD (cannabidiol). The complete NMR spectroscopic characterizations of the four isomers are reported. High-performance liquid chromatography analysis and 1H NMR spectra of the reaction mixture were used to assess the percentage ratio of the compounds formed.

MASS PRODUCTION AND APPLICATION OF DELTA 8 THC

A process of converting cannabidiol (CBD) to Δ8-tetrahydrocannabinol (Δ8-THC) or Δ9-tetrahydrocannabinol (Δ9-THC) can enable mass production of Δ8-THC and/or Δ9-THC, achieve greater yields and higher purity in comparison to previously reported processes while eliminating the use of organic solvent. The resultant hemp-derived Δ8-THC can be mixed with and absorbed by natural extracts, including tea extract, starch, sugar, lecithin, and other emulsifiers. Δ8-THC used in edible, topical and vaping products such as powdered Δ8-THC food ingredients, tablets or pills, suppositories, and vape formulations are disclosed. Further described are beverages and baked goods utilizing or incorporating the tablets or powdered Δ8-THC to create edible products containing an emulsified, tasteless, and odorless dose of Δ8-THC. The disclosure also describes a rectal suppository designed to provide improved comfort of use. A Δ8-THC liquid composition can be use in an electronic cigarette smoking device for pulmonary administration of Δ8-THC, which results in more effective absorption.

METHODS FOR CONVERTING CBD TO TETRAHYDROCANNABINOLS

This disclosure provides a method for converting CBD to a tetrahydrocannabinol featuring the use of cheap and non-toxic aluminum isopropoxide as a catalyst. The method comprises (a) providing a reaction mixture comprising a catalyst in an organic solvent, wherein the catalyst comprises aluminum isopropoxide; (b) adding a reagent comprising CBD to the reaction mixture; (c) mixing the reaction mixture and allowing a reaction for converting CBD to a tetrahydrocannabinol to occur for a predetermine period of time; (d) removing the catalyst by filtration upon the completion of the reaction; (e) removing the organic solvent; and (f) eluting the tetrahydrocannabinol from the organic phase.

METHODS FOR PREPARING CANNABINOIDS AND RELATED INSTRUMENTS

Methods and instrumentation for converting cannabidiol (CBD) and CBD-like compounds to other naturally-occurring or synthetic cannabinoids, such as THC, CBN and/or CBC, which processes may be solvent-free, Generally, the conversion of CBD is carried out in the presence of a Lewis acid, an oxidant or both, which may be present in catalytic amounts. A reaction may be a two-phase reaction with the Lewis acid present on a support material in a column or similar chamber through which CBD passes and is converted to the cannabinoids. The reactions allow direction of relative yields of certain cannabinoid products by altering the identity of the acid reagent.

CATALYTIC CONVERSATION OF CANNABIDIOL AND METHODS THEREOF

A method of converting cannabidiol (CBD) into Δ9-Tetrahydrocannabinol (Δ9-THC) and Δ8-Tetrahydrocannabinol (Δ8-THC). The method provides a polar aprotic solvent such as Tert-Butyl Methyl Ether, Tetrahydrofuran, dicloromethane, or chloroform. Cannabidiol starting material mixes into the polar aprotic solvent in a chemical reactor to make a cannabinoid solution. Adding a metallic catalyst capable of performing intramolecular hydroalkoxylation to the cannabinoid solution and mixing it converts the cannabidiol starting material into Δ9-Tetrahydrocannabinol (Δ9-THC) and Δ8-Tetrahydrocannabinol (Δ8-THC) in a ratio of at least 6:1. The catalyst is a metal such as a transition metal or is selected from the group consisting of ruthenium, aluminum, iron, gold, silver, copper, platinum, and combinations thereof. In one embodiment a co-catalyst is used such as a triflate salt. Regulating the temperature of the reaction to less than 20° C. yields a predominance of Δ9-THC, i.e. Δ9-THC is more than 75% of the cannabinoid mix.

STABLE CANNABINOID COMPOSITIONS

The present application discloses powder and aqueous formulations. These include but are not limited to water dispersible cannabinoid formulations, especially those comprising cannabidiol (CBD), cannabigerol (CBG), and cannabinol (CBN) as well as other cannabinoids. Generally, these embodiments do not include major amounts of Tetrahydrocannabinol (THC), but certain embodiments are envisioned that do contain measurable concentrations of THC. Embodiments may include one or more emulsifiers selected from the group consisting of Tween (polysorbate) 20, Tween 60, Tween 80, Span 20, Span 60, Span 80, Poloxamer 188, Vit E-TPGS (TPGS), TPGS-1000, TPGS-750-M, Solutol HS 15, PEG-40 hydrogenated castor oil, PEG-35 Castor oil, PEG-8-glyceryl capylate/caprate, PEG-32-glyceryl laurate, PEG-32-glyceryl palmitostearate, Polysorbate 85, polyglyceryl-6-dioleate, sorbitan monooleate, Capmul MCM, Maisine 35-1, glyceryl monooleate, glyceryl monolinoleate, PEG-6-glyceryl oleate, PEG-6-glyceryl linoleate, oleic acid, linoleic acid, propylene glycol monocaprylate, propylene glycol monolaurate, polyglyceryl-3 dioleate, polyglyceryl-3 diisostearate and lecithin.

Photochemistry of Cannabidiol (CBD) Revised. A Combined Preparative and Spectrometric Investigation

Cannabis is a plant with an astonishing ability to biosynthesize cannabinoids, and more than 100 molecules belonging to this class have been isolated. Among them in recent years cannabidiol (CBD) has received the interest of pharmacology as the major nonpsychotropic cannabinoid with many potential clinical applications. Although the reactivity of CBD has been widely investigated, only little attention has been given to the possible photodegradation of this cannabinoid, and the data available in the literature are outdated and, in some cases, conflicting. The aim of the present work is providing a characterization of the photochemical behavior of CBD in organic solvents, through a detailed GC-MS analyses, isolation, and NMR characterization of the photoproducts obtained.