Hexahydrocannabinol (HHC): all about its chemistry, pharmacology, effects and safety

Hexahydrocannabinol (HHC) is quickly emerging as one of the most discussed cannabinoids in the growing world of cannabis-derived compounds. In this article, we’ll explore its chemistry, synthesis, pharmacology, potential benefits, safety concerns, and legal status. With its roots in 20th-century research and its recent popularity in the marketplace, understanding HHC is crucial for consumers, healthcare professionals, and regulators.

HHC is a hydrogenated derivative of tetrahydrocannabinol (THC) and a semi-synthetic cannabinoid that can occur naturally in trace amounts in cannabis plants, although there is still no consensus on whether the plant is actually capable of producing it on its own.

Unlike its more famous counterpart, THC, HHC is typically produced by hydrogenation, a controlled chemical process. This process involves adding hydrogen atoms to the THC molecule, altering its structure and stability while maintaining its psychoactive properties.

Main Features:

• Organization: HHC does not have the double bonds present in the cyclohexyl ring of THC due to hydrogenation, which contributes to greater stability and a longer shelf life.
• Isomerism: HHC exists in two diastereomers (9R-HHC and 9S-HHC). Research shows that the 9R isomer exhibits binding affinities and effects similar to those of THC-delta-9, while the 9S isomer is significantly less potent.

The chemistry and synthesis of HHC

Chemical structure and isomerism

HHC’s unique chemical composition is critical to its function. Its structure, formally known as (6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,9,10,10a-hexahydro-benzo[c]chromen-1-ol, lacks the unsaturated bonds typical of THC molecules. This saturation not only increases its stability, but also impacts its interaction with cannabinoid receptors.

• Diastereomers:
  • 9R-HHC: It demonstrates a high binding affinity (approximately 15 nM at CB₁ receptors and 13 nM at CB₂ receptors) and is primarily responsible for the psychoactive effects.
  • 9S‑HHC: It has a significantly lower affinity for receptors, which makes it less potent.

Synthesis process

The production of HHC typically involves a multi-step chemical transformation, summarized below, which takes into account the steps that lead to commercially available products, which all come from hemp plants since there are no legal HHC products created directly from the delta-9-THC molecule:

1. Extraction: Cannabidiol (CBD) is extracted from hemp plants.
2. Conversion: CBD is chemically converted to THC isomers (usually delta-8-THC or delta-9-THC) by a process called acid-catalyzed cyclization.
3. Hydrogenation: The THC is then hydrogenated using a metal catalyst (e.g. palladium on carbon) to remove the double bonds and produce HHC.

This process can produce a mixture of both isomers, and refining methods are used to increase the proportion of the more potent isomer, 9R-HHC.

Pharmacology: How does HHC work?

Interaction with cannabinoid receptors

HHC exerts its psychoactive effects by binding to cannabinoid receptors – primarily CB₁ and CB₂ – located throughout the central nervous system and peripheral tissues.

• CB₁ receptors: Found predominantly in the brain, they are responsible for mediating psychoactive effects. Research indicates that 9R-HHC binds to CB₁ with an EC₅₀ similar to that of delta-9-THC, eliciting comparable responses in functional assays.
• CB₂ receptors: These are associated with immune modulation and anti-inflammatory responses. Although both isomers interact with CB₂, their activity at the CB₁ receptor is less selective compared to their activity at the CB₂ receptor.

Receptor binding and functional activity

Studies have shown that:

• 9R-HHC has a strong affinity and binding power, very similar to that of delta-9-THC.
• 9S‑HHC It has approximately ten times lower potency and binding affinity, contributing minimally to the overall activity.

This stereoselective behavior highlights the importance of chemical structure in determining the pharmacodynamics of cannabinoids.

Effects and potential therapeutic benefits

Psychoactive and physiological effects

HHC produces similar effects to THC, although in some cases they are slightly milder. Users often report:

• Euphoria and relaxation: A feeling of well-being and calm similar to that experienced with cannabis.
• Change in perception: Changes in sensory perception and notion of time.
• Body sensations: Slight analgesia and increased bodily sensations.

However, individual experiences vary significantly due to differences in product composition and user biology.

Therapeutic potential

Although preclinical studies are still emerging, HHC shows promise in some therapeutic areas:

• Pain control: Its partial agonist activity at CB₁ receptors suggests possible analgesic properties.
• Anti-inflammatory effects: Interaction with CB₂ receptors may provide benefits in reducing inflammation.
• Neuroprotection: As with other cannabinoids, HHC may play a role in neuroprotective mechanisms, although more research is needed in this field.

Safety, side effects and toxicity

Known side effects

HHC shares many side effects with traditional THC, including:

• Dry mouth and red eyes
• Changes in coordination and delay in reaction time
• Anxiety or paranoia, especially with higher doses
• Cognitive disturbance and memory changes

Toxicological considerations

The long-term safety of HHC consumption remains largely unknown. Major concerns include:

• Checking the quality: The synthesis of HHC involves metal catalysts; trace contaminants can pose health risks if not properly removed.
• Unreliable dosage: Many HHC products are not subject to standardized testing, which leads to variable potency and dosage.
• Potential for abuse: Given its psychoactive properties and receptor binding profile, HHC carries a risk of dependence and abuse.
• Lack of investigation: Most of the available data come from animal studies or empirical reports, with comprehensive studies in humans still pending.

Experts warn that without rigorous clinical research and regulatory oversight, the potential harms of HHC may outweigh its benefits.

Legal status and regulation

A regulatory grey area

HHC occupies a poorly defined legal space in many regions:

• United States: Some manufacturers claim that hemp-derived HHC is legal under the 2018 Farm Bill. However, federal and state regulations vary, and enforcement of the laws remains inconsistent.
• Europe: The legal status of HHC is evolving, with several countries classifying it as an uncontrolled substance or banning it altogether.
• other regions: In jurisdictions such as Japan and parts of Canada, the status of HHC is under review as authorities assess its safety profile. However, there is already strong evidence that HHC may be classified as a narcotic under international law.

Implications for consumers

Due to inconsistent regulation:

• security risks: Unregulated products may not meet quality standards, increasing the risk of contamination or incorrect labeling.
• Legal uncertainty: Consumers should stay informed about local laws to avoid inadvertent violations.
• Market surveillance: Ongoing research and government monitoring are essential to update policies as new data emerge.

Future research and industry perspectives

Research priorities

Key areas for future research include:

• Pharmacokinetics and Metabolism: Understanding how HHC is processed in the human body will clarify its duration of action and potential interactions.
• Long-term security: Extensive studies are needed to assess the effects of prolonged consumption, including cognitive and psychological outcomes.
• Therapeutic applications: Clinical trials may reveal new applications for HHC in pain management, inflammation reduction, or neuroprotection.

Industry trends

The growing popularity of HHC has sparked interest in:

• Normalization: Development of uniform quality control measures for HHC products.
• Product innovation: Refining the synthesis processes to optimize the proportion of active isomers.
• Regulatory clarity: Collaborative efforts between researchers, industry stakeholders and regulators to establish clear legal frameworks.

Hexahydrocannabinol (HHC) represents an intriguing but complex addition to the cannabinoid landscape. Its structural similarity to THC, combined with unique chemical modifications, gives it promising pharmacological properties and considerable safety concerns. Although early research suggests that the 9R-HHC isomer may offer similar therapeutic benefits to delta-9-THC, the lack of comprehensive human data and inconsistent product quality warrant caution.

For now, consumers are advised to prioritize safety by opting for well-regulated cannabis products and to remain vigilant about the legal status of HHC in their regions. As scientific knowledge deepens, the place of HHC in both recreational and medicinal settings will become clearer, guiding smarter choices by regulators and consumers alike.

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João Xabregas

More postsBiography

With a professional background in CAD technical drawing (2D and 3D), João Xabregas is an activist and advocate for all uses and applications of cannabis. He discovered and entered the world of cannabis during his youth, where he developed a special interest in the cultivation of the plant, which led him on a journey of self-learning through the world of cannabis that continues to this day. His adventures linked to cannabis cultivation began with the same goal as many others: to be able to guarantee the quality and eliminate any possible risks to his health of what he consumed, as well as to avoid any type of dependence on the illicit market. However, he quickly began to view the world of cannabis and everything related to it with a very different perspective. He admits the enormous passion he has for the most persecuted plant in the world and about which he is always willing to write and have a good conversation.

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