One study with 500 heavy users of cannabis showed that when trying to cease consumption, some experience one or more symptoms such as insomnia, restlessness, loss of appetite, depression, irritability, and anger.[54] Prolonged marijuana use produces both pharmacokinetic changes (how the drug is absorbed, distributed, metabolized, and excreted) and pharmacodynamic changes (how the drug interacts with target cells) to the body. These changes require the user to consume higher doses of the drug to achieve a common desirable effect (known as a higher tolerance), and reinforce the bodyʼs metabolic systems for synthesizing and eliminating the drug more efficiently.[14]