Although much research is still needed before a decision is finally made to use the substance in addicted patients, the discovery gives a glimmer of hope to people struggling with addiction. So far, there are very few drugs that eliminate withdrawal symptoms, and the effectiveness of pharmacotherapy of addiction is estimated at only about 30 percent.

In the journal Molecules, the team led by Dr. Joanna Listos from the Department of Pharmacology and Pharmacodynamics of the Medical University of Lublin published the results of a study showing that administering a compound called linagliptin to mice with a developed morphine addiction significantly reduced the severity of withdrawal symptoms and reduced emotional distress associated with withdrawal syndrome.

Linagliptin is a drug that is registered (but not reimbursed) in Poland for the treatment of type 2 diabetes. It belongs to the group of new generation antidiabetic drugs that increase the activity of glucagon-like peptide-1 (GLP-1). GLP-1 is secreted in the small intestine during food consumption and affects the activity of the pancreas: it increases insulin secretion and reduces glucagon. Thanks to this, it has an important role in the regulation of carbohydrate metabolism, in particular it contributes to lowering the level of postprandial glycemia.

GLP-1 has been known to scientists for quite a short time, because under physiological conditions it degrades very quickly, making it difficult to study. The enzyme responsible for this degradation is dipeptidyl peptidase-4 (DPP-4).

Talking to PAP, Dr. Listos said: “The half-life of GLP-1 is only 3-4 minutes.

“When in the beginning of the 21st century it was noticed that increasing the activity of this peptide had a beneficial effect on the regulation of postprandial glycemia, two groups of drugs increasing its activity were introduced. 

“They are still used in diabetes treatment. The first group consists of GLP-1 peptide analogues, i.e. drugs that directly stimulate GLP-1 peptide receptors. The second group, to which the aforementioned linagliptin belongs, are drugs that inhibit the activity of the DPP-4 enzyme (called DPP-4 inhibitors), which, by inhibiting the breakdown of endogenous GLP-1 peptide, indirectly contribute to the increase of GLP-1 activity in the body.”

She added: “The great advantage of these drugs is that, even at a higher dose, they do not cause hypoglycemia - a serious complication of insulin therapy and older oral antidiabetic drugs.”

It has been experimentally proven that GLP-1 receptors are found not only in the pancreas, but also in the heart, kidneys and brain, particularly in one of the regions of the brain known as the solitary nucleus. 

Dr. Listos said: “The solitary nucleus receives signals from the gastrointestinal tract and the circulatory system, carrying information about blood glucose, insulin, ghrelin and other peptides.

“These signals are then transferred to other brain structures that also contain GLP-1 receptors, including the nuclei of the hypothalamus involved in the regulation of food intake.”

The researcher explains that these signals also reach the structures of the mesolimbic system, which is the backbone of the reward system. It is responsible for regulating behaviours and reactions such as motivation, pleasure, discomfort, etc.

Listos continued: “Stimulation of the mesolimbic system structures determines satisfaction and increases the feeling of satiety and pleasure after a meal. It also reduces appetite.

“This means that GLP-1 in the brain plays an important role in regulating food intake and in its rewarding effect.

“This knowledge has already contributed to the approval of the GLP-1 peptide analogue - semaglutide in 2022 as a new drug used in the treatment of obesity.”

Taking into account the presence of GLP-1 receptors in the mesolimbic system of the brain and in the closely related structures (the hippocampus, amygdala and olfactory bulb, which are involved in the regulation of drive, motivational and emotional behaviour), the question arises whether in addition to reducing appetite, GLP-1 can also be an important factor to reduce craving for addictive substances.

Dr. Listos said: “The analysis of other authors' research results confirmed this hypothesis.

“In pre-clinical animal trials, administration of the GLP-1 analogue, exenatide, has been shown to reduce the feeling of pleasure after taking amphetamines, cocaine, nicotine, and ethanol. However, the results of experiments on addiction to opioids, including morphine, were inconclusive.”

Scientists in Lublin decided to check whether increasing the activity of the GLP-1 peptide would have an impact on morphine addiction.

They conducted their research on mice. To increase GLP-1 activity, the animals were given linagliptin, which inhibited the degradation enzyme DPP-4.

The mice were divided into two groups. In the first group, morphine was administered for eight days, and on the following day, in addition to morphine, naloxone, a substance that blocks morphine receptors and causes withdrawal syndrome, was also administered. The mice then exhibited jumps characteristic of the withdrawal syndrome.

The second group received linagliptin in addition to morphine for the first eight days. On the last day of the experiment, as in the previous group, the animals were given morphine and naloxone.

The rodents that received morphine and linagliptin had significantly fewer withdrawal signs (jumping), which “clearly shows that linagliptin reduces the severity of morphine withdrawal symptoms,” Dr. Listos said. 

The result encouraged the scientists to conduct further experiments. Since they knew that in people with opioid withdrawal, in addition to somatic symptoms such as pain or diarrhoea, also have psychological symptoms, including anxiety and depressive disorders, they tested whether linagliptin would also inhibit mental disorders caused by morphine withdrawal.

For this purpose, they administered morphine to mice for eight days, and then observed their behaviour after a short (60-hour) and long (14-day) substance withdrawal.

Importantly, they administered linagliptin in two regimens: together with morphine (when developing addiction), and only after discontinuing morphine to “investigate the activity of linagliptin in two aspects: prevention and treatment of withdrawal symptoms.”

At the end of the experiment, the depressive behaviour of the rodents was assessed by tests.

The scientists found that a short-term morphine withdrawal increased anxiety in animals, but linagliptin - given concurrently with morphine and during the withdrawal - reduced these conditions.

In addition, both short-term and long-term morphine withdrawal increased depressive behaviour in mice, and this effect was cancelled by linagliptin, but only when administered during the withdrawal period.

The scientists suggest that the reduction in the number of jumps in the tested animals after administration of linagliptin is associated with the presence of GLP-1 receptors in the striatum. 

Dr. Listos said: “We know that the administration of morphine increases the release of dopamine in the striatum, which is perceived as a feeling of pleasure (euphoria). On the other hand, the appearance of withdrawal symptoms is the result of a decrease in the level of dopamine in this part of the brain.

“Administration of linagliptin during morphine dependence could stimulate GLP-1 autoreceptors in the solitary nucleus and thus reduce the release of GLP-1 in the striatum. This may have contributed to the reduction of dopamine levels after the administration of subsequent doses of morphine and inhibition of adaptive changes in neurons. In turn, the reduction of depressive and anxiety behaviours during morphine withdrawal was probably the result of interactions in the brain between the GLP-1 peptide and other neurotransmitters involved in generating this type of behaviour, for example serotonin.”

Based on the experiments, the researchers conclude that increasing the GLP-1 activity may have a beneficial effect on the activity of the brain, the functioning of which has been altered due to long-term exposure to opioids. 

Listos said: “Increasing the activity of the GLP-1 peptide may contribute to both the reduction of the physical symptoms of addiction and the reduction of behavioural effects resulting from opioid withdrawal, such as depressive and anxiety behaviours."

PAP - Science in Poland, Katarzyna Czechowicz

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