Five Strategies to Make Cannabinoid Medicines Work Without the High
Emerging strategies for exploiting cannabinoid receptor agonists as medicines.
A veteran cannabinoid pharmacologist outlined five strategies for developing cannabinoid medicines that avoid psychoactive side effects — published three months after the rimonabant disaster proved the need.
In November 2008, Sanofi-Aventis suspended worldwide sales of rimonabant — the first cannabinoid receptor drug designed for mainstream medicine. Marketed as Acomplia for obesity, it had been approved in Europe just two years earlier. Then the psychiatric data came in: depression in up to 10% of patients, suicidal ideation in 1%, and in the massive CRESCENDO trial of over 9,000 patients, psychiatric adverse events exceeding 30%. The FDA had never approved it. Now Europe pulled it too.
The message seemed clear: you cannot safely target the cannabinoid system with drugs.
Three months later, Roger Pertwee — the pharmacologist who had been studying cannabinoids since 1968, who had co-founded the International Cannabinoid Research Society, who had just mapped the diverse pharmacology of THC, CBD, and THCV — published what amounted to a rebuttal in the form of a roadmap. Rimonabant failed, he argued, not because the cannabinoid system is untargetable, but because it was targeted badly. Here are five better ways.
The Starting Line: Three Medicines, Three Limitations
When Pertwee wrote this review, three cannabinoid medicines had already reached patients. Understanding their limitations is essential to understanding why the five strategies mattered.
All three medicines activate CB1 receptors in the brain. That is the source of both their therapeutic effects and their limitations. The psychoactive side effects — dizziness, euphoria, cognitive impairment — are not bugs in the drug design. They are the predictable consequence of activating the same receptor that THC activates to produce a high.
Pertwee's question: what if you could activate cannabinoid receptors where you need them and not where you don't?
The Five Strategies
Strategy 1: Stay Out of the Brain
The blood-brain barrier is a membrane that prevents most molecules from entering the central nervous system. If you design a cannabinoid drug that activates CB1 and CB2 receptors in peripheral tissues — gut, skin, joints, peripheral nerves — but physically cannot cross into the brain, you get pain relief without intoxication.
Pertwee highlighted ajulemic acid (CT-3), a synthetic analog of a THC metabolite, as the most promising example. It showed reduced brain penetration compared to THC while maintaining analgesic and anti-inflammatory effects in animal models. Other peripherally restricted compounds demonstrated antihyperalgesia in neuropathic pain models without the catalepsy (immobility) that signals central CB1 activation.
The caveat Pertwee flagged: the blood-brain barrier is not a fixed wall. In certain neurological diseases — stroke, traumatic brain injury, neuroinflammation — barrier permeability increases. A "peripherally restricted" drug might not stay peripheral in exactly the patients who need it most.
Strategy 2: Deliver to the Right Address
Rather than redesigning the molecule, redesign the delivery. Pertwee reviewed three routes:
Intrathecal (injected into the spinal canal): Activates CB1 and CB2 receptors in the spinal cord to produce antinociception — pain blockade — in acute, inflammatory, and neuropathic pain models. The drug concentration at the spinal cord is high; systemic exposure is minimal. Doses can be far lower than oral administration.
Transdermal (skin patches): HU-210, a potent synthetic cannabinoid, delivered via patch significantly reduced mechanical and thermal hyperalgesia from capsaicin injection — without any detectable psychological side effects. The drug acts on local nerve fibers and immune cells in the skin without reaching the brain in meaningful concentrations.
Topical (creams, gels): WIN55212 applied directly to skin produced antinociception without motor impairment. The skin contains CB1 and CB2 receptors on nerve fibers, mast cells, macrophages, and keratinocytes — a complete local cannabinoid system that can be activated without systemic exposure.
Strategy 3: Exploit the Disease
This is the most intellectually elegant strategy and the hardest to implement.
Pertwee offered an insight that reframed a clinical failure: THC had been shown to be ineffective against acute pain in healthy volunteers. This was interpreted as evidence that cannabinoids don't work for pain. But Pertwee argued the opposite — it might mean that in healthy tissue, with normal receptor density, a partial agonist like THC simply cannot produce enough receptor activation to relieve pain. In chronic pain patients, where CB receptors are upregulated by the disease process, the same drug might work because it has more receptors to act on.
This reinterpretation suggests that cannabinoid clinical trials in healthy volunteers may systematically underestimate efficacy in actual patients.
Strategy 4: The Other Receptor
CB2 receptors are expressed primarily on immune cells. They modulate cytokine secretion and immune cell trafficking. Crucially, they do not produce psychoactive effects when activated. A drug that selectively activates CB2 while ignoring CB1 should provide anti-inflammatory and analgesic effects with no high.
Pertwee documented preclinical efficacy of CB2-selective agonists in:
- Acute, inflammatory, post-operative, cancer, and neuropathic pain
- Multiple sclerosis
- ALS and Huntington's disease
- Stroke
- Atherosclerosis
- Gastrointestinal inflammation
- Chronic liver disease
- Cancer (anti-proliferative effects)
The list was long and the preclinical data were strong. But Pertwee noted complications. Some CB2-selective compounds showed species-dependent pharmacology — acting as agonists in human cells but inverse agonists in rodent cells. This meant that positive results in mice might not translate to humans, and negative results in mice might mask human efficacy. The pharmacology was messier than the concept.
Strategy 5: Stronger Together
The final strategy moves beyond the cannabinoid system entirely. Pertwee reviewed evidence that cannabinoids combined with other drugs — particularly opioids — produce synergistic effects at doses where neither drug works alone.
Pertwee (2009), Br J Pharmacol 156:397-411
This has massive clinical implications. If you can achieve the same pain relief with a fraction of the opioid dose by adding a low-dose cannabinoid, you reduce opioid side effects — including respiratory depression, constipation, and addiction. Pertwee also documented synergistic interactions between cannabinoids and clonidine, bupivacaine, nicotine, serotonin receptor agonists, and antidepressants.
He went further, proposing practical combination strategies: transdermal cannabinoid patches layered with transdermal opioid patches. Intrathecal cannabinoid with transdermal opioid. CB2-selective agonist delivered intrathecally to the spinal cord. Each combination stacks multiple strategies — you get peripheral restriction, tissue targeting, receptor selectivity, and multi-drug synergy simultaneously.
The Scorecard: 2009 to 2026
Pertwee published this roadmap seventeen years ago. What actually happened?
The pattern is striking. The strategy with the least molecular novelty — combining existing drugs — has progressed the furthest. The strategy with the most molecular novelty — CB2-selective agonists — has progressed the least. Drug development rewards pragmatism over elegance.
Why Cannabinoid Drugs Are So Hard
Myth vs. Reality
Rimonabant proved that you can't safely target the cannabinoid system with drugs.
Rimonabant was a CB1 inverse agonist that crossed the blood-brain barrier — it blocked the brain's endocannabinoid system globally. The psychiatric effects (depression in 10% of patients, suicidal ideation in 1%, psychiatric events in 30% in the CRESCENDO trial) were the predictable result of chronically suppressing a system that regulates mood, appetite, and stress. Pertwee's entire review is a catalog of strategies that avoid this mistake.
The Evidence
Peripheral restriction avoids the brain entirely. CB2 selectivity avoids psychoactive receptors. Tissue targeting limits exposure. Receptor upregulation exploits disease biology. Multi-targeting uses lower doses. All five strategies are specifically designed to prevent another rimonabant.
Pertwee (2009); EMA withdrawal of Acomplia (2008); CRESCENDO trial data
But if the strategies are sound, why has progress been so slow? Several factors:
Species translation — CB2-selective compounds that work beautifully in mice sometimes show opposite pharmacology in human cells. AM1241, one of the most-studied CB2 agonists, acts as an agonist in humans but an inverse agonist in some rodent assays. Preclinical success doesn't predict clinical success.
Selectivity is hard — Achieving high CB2/CB1 selectivity ratios is technically difficult. Lenabasum, the most clinically advanced CB2 agonist, has only ~12-fold selectivity for CB2 over CB1. At therapeutic doses, some CB1 activation may occur.
Regulatory complexity — Combination strategies (Strategy 5) require proving that each component contributes to efficacy, effectively doubling the regulatory burden. Tissue-targeted delivery (Strategy 2) requires demonstrating that systemic exposure stays below problematic levels across diverse patient populations.
The rimonabant shadow — After rimonabant, both regulators and pharmaceutical companies became cautious about cannabinoid drug development. Legitimate safety concerns became a general reluctance that slowed the entire field.
The Man Behind the Roadmap
Roger Pertwee began studying cannabinoids in 1968 — the same year the Beatles released the White Album and a year before Woodstock. He was a postdoctoral researcher at Oxford, working under Sir William Paton in the Department of Pharmacology. His materials were not synthesized in a chemistry lab. They were cannabis tincture — still a legal medicine in the UK — and plant-extracted THC and CBD.
His early work led to two foundational contributions: demonstrating that CBD is a potent inhibitor of liver drug-metabolizing enzymes (explaining why CBD changes how other drugs work in the body), and developing the "ring immobility test" — a behavioral assay for cannabinoid potency in mice that researchers still use today.
He moved to the University of Aberdeen in 1974 and never left. Over the next five decades, he co-founded the International Cannabinoid Research Society, co-chaired the IUPHAR Subcommittee on Cannabinoid Receptors (the body that officially classifies cannabinoid receptors), and published what may be the most comprehensive body of cannabinoid pharmacology reviews in existence — including the first 66 years (2006), THC vs. CBD vs. THCV (2008), this strategic roadmap (2009), the IUPHAR receptor classification (2010), and a follow-up strategies review (2012).
When Pertwee wrote "Emerging Strategies" in 2009, he was not speculating from the outside. He was the field's institutional memory proposing the field's future direction — with the authority of 40 years of continuous research behind every recommendation.
What This Means for Patients
For anyone wondering why cannabinoid medicines still mostly come from the plant rather than the pharmacy, this review explains the structural reasons. The science is not the bottleneck — Pertwee cataloged dozens of preclinical successes. The bottleneck is translating those successes through the practical challenges of species differences, selectivity engineering, delivery technology, regulatory requirements, and institutional caution.
The opioid-sparing approach — Strategy 5 — has gained the most traction precisely because it sidesteps these challenges. You don't need a novel molecule. You don't need exotic delivery. You combine two known drugs at lower doses. The pharmacology is synergistic, the regulatory path is clearer, and the clinical need — reducing opioid use — is urgent.
For patients using cannabis for chronic pain, the multi-targeting strategy validates something they already know experientially: cannabis combined with lower doses of conventional pain medication often works better than either alone. Pertwee's contribution was formalizing the pharmacological basis for that observation and proposing it as a systematic drug development strategy.
Key Takeaways
Frequently Asked Questions
Cite this study
Pertwee, Roger G. (2009). Emerging strategies for exploiting cannabinoid receptor agonists as medicines.. British journal of pharmacology, 156(3), 397-411. https://doi.org/10.1111/j.1476-5381.2008.00048.x