Two Synthetic Cannabinoids Are More Dangerous Together Than Either One Alone | Research

The takeaway

When two synthetic cannabinoids commonly found in "spice" products were given together at individually ineffective doses, they still impaired vision, altered pain response, and boosted dopamine, suggesting dangerous synergistic effects.

Read this if you want to understand why synthetic cannabinoid products are unpredictable and dangerous.

Sub-effective doses of two synthetic cannabinoids, combined, still impaired sensory function and boosted dopamine.

What the researchers found

Researchers tested JWH-250 and JWH-073, two synthetic cannabinoids frequently found together in "herbal blend" products, in mice. Both compounds individually caused hypothermia, increased pain threshold, caused catalepsy, reduced movement, impaired sensory responses (vision, hearing, touch), caused seizures, and promoted aggressiveness.

Both compounds also stimulated dopamine release in the brain's reward center (nucleus accumbens) in a dose-dependent manner. All effects were blocked by a CB1 receptor antagonist, confirming they work through the cannabinoid system.

Critically, when researchers combined doses of each compound that were individually too low to produce effects, the combination still impaired visual responses, altered pain thresholds, and stimulated dopamine release. This suggests a synergistic or at minimum additive interaction.

Why it matters

Synthetic cannabinoid products ("spice," "K2") typically contain mixtures of multiple synthetic cannabinoids. This study provides the first evidence that combining different synthetic cannabinoids can produce dangerous effects even at individually sub-threshold doses, which helps explain the unpredictable and often severe adverse reactions seen in emergency departments.

The numbers in context

Both JWH-250 and JWH-073 had nanomolar affinity at CB1 and CB2 receptors. Sub-effective doses combined still impaired visual sensorimotor responses and stimulated mesolimbic dopamine transmission.

How the study worked

The study used male CD-1 mice with in vitro receptor binding experiments and in vivo behavioral testing (tetrad test, sensorimotor assessments, neurological observations). Microdialysis in freely moving mice measured real-time dopamine release in the nucleus accumbens. The selective CB1 antagonist AM 251 was used to confirm receptor specificity.

What this study cannot tell us

This was a mouse study. The doses, routes of administration, and drug combinations used may not reflect human exposure patterns. Only two specific synthetic cannabinoids were tested, while products on the market may contain many different compounds.

How to read the evidence

Preliminary evidence from a well-conducted animal study. The synergistic mechanism is demonstrated in mice but has not been confirmed in humans.

When this study was published

Published in 2016. The synthetic cannabinoid market has continued to evolve with newer compounds.

The bigger picture

The synthetic cannabinoid market is characterized by constantly changing formulations with multiple compounds. Users rarely know what specific chemicals they are consuming. This study reveals that the practice of combining multiple synthetic cannabinoids in products is not just additive but potentially synergistic, creating unpredictable risk profiles that single-compound studies cannot capture.

Questions still open

Do other synthetic cannabinoid combinations show similar synergistic toxicity? Could understanding these interactions help emergency physicians better treat synthetic cannabinoid overdoses? Would the synergistic effect be more or less pronounced with chronic exposure?

Common questions

Why are synthetic cannabinoids more dangerous than cannabis?

Unlike THC which is a partial CB1 receptor agonist, many synthetic cannabinoids are full agonists with much higher potency. This study adds another factor: products containing multiple synthetic cannabinoids can have synergistic effects, making responses unpredictable.

What are JWH-250 and JWH-073?

They are synthetic cannabinoids with nanomolar affinity for CB1 and CB2 receptors, originally developed as research tools. They have been found in illicit "herbal blend" products sold as legal alternatives to cannabis.

Read the original research

Effect of JWH-250, JWH-073 and their interaction on "tetrad", sensorimotor, neurological and neurochemical responses in mice.

Progress in neuro-psychopharmacology & biological psychiatry, 67, 31-50

View on PubMed ↗Publisher’s paper ↗

Citation

Ossato, Andrea; Canazza, Isabella; Trapella, Claudio; Vincenzi, Fabrizio; De Luca, Maria Antonietta; Rimondo, Claudia; Varani, Katia; Borea, Pier Andrea; Serpelloni, Giovanni; Marti, Matteo. (2016). Effect of JWH-250, JWH-073 and their interaction on "tetrad", sensorimotor, neurological and neurochemical responses in mice.. Progress in neuro-psychopharmacology & biological psychiatry, 67, 31-50. https://doi.org/10.1016/j.pnpbp.2016.01.007