When you consider that the Farm Bill was just passed in 2018, it’s an unfortunate circumstance that cannabidiol (CBD) has fallen out of favor with so many people. It kind of makes sense though since it was put into such a wide array of consumer products from pillowcases to pet products that it likely caused the questioning of its medicinal aspects. Furthermore, most product forms are not allowed by the US Food & Drug Administration (FDA) under the Food, Drug and Cosmetic (FD&C) Act, greatly stifling product manufacturers looking to comply with federal regulations.
So, the overabundance of CBD-rich hemp extracts that were produced caused their price to plummet, and product manufacturers looked for new, creative ways to cash in on the fruits of their investments. They didn’t have to look far into the scientific literature to find that CBD can be transformed into Δ8-tetrahydrocannabinol (Δ8-THC), the psychoactive isomeric cousin of the naturally occurring Δ9-tetrahydrocannabinol (Δ9-THC). What has had people concerned is that some product manufacturers striving to create these cannabinoids do not have the scientific acumen of a skilled organic chemist and may not understand the myriad byproducts that can be routinely produced using less than adequate chemistry techniques.
This concerns anyone seeking to utilize cannabis products medicinally, and any product manufacturers wanting to create high quality, safe to consume finished goods. To better understand what can go wrong, I recently spoke with Mark Scialdone, Ph.D., a seasoned and respected organic chemist and the founder, president, and principal consultant of BetterChem Consulting that provides expertise to the essential oil and cannabis industries.
Witnessing the Magic
I first asked Dr. Mark how he got involved in the cannabis industry in the first place. “I started a consulting company in 2013 upon leaving DuPont after 19 years working in their central research and development group in Wilmington, DE. Mark began. “There, I had worked on a project that developed an insect repellent derived from a plant essential oil, that they decided not to commercialize. We had obtained an EPA registration of the active ingredient and formulations and it was indeed effective against biting flies and mosquitoes. My lab was responsible for the chemistry that underpinned this product which involved plant extraction, hydrogenation, and stereoisomers. When a startup company in San Francisco decided to commercialize it, I began consulting with them on the development of this product that I was very familiar with. The product itself is based on a hydrogenated plant oil for which a supply chain needed to be built that started with agriculture and led into essential oil chemistry. I didn’t take long to realize that my expertise in this area of natural product chemistry could be applied to cannabis and right around that time, I ran into an old friend that I knew from musical circles who suggested that I attend a Cannabis Cup to see what’s going on in this new industry. So, I went to my first Cup in Santa Rosa in the spring 2014 and met so many people who were growing and extracting. I met one hemp farmer from Loveland, CO with whom I had some common friends who just obtained an extractor. He asked if on my way back home, if I’d like to stop by his farm and help him to formulate some extract into oil. So, I did just that, and we made some hemp-derived CBD-enriched extract using a fondue pot in his kitchen to fully decarboxylate the extract. We added some coconut oil to the extract to target a particular dosage based on a local doctor’s success in treating epilepsy in children with CBD enriched oils. It was the first time that I made medicated oil and brought a syringe of it home as a souvenir of the experience.”
“After that, I started becoming involved in the growing movement for medical cannabis in Pennsylvania where I was living. I went to Harrisburg to attend a rally on the Capitol steps, and there, I met the mother of a child who had Dravet’s syndrome. When the young girl started having a seizure, I saw the fear that went through her mom in a second and witnessed the emotional gauntlet that these parents face so their kids won’t die during a seizure which could be their last one.”
Mark realized that he had a syringe of CBD oil at home that this family needs. Ultimately, through a trusted friend who was a known cannabis lawyer in Pittsburgh, the syringe of CBD oil made its way to the family. Mark had forgotten about it when several months later, he received a call from a Pittsburgh area code that he did not immediately recognize. It was a woman in tears who began thanking him for ‘bringing our angel to earth’. It turns out that the caller was the grandmother of the child with Dravet’s syndrome and she told Mark that the CBD oil had a beyond miraculous impact on the young girl. She was born with a brain defect that did not allow her the use of the right side of her body and was, for the most part, nonverbal for all of her eight years on earth heavily drugged on a pharmaceuticals including opiates and steroids to try to control her hundreds seizures she had every day. After taking the oil for the first time, she slept through the night without having any seizures, woke up with laughter and then spoke her first words ever saying “I’m hungry. I want something to eat” to her grandmother. She had been awakened and was now communicative.
The family sent an image of her daily report card from the school that she attended the following Monday, showing incredible to the point of unbelievable progress on all fronts. However, some at the school thought that there was something wrong with her miraculous turnaround, heard that she had taken cannabis and someone from the school called the police.
After getting a call from a detective, the mom consequently called a news reporter from a local television station, who had recently reported on the growing medical cannabis movement in Pennsylvania and asked her to come see her daughter to show what cannabis oil has donee. The station did a news story that night from their home showing the child playing as a normal, healthy child would after receiving the oil and pictures of her from a week earlier before getting the oil. It was a day and night difference. After that story aired, the police left the family alone and when the syringe ran out, the reporter accompanied the family to that farm in Loveland Colorado to meet the farmer and get more oil. When the newly elected democratic governor was elected that fall, he issued safe harbor letters to medical patients in Pennsylvania and she received one and when the legislation was signed by that governor, he used ten different black felt-tip pens and she got one of those as well.
This child ended up being an important example in our state of what this medicine can do to make lives better and that oil became a commercial CBD product called Remedy. “That’s how I learned that cannabis really impacts not just patients but the families of those patients,” Mark added. “The best Christmas present that I got that year was the gratitude of a family I didn’t even know.”
Delta-8
The contemporary story of Δ8-THC has it all: garage chemistry, politics, legalese, and a supposed loophole that is enabling many to cash in on bargain-basement CBD. The FD&C act enforced by the FDA precludes using an active ingredient of approved drugs in a food, feed, or cosmetics unless an exception is made. The recent FDA approval of Epidiolex legally complicates the use of CBD in many product forms creating a glut of CBD on the open market. While there is no mention of Δ8–THC in the 2018 Farm Bill that removed industrial hemp characterized as having less than 0.3% Δ9-THC, the Δ8 isomer which is thermodynamically favored over the naturally occurring Δ9 isomer is listed by name in the Controlled Substances Act (CSA).
Mark points out that based on the published data, that Δ8 isomer is no more harmful than the naturally occurring Δ9 isomer, but that some of the byproducts that are formed during the chemical conversion reaction are unknown in terms of being safe for human. I asked if he had identified any contaminants in Δ8-THC products that cause him concern.
“Most if not all Δ8-THC products being produced today are not derived from refinement of a plant extract from either industrial hemp or cannabis. They are being made in laboratory vessels starting with CBD isolate in a chemical reaction similar to the manufacture of other active pharmaceutical ingredients (APIs), often in a unoptimized process without proper analytical methods or standards to establish product specifications that are essential to guarantee product quality and safety.”
“I have co-authored a manuscript along with two medical doctors that is currently in press in Cannabis and Cannabinoid Research, about this very topic. We point out several recent studies that have analyzed Δ8-THC products currently being sold. Hemp processors use an acid-catalyzed ring closure of CBD (ACRCC) reaction to convert it into Δ8-THC and under thermodynamic control of that reaction, there’s the possibility of forming several non-natural THC isomers that have unknown impact on human safety when consumed.”
Mark was among several experts that participated in a conference call organized by the Cannabis Chemistry subdivision (CANN) of the American Chemical Society that occurred in August 2021 and is available on YouTube. “That was a very informative call that included valuable insight from Dr. Richard Sams an analytical chemist from KCA Laboratories in Kentucky, who has had a wealth of experience in analyzing Δ8-THC products. Dr. Sams pointed out that the non-THC isomers formed the ACRCC conversion reaction co-elute by most high-performance liquid chromatography (HPLC) methods making their identification and quantification problematic in the product mixtures.”
“If Δ9-THC was legal, we wouldn’t likely know what Δ8-THC is,” Mark commented. “When the Farm Bill was passed, did Congress contemplate the known conversion to Δ8-THC originally described by noted early cannabinoid chemist Professor Roger Adams and then in greater detail by Professor Raphael Mechoulam in the open chemical literature that included issued US patents?”
“Being more thermodynamically stable than Δ9-THC, any occurrence of Δ8-THC is due to isomerization of decarboxylated Δ9-tetrahydrocannabinolic acid (Δ9-THCA). The plant does not produce Δ8-configured cannabinoids and they only occur by isomerization of the double bond in the methyl-cyclohexenyl ring, moving it one carbon further away from the benzene ring fusion of the benzopyran ring system, which is lower in energy creating a slight preference for the Δ8 isomer over the Δ9 isomer.”
“This isomerization of the naturally occurring Δ9-configured cannabinoids can be catalyzed by trace amounts of acid and accelerated with heating (distillation). Standard laboratory glassware as well acidic clays and other silicates used for color and pesticide remediation can catalyze this conversion. So called “bleaching clays” used to refine vegetable oils to remove unwanted color and flavors have been used to convert Δ9-THC enriched distillates purified from cannabis extracts quantitatively into Δ8-THC distillate.”
The conversion from Δ9-THC to Δ8-THC turns out to be less complicated than converting CBD to Δ8-THC. “Using a strong acid (e.g., hydrochloric acid) creates a positively charged carbonium ion intermediate that can be promiscuous leading to the formation of several non-natural THC isomers and the potential to form chlorinated cannabinoid byproducts.
Mark pointed to a recent study by Meehan-Atrash and Rahman that analyzed several commercial Δ8-THC vape products using modern analytical chemistry techniques including HPLC and NMR. [1]
None of the vape products that were tested in that study had the correct amount Δ8-THC labeled on the product, and to Mark, the most alarming finding was the presence of olivetol in many of the samples. Olivetol is a well-known precursor in cannabinoid total synthesis but its presence in these products, according to Mark, is likely due to a degradation pathway of CBD under the ACRCC conversion reaction conditions.
“The finding in this study that olivetol is present in many Δ8-THC products is indeed troubling and points to a reaction pathway in the ACRCC conversion involving a retro-Friedel Crafts dealkylation of the terpenyl ring severing the carbon-carbon bond in CBD that connects the olivetol ring with the terpenyl ring. This results in the disassociation of the olivetol portion of the molecule as a negatively charged anion from the terpenyl ring as a positively charged cation. This ion pair can recombine in a non-stereoselective (started as trans in the natural configuration of CBD and now becomes a mixture of cis and trans) as well as in a non-regioselective fashion at the other two unsubstituted positions on the olivetol ring, all of which leads to the formation of pairs (cis and trans) of non-natural ortho and iso regioisomers of THC.
“However, the other distinct possibility supported by the presence of olivetol in the final product is that the terpenyl cation, rather than recombining with olivetol, can lose a proton from the acid catalyst (protonating the olivetol anion) and aromatize to form p-cymene, a naturally occurring terpene and leaving olivetol in the final product mixture. These product mixtures should be distilled to purify the higher boiling cannabinoids from the lower boiling olivetol but apparently, the ones tested still had olivetol present. Olivetol is a known respiratory hazard and something that shouldn’t be consumed in a vaporized product.”
“The formation and presence of the several non-natural THC isomers formed in the ACRCC conversion reaction as described in the chemical literature is the reason I believe that Δ8-THC products typically are reported to be less potent than corresponding Δ9-THC products on the assumption that the non-natural isomers formed are not CB1 agonists like pure Δ9-THC and Δ8-THC are. This is a testable hypothesis that we are currently exploring to better understand the activity of known byproducts formed in the ACRCC conversion reaction.”
THC to CBN
In addition to producing Δ8-THC from CBD, some poduct manufacturers look to create cannabinol (CBN) out of hemp-derived extracts. I asked Mark about some of the best and worst ways to go about this.
“Just like Δ8-THC, the plant does not produce CBN. They’re both formed as degradation products derived from isomerization and oxidation respectively of decarboxylated Δ9-THCA. While industrial hemp is defined as having 0.3% Δ9-THC or less, in extract or distillate concentrates of hemp, the amount of Δ9-THC exceeds the 0.3% limit defined in the 2018 Farm Bill. Separation of the Δ9-THC from those process fractions can be accomplished practically by two different chemical separations, namely traditional chromatographic separation methods or selective in situ oxidation of the Δ9-THC to CBN. It turns out that the oxidation route, which requires thermal aging of the material in the presence of air, converts the Δ9-THC into CBN without substantially degrading the CBD present in a process referred to as thermal remediation. This remediation process can be done on extracts or distillates to produce products that have no detectable Δ9-THC.”
Traditionally, the use of stoichiometric oxidants such as elemental sulfur and quinones have been described to convert Δ9-THC into CBN but another recently published method involves the use iodine which is not as clean of a conversion as the authors claim in the paper. Catalytic dehydrogenation of Δ9-THC using heterogeneous catalysts is likely a better, cleaner method than use of stoichiometric oxidants in the commercial manufacture of CBN.
Misconceptions and the Future
I asked Mark what he felt the most common misconceptions regarding the industry are, and what he foreshadows for the future.
“Oh, there are misconceptions all over the place. I always tell people that they are fooled by their own misconceptions. One main misconception is that Δ8-THC is made by the plant. No, it’s likely an artifact of how the analytical sample is prepared. The plant does not make Δ8-configured cannabinoids. THCA decarbs to Δ9-THC which turns out to be metastable then converts to Δ8-THC by isomerization which is thermodynamically favored over the naturally occurring Δ9-configuration.”
“Another misconception is that cannabis is a drug. It’s not, it’s a medicated herb and it needs to be regulated as such and needs to be removed from the CSA. Whenever a medicated herb can provide relief to a medical condition or ailment, it should not only be legal to access, it should also be encouraged by medical professionals before taking pharmaceuticals with their litany of toxic side effects not present when using cannabis. Since cannabis is not dangerous like tobacco and alcohol, both of which are legal, easily accessible, and can be deadly if misused, it does not need to be controlled under the CSA where it is still categorized as Schedule 1, which by definition, has no known medical use and can easily be abused. How does that make sense when there are FDA approved drugs with active ingredients (THC and CBD) that are derived from the same plant? The FDA needs to recognize the role that medicated herbs have and there’s many similarities in other agricultural industries that need to be firmly planted to ensure product quality and consumer safety. Humans have freely used this plant for a many thousands of years until last century, the cannabis-deficient century, due to unjust prohibition laws. We’re witnessing the end of federal cannabis prohibition in this century resulting in a re-unification of humans with this amazing plant and all that it can do to make lives better. It is not nuclear waste, the sky has not fallen, and the kids are alright.”
“An exception to the FD&C act needs to be made by the Secretary of the Department of Human and Health Services (HHS) for cannabinoids so that cannabis-based products can be made and sold throughout the country. That’s the same government agency that represents the United States of America as the assignee of patent US 6630507 claiming a method of treating disease by neuroprotection from oxidative stress filed in the late 90s and issued in October of 2003. How does this finding of neuroprotection paid for with US taxpayer dollars square up with the Schedule 1 listing of cannabis under the CSA? It doesn’t at all and needs to be unraveled.”
“With the ending of federal cannabis prohibition on the horizon, we’re at the birth of a new (old) industry of cultivation, extraction, and formulation science. We’re at the front end of a steep innovation S-curve with no plateau in sight. There’s lots of creative innovation going on in the biology, chemistry, and engineering of the plant and its constituents. If we learn anything from the cannabis plant, there’s way more still to understand about its bounty of benefits which is way more than the sum of its individual parts. We researchers need to be free to carry out fundamental academic and scientific research of the plant, its constituents, related derivatives such as Δ8-THC, CBN, and any other chemical derivative only limited only by the imagination of scientists. It’s not just about THC anymore as we learn more about the known and new cannabinoids and their synergy with each other and in the human body. The terpenes and terpenoid components that bring flavors and aromas, for example, are as important in cannabis as the cannabinoid actives themselves.”
While he ponders that notion, Mark laments, “while it’s true that terpenes and terpenoids originally attracted humans to cannabis, it was the cannabinoids that made them stay.”
Reference
[1] Meehan-Atrash J, Rahman I. Novel Δ8-tetrahydrocannabinol vaporizers contain unlabeled adulterants, unintended byproducts of chemical synthesis, and heavy metals. Chem Res Toxicol. 2022;35(1):73-76.
