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.
Read this if you want to understand why cannabinoid medicines haven't progressed faster despite strong preclinical science, and which strategies are most likely to succeed.
5 strategies to make cannabinoid drugs work without the high — proposed after rimonabant's 30% psychiatric adverse event rate killed the first approach
The Backstory
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.
Cesamet (nabilone)
- Synthetic THC analog
- Approved for chemotherapy-induced nausea and vomiting
- Oral capsule — slow, variable absorption
- Psychoactive side effects limit dose escalation
- Dizziness, drowsiness, and euphoria common
- Cannot be used in patients who need to remain functional
Works, but the high is a side effect patients tolerate, not a feature
Marinol (dronabinol)
- Synthetic THC in sesame oil capsule
- Approved for chemo nausea AND appetite stimulation (HIV/AIDS wasting)
- Same psychoactive limitations as nabilone
- Highly variable pharmacokinetics — fat-soluble drug in an oil capsule
- Onset: 30-60 min, peak: 2-4 hours, unpredictable
- Some patients prefer it precisely because of the high
Broader use than Cesamet, same fundamental limitation
Sativex (nabiximols)
- Botanical extract: THC + CBD in roughly 1:1 ratio
- Oromucosal spray — faster, more predictable absorption
- Approved for neuropathic pain in MS and cancer pain
- CBD component modulates THC's psychoactivity
- Better tolerability profile than pure THC drugs
- Still causes dizziness, fatigue, and disorientation
The best of the three — but still limited by central side effects
Pertwee (2009), Br J Pharmacol 156:397-411
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
Process
Pertwee's Roadmap: Five Strategies for Better Cannabinoid Medicines
Strategy 1: Stay Out of the Brain
Design drugs that activate cannabinoid receptors in the body but cannot cross the blood-brain barrier. Peripheral pain relief without intoxication.
Strategy 2: Deliver to the Right Address
Use intrathecal, transdermal, or topical delivery to concentrate the drug where it's needed. Spinal injection for pain. Skin patches for local inflammation.
Strategy 3: Exploit the Disease
Some diseases cause cannabinoid receptors to upregulate. A partial agonist that barely works in healthy tissue becomes potent where receptors are dense. Target the disease, not the whole body.
Strategy 4: The Other Receptor
CB2 receptors are mainly on immune cells and do not produce psychoactive effects. CB2-selective drugs could treat inflammation, pain, and neurodegeneration without any high.
Strategy 5: Stronger Together
Combine cannabinoids with opioids or other drugs at sub-effective doses. Neither works alone at that dose. Together, they produce full analgesia with fewer side effects from either.
Pertwee (2009), Br J Pharmacol 156:397-411
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.
Biological Mechanism
How Disease Creates a Therapeutic Window
Healthy tissue
Normal density of cannabinoid receptors. A partial agonist like THC produces moderate activation — including unwanted side effects if the tissue is in the brain.
Disease triggers upregulation
Stroke, epilepsy, intestinal inflammation, neuropathic pain, atherosclerosis, and MS all cause local increases in CB1 or CB2 receptor density. The body is trying to protect itself.
Partial agonist becomes selective
A partial agonist's maximum effect depends on receptor density. In tissue with upregulated receptors, it achieves stronger activation. In healthy tissue with normal receptor density, it barely works. The disease itself creates the drug's selectivity.
Therapeutic window opens
The drug is most effective where it's most needed — in diseased tissue — and least effective where side effects would occur. No targeting technology required. The biology does the targeting.
Pertwee (2009), Br J Pharmacol 156:397-411
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
Related Research
The Pertwee Trilogy and the System It Maps
This 2009 roadmap is the third installment in Pertwee's systematic mapping of cannabinoid pharmacology. Each paper builds on the last — from history to molecular pharmacology to therapeutic strategy.
Cannabinoid pharmacology: the first 66 years
Pertwee (2006)
The history — 66 years of discoveries that created the field this roadmap navigates
The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids
Pertwee (2008)
The molecular basis — THC activates, CBD blocks, THCV switches. The pharmacology the five strategies build on
The endocannabinoid system as an emerging target of pharmacotherapy
Pacher, Batkai & Kunos (2006)
The parallel case for the ECS as a drug target — from a different angle than Pertwee
Molecular characterization of a peripheral receptor for cannabinoids
Munro, Thomas & Abu-Shaar (1993)
The discovery of CB2 — the receptor at the center of Strategy 4
Structure of a cannabinoid receptor and functional expression of the cloned cDNA
Matsuda et al. (1990)
The cloning of CB1 — the receptor all five strategies are trying to work around
Can cannabinoid medicines work without making you high?
Yes — that is the entire premise of this review. Five strategies can potentially achieve it: restricting the drug to tissues outside the brain, delivering it directly to the target tissue, exploiting disease-related receptor increases, targeting CB2 receptors (which don't produce psychoactive effects), or combining low-dose cannabinoids with other drugs. Several of these approaches are in clinical development, though none has yet produced an approved non-psychoactive cannabinoid medicine.
Why haven't any of these strategies produced approved drugs yet?
Three main obstacles. First, CB2-selective compounds often behave differently in humans than in mice, making preclinical data unreliable for predicting clinical outcomes. Second, achieving high receptor selectivity is technically difficult — the most advanced CB2 drug has only 12-fold selectivity. Third, the rimonabant withdrawal in 2008 made regulators and pharmaceutical companies cautious about the entire cannabinoid drug class, slowing investment and trial approvals across all strategies.
What is the cannabinoid-opioid synergy and why does it matter?
When cannabinoids and opioids are given together, they produce pain relief greater than the sum of their individual effects — a phenomenon called synergy. In preclinical studies, sub-effective doses of THC combined with sub-effective doses of morphine produced full analgesia. In a clinical trial, adding Marinol to stable opioid doses provided significant additional pain relief. This matters because it suggests opioid doses could be substantially reduced by adding a cannabinoid — potentially decreasing opioid side effects, dependence, and overdose risk. This strategy has gained urgency during the opioid crisis.
What the researchers found
Five strategies for improving cannabinoid therapeutics while reducing psychoactive side effects: (1) peripheral restriction — drugs that cannot cross the blood-brain barrier; (2) tissue-specific delivery — intrathecal, transdermal, topical routes; (3) receptor upregulation — exploiting disease-induced increases in receptor density; (4) CB2 selectivity — targeting immune receptors that don't cause intoxication; (5) multi-targeting — synergistic combinations, especially cannabinoid-opioid at sub-effective doses.
Why it matters
Published three months after rimonabant's worldwide withdrawal for psychiatric side effects, this review reframed the narrative: the cannabinoid system is targetable if you avoid global CB1 blockade in the brain. The five strategies became a roadmap for the next decade of cannabinoid drug development, with multi-targeting/opioid-sparing proving most clinically viable.
The numbers in context
Three approved cannabinoid medicines reviewed: Cesamet (nabilone), Marinol (dronabinol), and Sativex (THC + CBD). Five therapeutic strategies outlined.
How the study worked
Narrative review synthesizing preclinical and early clinical evidence supporting five pharmacological strategies for improving the therapeutic profile of cannabinoid receptor agonists. Published in the British Journal of Pharmacology.
What this study cannot tell us
Highly optimistic about timelines — most strategies have taken far longer to translate than the review implied. CB2-selective pharmacology proved more complex than expected (species differences, protean agonism). Receptor upregulation strategy remains largely theoretical in clinical practice. Multi-targeting faces regulatory challenges requiring separate efficacy proof for each component.
How to read the evidence
Authoritative narrative review by the most published cannabinoid pharmacologist, synthesizing decades of preclinical evidence. Strong conceptual framework, but strategies varied widely in subsequent clinical validation.
When this study was published
Published in 2009. Of the five strategies, multi-targeting (especially cannabinoid-opioid combinations) has advanced most. CB2-selective agonists remain in clinical trials with no approvals. Peripheral restriction and receptor upregulation concepts are still being developed.
The bigger picture
This review by Roger Pertwee — co-founder of the ICRS, co-chair of the IUPHAR cannabinoid subcommittee, 40+ years in the field — was the most authoritative statement of how cannabinoid drug development should proceed after the rimonabant disaster. The multi-targeting strategy has gained particular urgency during the opioid crisis, as cannabinoid-opioid combinations offer a path to reducing opioid doses.
Questions still open
- Why has CB2-selective drug development stalled despite extensive preclinical success? Could receptor density serve as a patient selection biomarker for cannabinoid clinical trials? How much can opioid doses be reduced with cannabinoid co-administration in practice? Will peripherally restricted cannabinoid agonists eventually reach approval?
Common questions
Can cannabinoid medicines work without making you high?
Why haven't CB2-selective drugs been approved despite strong preclinical data?
What is cannabinoid-opioid synergy?
Read the original research
Emerging strategies for exploiting cannabinoid receptor agonists as medicines.
British journal of pharmacology, 156(3), 397-411
Citation
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
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