The medical use of ketamine to alleviate symptoms of depression carries a low risk of addiction, suggests new research from the University of Geneva (UNIGE).
Whilst ketamine is most commonly used an anaesthetic, there has been an increasing interest in its use as a therapeutic for depression due to its rapid effects. Ketamine works within hours of administration compared to traditional antidepressants, which can often take weeks to begin working.
Recent research revealed the substances fast acting anti-depressive effects are due to the substance’s ability to produce behavioural changes by increasing the activity of existing new neurons in the brain – which can happen as soon as the cells are activated by the ketamine. This differs from traditional antidepressants, as these medicines often increase the number of neurons, which can take weeks.
Whilst more research investigates ketamine as an antidepressant, the substances use as a depression therapy is becoming increasingly common, so knowing the risk for addiction when using ketamine in this way is vital.
The team at UNIGE has now investigated the medical use of ketamine’s risk for addiction by administering the drug to mice.
The study, published in the journal Nature, used a device that allowed the mice to self-administer doses of ketamine, finding that the level of dopamine increased with each dose and induced a positive reinforcement in the mice. This motivated them to repeat the self-administration.
‘‘Some people believe that ketamine presents a strong addictive risk if taken for a long time, others do not. The whole point of our research was to try to provide some answers,” said Professor Christian Lüscher at the Department of Basic Neurosciences, UNIGE Faculty of Medicine and a specialist in the mechanisms underlying addiction.
Whilst addiction is defined as the compulsive use of a substance despite its negative consequences, dependence is defined by the appearance of one or more withdrawal symptoms on abrupt cessation of use.
Postdoctoral Scholar in the Department of Basic Neuroscience at the UNIGE Faculty of Medicine, Yue Li, commented: “The drugs intensely stimulate the reward system in the brain, which leads to an increase in dopamine levels. The first step was to observe whether this mechanism was also at work when taking ketamine.
‘‘However, unlike cocaine, for example, we found that the dopamine level fell very quickly after taking the drug.”
In an attempt to understand this, the team discovered that ketamine triggered an increase in dopamine by inhibiting a molecule called the NMDA receptor – a glutamatergic receptor – in the reward centre of the rodent brain.
The dopamine then binds to another receptor called the D2 receptor, acting as a rapid brake on the increase in dopamine.
The researchers also confirmed that the action of the NMDA receptor is necessary to modify the communication between the nerve cells that underlie the behavioural change leading to addiction. Ketamine’s inhibition of the NMDA receptor makes this modification impossible.
Lüscher said: ’‘The consequence of this dual action of ketamine is that it does not induce the synaptic plasticity that addictive drugs do and that persists in the brain after the substance has worn off.
“It is this memorisation of the product in the reward system – absent in the case of ketamine – that drives the repetition of consumption.
“Therefore, the addictive risk of ketamine appears to be zero in rodents. Is this also the case in humans? Could this risk vary according to the individual? Our study provides a solid framework for debating access to its therapeutic use.”
[activecampaign form=52]
