Section 2.3: Lab-Based Transformations: The Chemical Conversion of Cannabinoids
Distinct from the plant's natural biosynthesis, cannabinoids can be chemically converted, modified, or synthesized in a laboratory setting. These processes often start with a naturally occurring cannabinoid, such as Cannabidiol (CBD) or Tetrahydrocannabinol (THC) extracted from cannabis or hemp, which then undergoes chemical reactions to produce different cannabinoids.
2.3.1: Focus: CBD Isomerization to Delta-8-THC
Delta-8-tetrahydrocannabinol (Δ⁸-THC) is a psychoactive cannabinoid and an isomer of the more abundant Delta-9-tetrahydrocannabinol (Δ⁹-THC). Due to its low natural abundance, commercial Δ⁸-THC is predominantly manufactured by chemically converting hemp-derived CBD using strong acid catalysts and organic solvents. This harsh reaction is prone to creating a variety of impurities and byproducts, including various iso-tetrahydrocannabinols (e.g., Δ⁴,⁸-iso-THC), Olivetol, and Cannabinol (CBN), many of which are not well-characterized pharmacologically and may not be disclosed on a Certificate of Analysis (CoA).
The Conversion Process:
The conversion of CBD to Delta8-THC is an isomerization reaction, specifically involving a ring closure (cyclization) of the CBD molecule. This chemical transformation is typically achieved under what are often described as "harsh reaction conditions". The process generally involves:
- Starting Material: CBD isolate or distillate extracted from hemp.
- Solvents: Organic solvents such as toluene, heptane, hexane, or dichloromethane are commonly used to dissolve the CBD and facilitate the reaction.
- Acid Catalysts: Strong acids are employed as catalysts to promote the cyclization reaction. Examples include p-toluenesulfonic acid (tosylic acid), hydrochloric acid, sulfuric acid, or Lewis acids like indium(III) triflate.
- Heat: The reaction often requires heating to proceed at a reasonable rate.
Impurities and Byproducts:
The chemical synthesis of Delta8-THC from CBD is known to be prone to side reactions, which can lead to the formation of a variety of impurities and byproducts. The nature and quantity of these byproducts can vary depending on the specific reaction conditions, catalysts, solvents used, and the skill of the chemist, as well as the thoroughness of post-synthesis purification processes.
Concerns regarding these impurities are significant because many are not well-characterized pharmacologically, and their presence may not be disclosed on product CoAs. Studies have reported finding such impurities in commercial Delta8-THC products at concentrations far exceeding what might be declared, if declared at all.
Identified impurities and byproducts in Delta8-THC samples have included:
- Delta9-THC (often above the legal limit for hemp products)
- Olivetol (a precursor in cannabinoid biosynthesis, but its presence here indicates side reactions or degradation)
- Cannabinol (CBN)
- Various iso-tetrahydrocannabinols (e.g., Delta4,8-iso-THC, Delta4-iso-THC, Delta8-cis-iso-THC)
- 8-hydroxy-iso-tetrahydrocannabinol
- 9β-hydroxyhexahydrocannabinol
- Other unidentified compounds
A major issue compounding this problem is the apparent inadequacy of testing for these specific conversion byproducts by some producers and third-party laboratories. Standard cannabinoid potency tests may not screen for these novel impurities.
2.3.2: Focus: Synthesis of Hexahydrocannabinol (HHC)
Hexahydrocannabinol (HHC) is a hydrogenated derivative of THC. It's typically produced in a two-step process: first converting CBD to THC, then adding hydrogen using a metal catalyst (like palladium or platinum). Purity is a significant concern, as final products can be contaminated with residual heavy metals from the catalyst if not properly purified. The final product is also a mix of active (9R-HHC) and largely inactive (9S-HHC) epimers, leading to inconsistent potency.
The Synthesis Process:
The most common route for producing HHC on a commercial scale involves a two-step process starting from hemp-derived CBD:
- Conversion of CBD to THC Isomers:
- CBD extract is first chemically converted into a mixture of Delta8-THC and Delta9-THC.
- This step is similar to the Delta8-THC synthesis described above, typically using an acid catalyst for cyclization.
- Hydrogenation of THC to HHC:
- The resulting THC mixture is then subjected to catalytic hydrogenation.
- This chemical reaction involves exposing the THC to hydrogen gas (H₂) under pressure in the presence of a metal catalyst.
- Common catalysts include palladium on carbon (Pd/C), platinum dioxide (Adams' catalyst), nickel, iridium, or rhodium.
- The hydrogen atoms add across the double bond in the THC structure, yielding HHC.
An older, less common method described in some literature involves the conversion of CBD to HHC isomers (specifically 9α-OH-HHC and 8-OH-iso-HHC) along with Delta9-THC using synthetic gastric juices. The Delta9-THC produced in this reaction would then need to be separated from the HHC products.
2.3.3: Focus: Synthesis of THC-O-Acetate
THC-O-acetate (THCO) is a synthetic ester of THC. It is considered a prodrug, becoming active after being metabolized by the body. The most alarming safety concerns arise when THCO is heated for inhalation. When heated, THCO can decompose to form both highly toxic ketene gas and Vitamin E acetate, both of which are severe lung toxicants strongly associated with the EVALI (E-cigarette or Vaping product use-Associated Lung Injury) outbreak.
Impurities and Toxicants in Semi-Synthetic Cannabinoids
| Product/Process | Associated Impurities or Toxicants | Source & Reason for Concern |
|---|---|---|
| Delta-8-Tetrahydrocannabinol (Δ⁸-THC) (from CBD) |
|
Source: Acid-catalyzed isomerization of CBD. The harsh reaction is not perfectly specific and creates numerous side-reaction products.
Concern: The toxicity of many of these novel impurities is unknown. Standard potency tests may not screen for them. |
| Hexahydrocannabinol (HHC) (from THC) |
|
Source: Catalytic hydrogenation of THC.
Concern: Inadequate purification can leave toxic heavy metals in the final product. Potency is inconsistent due to unknown epimer ratios. |
| THC-O-Acetate (THCO) (Vaped/Heated) |
|
Source: Thermal decomposition of the acetate group upon heating.
Concern: Both THCO and Vitamin E Acetate are acetate esters that produce highly toxic ketene gas when vaped. Vitamin E Acetate itself is a severe lung toxicant that can cause lipoid pneumonia. These compounds were strongly implicated in the EVALI public health crisis, which caused severe lung injuries and deaths. |
| Tetrahydrocannabiphorol (THCP) |
|
Source: Synthetic reaction of a resorcinol with a terpene derivative.
Concern: Creates multiple isomers whose pharmacological and toxicological profiles are unknown. Incomplete purification can leave behind unreacted industrial chemicals. |
⚠️ Special Warning: Vaping Acetate Compounds
The connection between THC-O-Acetate and Vitamin E Acetate is particularly concerning for consumer safety. When heated during vaping:
- Both compounds can decompose to form ketene gas (CH₂=C=O), a highly toxic lung toxicant
- Vitamin E Acetate can also coat lung tissue, leading to lipoid pneumonia
- These mechanisms were central to the 2019-2020 EVALI outbreak, which caused thousands of hospitalizations and multiple deaths
- There is NO SAFE WAY to vape or heat these acetate compounds
Understanding these laboratory-based transformations is crucial for consumers, as they highlight the complexity of synthetic cannabinoid production and the potential risks associated with impurities and byproducts. The formation of toxic compounds like ketene gas and the presence of Vitamin E Acetate in THCO products represents a particularly severe risk that has already caused significant public health impacts.