Amlodipine and Cannabis Interaction Profile: What Patients and Clinicians Need to Know

What the amlodipine label says about CYP3A inhibitors

The amlodipine label treats CYP3A inhibitors as a class. Co-administration with moderate and strong CYP3A inhibitors increases systemic exposure to amlodipine and may require a dose reduction, and the label directs monitoring for symptoms of hypotension and edema to determine whether the dose needs adjusting [2]. The size of that effect with a real inhibitor is not trivial: diltiazem 180 mg daily given with amlodipine 5 mg to elderly hypertensive patients raised amlodipine exposure by 60% [2].

CBD and CYP3A4: laboratory evidence

In assays using microsomes that overexpress individual P450 enzymes, CBD competitively inhibited CYP3A4, along with CYP2B6, CYP2C9, CYP2D6 and CYP2E1 [1]. The investigators' static modeling suggested possible pharmacokinetic interactions between cannabinoids and drugs extensively metabolized by CYP2B6, CYP2C9 and CYP2D6; CYP3A4 was not named in that conclusion [1]. These results are an enzyme-level signal, not a measured change in amlodipine blood levels.

THC points at different enzymes

In the same set of assays, THC competitively inhibited CYP1A2, CYP2B6, CYP2C9 and CYP2D6, and its main metabolites inhibited CYP2B6, CYP2C9 and CYP2D6 [1]. CYP3A4 is not among the enzymes listed for THC, so the CYP3A inhibitor warning in the amlodipine label gives a weaker basis for expecting an interaction with THC than with CBD [1][2].

Blood pressure, heart rate and fluid retention

Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to reduce peripheral vascular resistance and blood pressure [2]. Its labeled warning is symptomatic hypotension, particularly in severe aortic stenosis, and the label says acute hypotension is unlikely because the onset of effect is gradual [2].

In amlodipine's placebo-controlled trials, the effects the label reports as dose related were edema in 1.8% at 2.5 mg, 3.0% at 5 mg and 10.8% at 10 mg against 0.6% on placebo; dizziness in 3.4% at both 5 mg and 10 mg against 1.5%; flushing in 2.6% at 10 mg against 0%; and palpitation in 4.5% at 10 mg against 0.6% [2]. These are not measurements of amlodipine combined with CBD or cannabis.

Cannabis has cardiovascular risks of its own. The American Heart Association's 2020 scientific statement on cannabis and cardiovascular health concluded that few of cannabis's therapeutic benefits are cardiovascular, that many of its concerning health implications are cardiovascular, and that those effects may be mediated by how cannabis is delivered [3].

What the label does and does not say

The drug interactions section of the amlodipine besylate tablet label names CYP3A inhibitors, CYP3A inducers, sildenafil, simvastatin, and the immunosuppressants cyclosporine and tacrolimus [2]. It does not name cannabis, THC or CBD. The inhibitor instruction is written for moderate and strong CYP3A inhibitors as a class [2].

Patients who may already have higher amlodipine exposure

The label notes that amlodipine is extensively metabolized by the liver and that the plasma elimination half-life is 56 hours in patients with impaired hepatic function, so titration should be slow in severe hepatic impairment [2]. Patients with hepatic insufficiency may be started on 2.5 mg once daily, and the label advises cautious dose selection in older patients, usually starting at the low end of the dose range [2].

What the label says about too much amlodipine effect

The label describes amlodipine overdose as excessive peripheral vasodilation with marked hypotension and possibly reflex tachycardia, and notes that hemodialysis is unlikely to help because amlodipine is highly protein bound [2].