CANNABIS MIGRAINE
(2024)Objective
To assess the efficacy and safety of vaporized cannabis flower (THC-dominant, CBD-dominant, and THC+CBD combination) versus placebo for the acute treatment of migraine attacks in a randomized controlled trial.
Study Summary
• THC+CBD also achieved superior 24-hour sustained pain freedom (28.0% vs 10.7%, OR 3.45, p=0.029) and sustained MBS freedom at 24 hours (46.0% vs 25.0%, p=0.031) and 48 hours (39.6% vs 18.4%, p=0.018).
• THC-dominant (6% THC) was superior to placebo for 2-hour pain relief (68.9% vs 46.6%, OR 3.14 [1.35–7.30], p=0.008) but not for pain freedom or MBS freedom, with no sustained benefit at 24 or 48 hours.
• CBD-dominant (11% CBD) was not superior to placebo for any primary or secondary 2-hour endpoint.
• No serious adverse events across all four treatment arms in 247 treated attacks.
Intervention
Vaporized cannabis flower in three active formulations — 6% THC-dominant, 11% CBD-dominant, and 6% THC+11% CBD — compared to placebo cannabis flower (<0.025% THC), administered via the Foltin Uniform Puff Procedure (4 puffs at 180°C) for qualifying migraine attacks (headache <4 hours from onset, moderate or severe intensity, associated with photophobia/phonophobia and/or nausea, and no acute treatments used since attack onset).
Inclusion Criteria
Ages 21–65; migraine per ICHD-3 criteria; 2–23 headache days and 2–23 migraine days per month; agreement to avoid non-study cannabis, opioids, and barbiturates. Initial protocol required THC use within the prior 2 years; this eligibility requirement was removed by amendment on March 18, 2021 due to slow recruitment and no serious adverse events at that time.
Study Design
Arms: THC+CBD (6% THC+11% CBD, ~58 attacks) vs THC-dominant (6% THC, ~61 attacks) vs CBD-dominant (11% CBD, ~57 attacks) vs Placebo (<0.025% THC, ~58 attacks); 4-treatment crossover design, 92 participants enrolled
Patients per Arm: Crossover design; 92 enrolled, 73 participants contributed 247 treated attacks in ITT; approximately 57–61 attacks per arm in mITT (234 total attacks)
Outcome
• THC+CBD sustained benefit: 24-hr pain freedom 28.0% vs 10.7% (OR 3.45 [1.14–10.50], p=0.029); 24-hr MBS freedom 46.0% vs 25.0% (OR 2.83, p=0.031); 48-hr MBS freedom 39.6% vs 18.4% (OR 3.39, p=0.018).
• THC-dominant superior for 2-hr pain relief only (68.9% vs 46.6%, OR 3.14 [1.35–7.30], p=0.008); no benefit for pain freedom or MBS freedom at 2 hours or sustained endpoints.
• CBD-dominant not superior to placebo on any 2-hour primary or secondary outcome.
• No serious adverse events; THC-dominant had greatest subjective highness (mean 3.5/10 at 1 hr) and cognitive impairment; THC+CBD had less psychoactive burden than THC-dominant.
Bottom Line
Vaporized 6% THC+11% CBD cannabis flower was superior to placebo for 2-hour pain relief, pain freedom, and MBS freedom, with sustained benefits at 24 and 48 hours and no serious adverse events — the first RCT evidence supporting cannabinoid use for acute migraine.
Major Points
- THC+CBD (6% THC + 11% CBD) was superior to placebo for 2-hour pain relief (67.2% vs 46.6%, OR 2.85 [1.22–6.65], p=0.016), 2-hour pain freedom (34.5% vs 15.5%, OR 3.30 [1.24–8.80], p=0.017), and 2-hour MBS freedom (60.3% vs 34.5%, OR 3.32 [1.45–7.64], p=0.005).
- THC+CBD achieved superior sustained benefits: 24-hour sustained pain freedom (28.0% vs 10.7%, OR 3.45 [1.14–10.50], p=0.029), 24-hour sustained MBS freedom (46.0% vs 25.0%, OR 2.83 [1.10–7.26], p=0.031), and 48-hour sustained MBS freedom (39.6% vs 18.4%, OR 3.39 [1.24–9.32], p=0.018).
- THC-dominant (6% THC) was superior to placebo for 2-hour pain relief (68.9% vs 46.6%, OR 3.14 [1.35–7.30], p=0.008) but not for 2-hour pain freedom or MBS freedom, and showed no sustained benefit at 24 or 48 hours.
- CBD-dominant (11% CBD) was not superior to placebo for any primary or secondary 2-hour endpoint.
- At 1 hour, all three active arms achieved superior pain relief vs placebo (THC+CBD 53.6%, THC-dominant 65.5%, CBD-dominant 58.9% vs placebo 36.7%); only THC-dominant achieved superior 1-hour pain freedom (17.2% vs 5.0%, OR 4.90, p=0.034).
- THC+CBD reduced photophobia and phonophobia at 2 hours but not nausea or vomiting, arguing against a purely antiemetic mechanism.
- THC+CBD produced less subjective highness (2.4/10 vs 3.5/10 at 1 hour), euphoria, and cognitive impairment than THC-dominant, consistent with CBD acting as a negative allosteric modulator of CB1.
- Blinding was well maintained — participants correctly identified their treatment at rates near or below chance across all arms.
- No serious adverse events were reported across 247 treated attacks.
- This is the first randomized, double-blind, placebo-controlled trial establishing efficacy of cannabinoids for the acute treatment of migraine.
Study Design
- Study Type
- Randomized, double-blind, placebo-controlled, 4-treatment crossover trial
- Randomization
- Yes
- Blinding
- Quadruple-blind (participants, research coordinators, investigators, and statisticians); only research pharmacists were unblinded
- Sample Size
- 92
- Follow-up
- 48 hours per treated migraine attack; ≥1 week washout between treated attacks; up to 4 attacks treated per participant
- Centers
- 1
- Countries
- United States
Primary Outcome
Definition: Pain relief at 2 hours post-vaporization, defined as reduction of headache pain from moderate or severe to mild or none (per IHS guidelines); attacks without 2-hour data counted as failures in ITT
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Placebo: 46.6% (mITT) | THC+CBD: 67.2%; THC-dominant: 68.9%; CBD-dominant: 52.6% (all mITT) | 2.85 (THC+CBD: [1.22–6.65]; THC-dominant: [1.35–7.30]) | THC+CBD: p=0.016; THC-dominant: p=0.008; CBD-dominant: p>0.05 |
Limitations & Criticisms
- Single-center study (UCSD) limits generalizability
- Only one potency of THC (6%) and CBD (11%) and one THC:CBD ratio studied; no dose-response data available
- NIDA-supplied cannabis contained <1% minor cannabinoids and was devoid of terpenes; findings may not generalize to commercially available whole-plant products
- Crossover design: not all 92 enrolled participants completed all 4 treatment arms (73 contributed to ITT)
- No assessment of long-term use, repeated dosing, medication overuse headache risk, or cannabis use disorder risk
- Preprint — not peer-reviewed at time of medRxiv posting
- Participants required to withhold other acute migraine treatments for 2 hours post-dose, which may not reflect real-world practice
- Blinding partially challenged by psychoactive effects of THC, though formal blinding assessment showed near-chance treatment identification rates
Citation
Schuster NM, Wallace MS, Marcotte TD, Buse DC, Lee E, Liu L, Sexton M. Vaporized Cannabis versus Placebo for Acute Migraine: A Randomized Controlled Trial. medRxiv. 2024. doi:10.1101/2024.02.16.24302843