Double-action mechanism found that makes ketamine less addictive

Good news! Could this become a break in the epidemic of substance use disorders?

Now, ketamine could be prescribed more often to treat depression.

"Fast-acting psychotropic drug ketamine is increasingly used as an anesthetic, as well as to rapidly relieve depression. ...
Ketamine has found a variety of uses in medicine, and its ability to alter a person's perception of reality has made it a popular recreational drug as well, if an illegal one in most jurisdictions. ...

But they found something different as compared to other drugs of addiction. "Unlike cocaine, for example, we found that the dopamine level fell very quickly after taking the drug,’’ ... The mice wanted more ketamine, but they never reached the point of "uncontrolled self-administration."

Looking closer, the researchers found a mechanism that could explain why. One of ketamine's known effects in the brain is to block a protein receptor called N-methyl-D-aspartate, or NMDA. This triggers an increase in dopamine, which then binds to another receptor called the D2 receptor, and this D2 receptor triggers a rapid brake on the increase in dopamine. ...
The researchers found that with the NMDA system blocked, the state of deep-brain plasticity leading to behavioral change can't occur. ..."

"... For the past ten years or so, ketamine has also been prescribed to treat the depressive symptoms of people who are resistant to conventional treatments. Its action has the advantage of being very rapid: its effect is felt a few hours after the first dose, whereas traditional antidepressants take several weeks to act. Although its prescription is increasing for this type of treatment, this substance is still widely debated within the scientific community. ..."

From the abstract:

"Ketamine is used clinically as an anaesthetic and a fast-acting antidepressant, and recreationally for its dissociative properties, raising concerns of addiction as a possible side effect. Addictive drugs such as cocaine increase the levels of dopamine in the nucleus accumbens. This facilitates synaptic plasticity in the mesolimbic system, which causes behavioural adaptations and eventually drives the transition to compulsion. The addiction liability of ketamine is a matter of much debate, in part because of its complex pharmacology that among several targets includes N-methyl-D-aspartic acid (NMDA) receptor (NMDAR) antagonism. Here we show that ketamine does not induce the synaptic plasticity that is typically observed with addictive drugs in mice, despite eliciting robust dopamine transients in the nucleus accumbens. Ketamine nevertheless supported reinforcement through the disinhibition of dopamine neurons in the ventral tegmental area (VTA). This effect was mediated by NMDAR antagonism in GABA (γ-aminobutyric acid) neurons of the VTA, but was quickly terminated by type-2 dopamine receptors on dopamine neurons. The rapid off-kinetics of the dopamine transients along with the NMDAR antagonism precluded the induction of synaptic plasticity in the VTA and the nucleus accumbens, and did not elicit locomotor sensitization or uncontrolled self-administration. In summary, the dual action of ketamine leads to a unique constellation of dopamine-driven positive reinforcement, but low addiction liability."

Double-action mechanism found that makes ketamine less addictive

Low addiction risk with medical use of ketamine By demonstrating that ketamine induces only a brief increase in dopamine and does not alter neuronal communication, a team from the UNIGE suggests that its therapeutic use may be safe.

Dual action of ketamine confines addiction liability (no public access)