CBD biphasic effect: why 300 mg beat 600 mg

Most people expect a bigger dose to give a bigger effect, and a biphasic response breaks that rule. With the dose on the horizontal axis and the effect on the vertical one, the curve climbs, reaches a peak and drops. Pharmacologists speak of an inverted U-shaped or bell-shaped curve.

CBD is not the only substance with this pattern. As the authors of the 2019 trial point out, the anxiolytic effect of cannabidiol had already followed bell-shaped curves in animals. Anxiolytic here means lowering the anxiety measured during the experiment. Researchers still had to find out whether humans would show the same profile.

A first answer came from the University of São Paulo at Ribeirão Preto. In 2017, Antonio Zuardi and colleagues divided 60 volunteers of both sexes, aged 18 to 35, into five groups: placebo, clonazepam 1 mg (a reference anti-anxiety drug), and CBD at 100, 300 or 900 mg. Each participant gave a speech in front of the others. Afterwards, only the clonazepam and CBD 300 mg groups reported less anxiety than placebo.

The same team repeated the test in 2019 with different doses. In the trial by Linares and colleagues, published in the Brazilian Journal of Psychiatry, researchers gave 150, 300 or 600 mg of CBD, or a placebo, to 57 healthy men. Participants swallowed the capsules 90 minutes before a simulated public speaking test. During the speech, only the 300 mg group had clearly lower anxiety than placebo. Scores at 150 mg, at 600 mg and on placebo showed no difference.

The mechanism has not been demonstrated in humans. The lead cited most often is a rat experiment published in 2009, in which Alline Campos and Francisco Guimarães injected CBD into a midbrain area involved in anxiety responses. The low dose had an anxiolytic effect, the high dose did not. With TRPV1 receptors blocked beforehand, the high dose regained an effect.

Their hypothesis has two parts. At high concentrations, CBD would also activate these TRPV1 receptors, which raise the release of glutamate, an excitatory chemical messenger. This would counteract the effect that passes through other targets, such as serotonin 5-HT1A receptors. The authors of the 2019 trial present this explanation only as a possibility.

A biphasic response appears with THC too. At the University of Chicago, Emma Childs and colleagues gave 0, 7.5 or 12.5 mg of oral THC to 42 adults before a social stress test. At 7.5 mg, reported distress after the test went down; at 12.5 mg, negative mood went up, both before and during the tasks. THC is a narcotic in France; the example simply shows that CBD is not alone in having this profile.

The results are valid within a narrow frame. The main limits, several of them listed by the authors themselves:

• 12 to 15 people per dose group;
• one single dose, with no repeated use;
• a single situation, public speaking, in volunteers without an anxiety disorder;
• in 2019, men only, with self-reported anxiety and no hormone measurement;
• several authors are co-inventors of a patent on CBD derivatives, as the paper discloses.

300 mg does not become a "good dose" because of these trials. They show that, in this protocol, dose and effect did not follow a straight line. They give no grounds for crediting CBD with an effect on an anxiety disorder either. The only authorised CBD-based medicine, Epidyolex, is prescribed for rare forms of epilepsy. Our overview of what clinical studies really say places this work within the wider research.

300 mg is a large amount. On 9 February 2026, the EFSA published a provisional safe level of 0.0275 mg per kilo of body weight per day for CBD in food supplements, about 2 mg for a 70 kg adult. The trial dose is 150 times higher. It equals 15 capsules of 20 mg, or 3 ml of an oil at 100 mg per millilitre.

According to the EFSA, the level does not apply to people under 25, to pregnancy and breastfeeding, or to people taking medication. CBD alters the activity of some liver enzymes that clear medicines, a risk our article on the grapefruit effect explains. CBD foods and supplements are also not authorised in France, as our piece on the EFSA reference dose sets out.

The practical lesson is a modest one: "more" does not mean "stronger". With a CBD oil, you convert drops into milligrams using the concentration on the label. Our article on taking CBD under the tongue explains how the route of intake changes the amount reaching the blood.