Why does cannabis cause anxiety in some people but relieve it in others?

The cannabis-anxiety paradox — the same substance that relieves anxiety in some users causes it in others — is one of the most clinically important questions in cannabinoid medicine. Key factors: (1) Dose: THC has a biphasic anxiety response — low doses are anxiolytic, high doses are anxiogenic. This is the most consistent finding across studies. (2) THC:CBD ratio: CBD attenuates THC-induced anxiety via CB1 negative allosteric modulation and 5-HT1A agonism. High-THC, low-CBD products carry higher anxiety risk. (3) Individual genetics: FAAH gene variants affect anandamide levels and anxiety sensitivity. AKT1 and COMT variants affect dopamine regulation and psychosis/anxiety risk. (4) Prior experience: naive users are more likely to experience anxiety than experienced users. (5) Set and setting: anxiety is more likely in unfamiliar, stressful environments. (6) Route: rapid-onset inhalation is more likely to cause anxiety than slow-onset oral dosing. (7) Baseline anxiety: paradoxically, people with high baseline anxiety may be more sensitive to THC-induced anxiety. Clinical implication: for anxiety treatment, CBD-dominant preparations at low doses in familiar settings are most likely to be beneficial.