Emerging evidence from basic research has pointed to GLP-1 receptors as a possible target for developing new pharmacological treatment options for addiction, writes Terry Maguire
He gave his initials sometimes as LV, at other times LB, and his date of birth varied between July ’94 and July ’96. He visited the pharmacy frequently after his release from prison, normally falling through the door; advancing up the shop with a gyrating gait as if arresting a fall down a steep embankment. He swept towards our consultation area beside the dispensary, gesturing with pointed finger to whoever was standing around that he wished access to our needle and syringe exchange scheme.
There was a serious intensity pained on his face. He could not stand still, moving backwards and forwards from foot-to-foot. I asked what he wanted and when, following a number of attempts, his wishes remained unclear, I handed him a 0.5ml syringe pack (needles with associated paraphernalia), as acute and excessive cocaine use could be the only explanation for this mental and physical manifestation. Accepting the pack, he ripped it open, removing only items of interest. Had I got a bag, he would ask. I did, but I always insisted he took the Cin-Bin, knowing it would end up in a nearby litter bin.
If it was Thursday, he would return to the main shopping area and at the edge of the counter extract from his anorak a large wodge of bank notes, mostly £20s, and studiously sort them into three neat piles. The largest was rolled up and placed into a zipped pocket in an inner jacket. The medium one was rolled and stuffed into a trouser pocket, and the smallest pile was rolled and put into the outer pocket of his anorak. All the while he fidgeted, stepped back and forward, and was oblivious to all around him. He exited as he entered.
Addicted to Addiction
I remain fascinated by addiction, or Substance Use Disorder (SUD), as it is now known; that less pejorative, not so stigmatising, more caring moniker.
The incredible power of a molecule to take control of a person, so absolutely, so completely, is something truly to be feared. Addiction remains poorly understood, which is surprising given the excessive and obscene investment in addiction research over recent years. We still only, it seems, have a general idea, a lot of ideology, plenty of empathy, and some small hope for those caught in this unfortunate snare of the human condition.
It’s accepted that addiction is an artifact of brain structures that develops due to a combination of genetic predisposition and environmental stresses. Dopamine, ‘the molecule of more’, is key to the emergence of the brain systems of addiction at the cost of personal wellbeing, family and community. The addict is more selfish than a two-year-old in a toy shop.
Dopamine should be, and for most of us is, a positive molecule. It is responsible for identifying positive options, making plans, setting goals, and motivating the chase towards these goals through rewards that focus our activity. Where dopamine gets over-egged, we get problems.
Ropinirole on the BBC
In February this year, the BBC reported on an increasing problem with the use of Ropinirole, the dopamine receptor agonist (DRA) drug used in Parkinson’s disease and in restless leg syndrome. Patients using the drug find they develop impulse control disorders manifesting as addictions to shopping, gambling, food, and sex. BNF warns that all DRA drugs have a similar potential and the impact is very real, with patients losing tens of thousands of pounds, being found guilty of sex offenses, becoming shopaholics, and some losing their jobs. One patient told BBC she felt “there was something controlling me”. She was right; it was dopamine.
‘Liking’ Becomes ‘Wanting’
As an individual becomes more addicted, ‘wanting’ will overshadow ‘liking’ and eventually becomes independent of ‘liking’. ‘The dark side’ theory of addiction says that impulsivity, compulsivity and negative-urgency are derived from stress experienced during withdrawal. The neurocircuitry identified involves several neuropeptides but dopamine is prominent in the immediate reinforcing/rewarding effects of drugs, giving us ‘the dopamine theory’ of addiction.
One way or other, all drugs of addiction increase dopamine activity in specific brain regions. Blocking dopamine might offer a treatment for addiction, but so far that theory has proved too simplistic.
Treatment of Addiction
For centuries, society tried stigmatising addicts, locking them up and generally making their lives a living hell when in fact no-one, other than addicts themselves, seemed to realise that they were already living in a hell and society was only making things worse.
When, as a more enlightened generation, we found the putative approach generally unsuccessful, we changed tact. We sought to recognise addiction as a disease so we can treat it like cancer or asthma and we cared for and empathised with the addict without blaming them. In principle, and generally, this is a good and humane thing.
Harm Reduction
Pharmacy as a profession, has, over the short period of my career, totally changed its attitude towards the addict. For a profession set up to control access to addictive drugs while retaining professional empathy, before the 1980s we mainly policed access.
We retain this role but now we also support addicts with clean needles and other drug-taking paraphernalia, distribute naloxone to revive addicts in overdose, and of course observe substitution medicine taking so they can get some relief from the horrors of withdrawal and hopefully move into recovery. Pharmacy is core to the harm reduction approach.
Pharmacy as a profession, has, over the short period of my career, totally changed its attitude towards the addict
In addition, addicts are provided with sufficient money so they don’t need to turn to criminal behaviour to feed their habit, as JB or JV demonstrated every Thursday.
Medicines
Pharmacological treatments for addiction exist for opioids, tobacco and alcohol. But no medication is approved for treatment of cocaine or other stimulant use disorders. Even when pharmacotherapy is available, success rates are modest to say the least.
In the case of opioids and tobacco, it is the drug itself that is used but in a less addictive delivery formulation as the speed of delivery to the brain is key to addiction. Alcohol is much too toxic so currently, approved medications to treat alcohol use disorder – disulfiram, naltrexone and acamprosate – reduce drinking through different mechanisms of action: (i) unpleasant effects when consuming alcohol, (ii) reduced rewarding/reinforcing effects of alcohol, and (iii) reduced negative state when abstinent.
GLP-1s
Glucagon-like peptide 1 (GLP-1), beyond its spectacular rise to fame in obesity management, is receiving much attention in the treatment of addiction. Observational studies in humans and animals suggest it reduces the compulsion associated with addiction and might be helpful as a treatment tool.
GLP-1 increases insulin secretion, inhibits glucagon secretion, slows gastric emptying and reduces appetite. GLP-1 is also produced in the brain stem and released as a neurotransmitter in several brain regions, including brain regions believed to be involved in reward and addiction. It reduces the reward associated with an activity and is thought to directly suppress dopamine activity in the brain’s reward centres. It is not acting directly as a dopamine receptor antagonist, but is doing so indirectly.
One of the possible mechanisms proposed for GLP-1s to suppress cocaine self-administration involves modulation of stress systems. Studies suggest that activation of stress systems contributes to the addictive effects of various drugs, in the withdrawal and ‘negative affect’ stages of addiction.
Emerging evidence from basic research has pointed to GLP-1 receptors as a possible target for developing new pharmacological treatment options for addiction. Overall, preclinical research has identified potent reductions in substance use and attenuation of drug-seeking behaviour with several different GLP-1 receptor agonists.
However, it’s unlikely that the current GLP-1s used for obesity management will be of much clinical use. They are known to cause pancreatic problems and acute weight loss, so not ideal for someone with a poly-drug addiction.
Too Late for Some
For JB, or is it JV, it’s a bit late anyway. He did come to us some years ago before prison and was doing well on methadone for his opioid addiction. He had a slip on his road to recovery. Prison opened up a myriad of new drug options and on release, cocaine was his problem. When he died at the age of 33, on a Sunday in April this year, cocaine, alcohol and benzodiazepines were identified in his system. Poly-drug deaths, it seems, are now the norm and it’s unlikely that we will see a pharmacological breakthrough anytime soon.
I do worry we are too focused on harm reduction. For a society wishing to ignore the ‘pests’ on the streets and not have them break into their homes and steal their TV, it might be the convenient policy. For the addict, greater focus on the more difficult and, lets be honest, less palatable and potentially more expensive ‘recovery’ approach would be better if we really want to save lives.
