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Marijuana and the Human Brain

Marijuana tolerance: equilibrium, not addiction

Research into drug tolerance is in its infancy. There are actually three forms of tolerance. Dispositional tolerance is produced by changes in the way the body absorbs a drug. Dynamic tolerance is produced by changes in the brain caused by an adaptive response to the drug's continued presence, specifically in the receptor sites affected by the drug. Behavioral tolerance is produced by familiarity with the environment in which the drug is administered. "Familiarity" and "environment" are two alternative terms for what Timothy Leary called "set" and "setting" - the subjective emotional/mental factors that the user brings to the drug experience and the objective external factors imposed by their surroundings. Tolerance to any drug can be produced by a combination of these and other mechanisms.

Brain receptor sites act as switches in the brain. The brain's neurotransmitters, or drugs which mimic them, throw the switches. The basic theory of tolerance is that repeated use of a drug wears out the receptors, and makes it difficult for them to function in the drug's absence. Worn-out receptors were supposed to explain the connection of tolerance to addiction. This phenomenon has been associated with chronic use of benzodiazepines (Valium, Prozac, etc.), for example, but not with cannabinoids.

An alternative hypothesis about how dynamic tolerance to marijuana operates involves receptor "down-regulation," in which the body adjusts to chronic exposure to a drug by reducing the number of receptor sites available for binding. A 1993 paper published in Brain Research by Angelica Oviedo, John Glowa and Herkenham indicates that tolerance to cannabinoids results from receptor down-regulation. This, as we shall see, is good news. It means that marijuana tolerance is actually the brain's mechanism to maintain equilibrium.

Read next part The N.I.M.H. tolerance study

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