The role of glucagon‐like peptide 1 (GLP‐1) in addictive disorders

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Endogenous GLP-1 is made by cleavage of proglucagon in intestinal L cells and released after food intake.

“Endogenous GLP-1 is produced by cleavage of the prohormone proglucagon in the intestinal endocrine L cells and is released in response to food intake.”

• cites Holst, 2007Not checked yet

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May combine two claims.

Systemic exenatide or AC3174 and central exenatide into several brain regions significantly decrease alcohol intake in a two-bottle choice paradigm.

“Systemically administered exenatide (Egecioglu, Steensland, et al., 2013;Shirazi et al., 2013;Sirohi et al., 2016) or the exenatide analogue AC3174 (Suchankova et al., 2015) and centrally administered exenatide into the VTA (Colvin et al., 2020;Shirazi et al., 2013), NTS (Vallöf, Vestlund, et al., 2019), NAc, dorsal hippocampus, lateral hypothalamus (Colvin et al., 2020), NAc shell (Colvin et al.,”

• cites Egecioglu, Steensland, et al., 2013Not checked yet

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• cites Shirazi et al., 2013Not checked yet

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• cites Sirohi et al., 2016Not checked yet

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Classified as probably not a substantial claim. May combine two claims.

AUD involves continued drinking despite negative consequences, and studies addressing this aspect are lacking.

“AUD is characterized by continued drinking despite negative consequences, and studies addressing this aspect of AUD are lacking.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

GLP-1 is also produced in the brain stem NTS and released as a neurotransmitter in several brain regions.

“GLP-1 is also produced in the nucleus tractus solitarius (NTS) of the brain stem and is released as a neurotransmitter in several brain regions.”

May combine two claims.

One rat study reported delayed ethanol withdrawal-induced anxiety after DPP-4 inhibitor treatment, but the neural mechanism is unclear.

“One study of ethanol withdrawal-induced anxiety in rats reports delayed withdrawal-induced anxiety after treatment with a DPP-4 inhibitor (Sharma et al., 2015a), but it is not clear what the neural mechanism behind this effect might be.”

• cites Sharma et al., 2015aNot checked yet

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May combine two claims.

The effects of systemic exenatide on alcohol intake were abolished in mice with CNS GLP-1 receptor ablation, indicating that these effects are likely centrally rather than peripherally mediated.

“The effects of systemically injected exenatide were abolished in mice where GLP-1-receptors were ablated in the CNS, indicating that the effects on alcohol intake are most likely to be centrally rather than peripherally mediated (Sirohi et al., 2016).”

• cites Sirohi et al., 2016Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

GLP-1 is quickly broken down by DPP-4, with a half-life of only 1-2 minutes.

“It is rapidly inactivated with a half-life of just 1-2 min by the enzyme, dipeptidyl peptidase 4 (DPP-4).”

• cites Holst, 2007Not checked yet

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May combine two claims.

Most studies of GLP-1 receptor agonists and alcohol have examined acute effects, while more recent work has also tested subchronic or repeated dosing.

“Most studies have focused on acute effects, but more recent investigations have also assessed the effects of subchronic or repeated dosing regimens (Marty et al., 2020;Thomsen, Barrett, et al., 2017).”

• cites Marty et al., 2020Not checked yet

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• cites Thomsen, Barrett, et al., 2017Not checked yet

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May combine two claims.

Because some GLP-1 receptor agonists are already used clinically, they could become available quickly to AUD or SUD patients if the approach works.

“a number of these compounds are already used clinically, meaning that they could become available rapidly to AUD or SUD patients if the approach proves successful.”

• AssumptionRests on an assumption: Reductions in alcohol and drug intake produced by GLP-1 receptor agonists in preclinical species are predictive of clinical benefit in patients with AUD or SUD.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

DPP-4 degrades endogenous GLP-1 within minutes, and DPP-4 inhibitors are approved for Type 2 diabetes as an indirect way to stimulate GLP-1 receptors.

“DPP-4 degrades endogenous GLP-1 within minutes, and DPP-4 inhibitors are approved for treatment of Type 2 diabetes (Deacon, 2020) as an indirect way to stimulate GLP-1 receptors (Łupina et al., 2020).”

• cites Deacon, 2020Not checked yet

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• cites Łupina et al., 2020Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

GLP-1 receptor activation effects on alcohol consumption have been studied more extensively in laboratory animals than for other substances of abuse.

“The effects of GLP-1 receptor activation on alcohol consumption in laboratory animals have been investigated more extensively compared with other substances of abuse.”

Probably not a substantial claim: may not pass S3 (load-bearing).

GLP-1 receptors occur in many tissues throughout the body.

“GLP-1 receptors are present in many tissues throughout the body”

• cites Holst, 2007Not checked yet

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May combine two claims.

In a relapse model, subchronic exenatide attenuated binge-like increases in alcohol drinking, prolonged latency to the first drink, and reduced drinking bouts.

“Finally, a model of relapse behaviour reported an attenuated binge-like increase in alcohol drinking, with protracted latency to the first drink and reduced drinking bouts, after subchronic treatment with exenatide (Thomsen, Dencker, et al., 2017).”

• cites Thomsen, Dencker, et al., 2017Not checked yet

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May combine two claims.

Because AUD is chronic and relapsing and usually needs long-term treatment, acute effects do not always predict the effectiveness of repeated or chronic dosing.

“This is important, as AUD is a chronic, relapsing illness that typically requires long-term treatment, and acute effects do not always adequately predict the effectiveness of repeated or chronic dosing.”

May combine two claims.

Most published studies of GLP-1 receptor agonists and alcohol used animals exposed to modest alcohol quantities in models of reinforcing effects, and studies in truly alcohol-dependent animals are lacking.

“A notable omission from the published reports are those on the effects of GLP-1 receptor agonists on truly alcohol-dependent animals.In most of the studies described above, animals were exposed to modest quantities of alcohol in models focusing on the reinforcing aspects of alcohol consumption.”

May combine two claims.

Systemic exendin-9 increased alcohol intake, supporting a role for endogenous GLP-1 in modulating alcohol consumption.

“However, systemic administration of the GLP-1 receptor antagonist exendin-9 increased alcohol intake (Shirazi et al., 2013), supporting a role for endogenous GLP-1 in modulating alcohol consumption.”

• cites Shirazi et al., 2013Not checked yet

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May combine two claims.

The failure of GPR119 agonists to reduce alcohol intake may reflect rapid degradation or limited brain access of native GLP-1 and supports central mediation of GLP-1 effects on alcohol consumption.

“This might be due to rapid degradation or limited access to the brain of systemically released native GLP-1 and supports the contention that GLP-1 effects on alcohol consumption are centrally mediated.”

• cites Marty et al., 2020Not checked yet

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May combine two claims.

Liraglutide and semaglutide strongly reduced ethanol intake acutely, but repeated administration produced only transient effects lasting no more than 48 hours.

“In one study, the GLP-1 receptor agonists liraglutide and semaglutide potently decreased ethanol intake when given acutely, but when testing repeated administration, effects were transient, not lasting more than 48 h (Marty et al., 2020).”

• cites Marty et al., 2020Not checked yet

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May combine two claims.

Another meta-analysis including 55,921 patients confirmed no significant association with cardiovascular outcome, and studies comparing pancreatitis or pancreatic cancer risk with other antidiabetic medications also supported this.

“Another meta-analysis confirmed this finding in data based on GLP-1 receptor agonist therapy and cardiovascular outcome, including 55,921 patients (Abd El Aziz et al., 2020), as well as studies comparing the risk of pancreatitis (Azoulay et al., 2016a) or pancreatic cancer (Azoulay et al., 2016b) between GLP-1 receptor agonists and other antidiabetic medications.”

• cites Abd El Aziz et al., 2020Not checked yet

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• cites Azoulay et al., 2016aNot checked yet

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• cites Azoulay et al., 2016bNot checked yet

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May combine two claims.

In rats, exenatide given systemically or into the NAc shell decreased oxycodone self-administration and reinstatement responding.

“it was reported that exenatide injected systemically or centrally into the NAc shell region decreased oxycodone selfadministration, as well as responding in a reinstatement paradigm (Zhang et al., 2020).”

• cites Zhang et al., 2020Not checked yet

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May combine two claims.

Both systemic exenatide in mice and central exenatide into the VTA in rats decreased intravenous cocaine self-administration.

“Both systemically administered in mice and centrally administered exenatide into the VTA in rats decreased cocaine self-administration (Schmidt et al., 2016;Sørensen et al., 2015).”

• cites Schmidt et al., 2016Not checked yet

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• cites Sørensen et al., 2015Not checked yet

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May combine two claims.

Fluorescently labelled exenatide crossed the blood-brain barrier and bound putative GLP-1 receptors on dopamine D1 and D2 receptor-expressing GABAergic medium spiny neurons in the NAc shell.

“a group of rats was injected systemically with fluorescently labelled exenatide, which was shown to cross the blood-brain barrier and bind putative GLP-1 receptors expressed on dopamine D 1 and D 2 receptors, expressing GABAergic medium spiny neurons in the NAc shell (Zhang et al., 2020).”

• cites Zhang et al., 2020Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

It is unclear whether the decreased postprandial GLP-1 result is due to alcohol rather than other nutrients.

“It is thus unclear whether the latter result can be attributed to alcohol ingestion, as opposed to other nutrients.”

May combine two claims.

In male mice, morphine-conditioned place preference, intravenous remifentanil self-administration, morphine-stimulated locomotor activity, and somatic morphine withdrawal symptoms were not affected by exenatide.

“The first study was performed in male mice and reported that morphine-conditioned place preference, intravenous self-administration of the short-acting synthetic opioid remifentanil, morphine-stimulated locomotor activity and somatic symptoms of morphine withdrawal (measured as jumps) were not affected by exenatide treatment (Bornebusch et al., 2019).”

• cites Bornebusch et al., 2019Not checked yet

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May combine two claims.

The selective DPP-4 inhibitor linagliptin reduced morphine-conditioned place preference and facilitated extinction of morphine preference in rats.

“Treatment with the selective DPP-4 inhibitor linagliptin was also reported to reduce morphine-conditioned place preference and facilitate extinction of the morphine preference in rats (Łupina et al., 2020).”

• cites Łupina et al., 2020Not checked yet

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A genetic study of four human association studies found that the GLP-1 receptor 168Ser allele is associated with increased alcohol self-administration and higher fMRI BOLD response in the globus pallidus during rewarding feedback.

“a genetic study composed of four human genetic association studies has shown that the GLP-1 receptor 168Ser allele is associated with increased alcohol selfadministration and a higher fMRI blood-oxygen-level-dependent (BOLD) response in the globus pallidus when receiving rewarding feedback in the monetary incentive delay task.”

• cites Suchankova et al., 2015Not checked yet

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May combine two claims.

Systemic exenatide or the DPP-4 inhibitor sitagliptin decreased intravenous nicotine self-administration in mice, and GLP-1 receptor knockout mice self-administered more nicotine than wild-type controls.

“The second study found that systemic exenatide or the DPP-4 inhibitor sitagliptin decreased intravenous nicotine selfadministration in mice and that GLP-1 receptor knockout mice, that is, mice lacking GLP-1 receptors, self-administered more nicotine than the wild-type controls (Tuesta et al., 2017).”

• cites Tuesta et al., 2017Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

No clinical trials have or are currently investigating GLP-1 receptor activation as a treatment for central stimulant use disorder in humans.

“To the best of our knowledge, no clinical trials have or are currently investigating GLP-1 receptor activation as a treatment of central stimulant use disorder in humans.”

May combine two claims.

Acute exenatide inhibits cocaine-stimulated locomotor hyperactivity and decreases or abolishes cocaine-induced dopamine release in the NAc and lateral septum in mice.

“Acute exenatide has been reported to inhibit cocaine-stimulated locomotor hyperactivity and decrease or abolish cocaine-induced dopamine release in the NAc and lateral septum in mice (Egecioglu, Engel, & Jerlhag, 2013a;Reddy et al., 2016;Sørensen et al., 2015).”

• cites Egecioglu, Engel, & Jerlhag, 2013aNot checked yet

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• cites Reddy et al., 2016Not checked yet

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• cites Sørensen et al., 2015Not checked yet

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May combine two claims.

Cocaine self-administration and expectancy of cocaine injections increased endogenous GLP-1 in rats.

“Self-administration of cocaine, and expectancy of cocaine injections, increased endogenous GLP-1 in rats (You et al., 2019).”

• cites You et al., 2019Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The discrepant self-administration results may indicate species differences between rats and mice.

“The discrepant results in the self-administration paradigm may indicate species differences between rats and mice.”

May combine two claims.

Viral vector-mediated expression of GLP-1 receptors in the lateral septum reversed these effects, indicating a crucial role of this structure in GLP-1 modulation of cocaine effects.

“The effects were reversed by viral vectormediated expression of GLP-1 receptors in the lateral septum, indicating a crucial role of this structure in GLP-1 modulation of cocaine effects (Harasta et al., 2015).”

• cites Harasta et al., 2015Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Detoxified AUD patients have lower serum DPP-4 concentrations than healthy controls, and it has been hypothesized that this diminished activity may be involved in the neuroendocrine pathophysiology of alcohol dependence.

“Detoxified patients with AUD have been reported to have a lower serum DPP-4 concentration than healthy controls, and it is hypothesized that this diminished activity, may be involved in the neuroendocrine pathophysiology of alcohol dependence (Maes et al., 1999).”

• cites Maes et al., 1999Not checked yet

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May combine two claims.

Systemic exenatide suppresses both acquisition and expression of cocaine-conditioned place preference in mice.

“Systemic exenatide administration has been reported to suppress both the acquisition and the expression of cocaineconditioned place preference in mice (Egecioglu, Engel, & Jerlhag, 2013a;Graham et al., 2013).”

• cites Egecioglu, Engel, & Jerlhag, 2013aNot checked yet

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• cites Graham et al., 2013Not checked yet

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Classified as probably not a substantial claim.

These early human findings do not rule out the possibility that different doses, ligands, or dosing regimens could modulate cocaine-taking behaviour in CUD patients.

“they do not preclude the possibility that different doses, ligands, dosing regimens (e.g., subchronic) could modulate cocainetaking behaviour in patients with CUD (Angarita et al., 2021).”

• cites Angarita et al., 2021Not checked yet

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May combine two claims.

Exenatide injected into the interpeduncular nucleus decreased nicotine self-administration and prevented nicotine from modulating intracranial self-stimulation threshold in rats.

“The study further reports that exenatide injected into the interpeduncular nucleus decreased nicotine self-administration and prevented nicotine from modulating intracranial self-stimulation threshold in rats (Tuesta et al., 2017).”

• cites Tuesta et al., 2017Not checked yet

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May combine two claims.

Preclinical studies show promising effects of GLP-1 receptor agonists against cocaine intake, but little is known about cocaine's effects on the GLP-1 system or GLP-1 as a predisposing factor for CUD.

“In summary, preclinical studies show promising effects of GLP-1 receptor agonists against cocaine intake, but little information is yet available regarding possible effects of cocaine use on the GLP-1 system or GLP-1 as a predisposing factor to developing CUD.”

May combine two claims.

Acute systemic exenatide attenuated nicotine-induced locomotor hyperactivity and sensitization, nicotine-conditioned place preference, and nicotine-induced accumbal dopamine release in rodents.

“The first study reported attenuation of nicotine-induced locomotor hyperactivity and sensitization, nicotine-conditioned place preference and nicotineinduced accumbal dopamine release (measured by microdialysis) after acute systemic exenatide administration (Egecioglu, Engel, & Jerlhag, 2013b).”

• cites Egecioglu, Engel, & Jerlhag, 2013bNot checked yet

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May combine two claims.

Fewer studies have examined GLP-1 receptor activation effects on central stimulant effects, and all used D-amphetamine.

“Fewer studies have examined the effects of GLP-1 receptor activation on central stimulant effects, all of them using D-amphetamine.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Reduced postsynaptic dopamine receptor availability is suggested as one explanation for lower dopamine function in these patient groups.

“which is suggested as one of the explanations for lower dopamine function in this group of patients (Nutt et al., 2015)”

• cites Nutt et al., 2015Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

As addiction progresses, wanting overshadows liking and becomes independent of liking.

“As an individual becomes more addicted, 'wanting' will overshadow 'liking' and become independent of 'liking' (Berridge & Robinson, 2016).”

• cites Berridge & Robinson, 2016Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Wanting is believed to arise in the dopaminergic mesolimbic system projecting from the VTA to the NAc, while liking comes from hedonic hotspots and does not depend on dopamine release.

“'Wanting' is believed to be generated in the dopaminergic mesolimbic system, projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), whereas 'liking' comes from tiny hedonic hotspots in the brain and is not dependent on dopamine release.”

• cites Berridge & Robinson, 2016Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Cocaine blocks the dopamine transporter, inhibiting dopamine reuptake and increasing or prolonging synaptic dopamine levels.

“Cocaine inhibits dopamine reuptake by blocking the dopamine transporter (DAT), increasing or prolonging synaptic dopamine levels”

• cites Volkow et al., 2002Not checked yet

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May combine two claims.

Pharmacological treatments are available for AUD, OUD, and tobacco use disorder.

“Pharmacological treatments against AUD, opioid use disorder (OUD) and tobacco use disorder are available (see Table 1)”

• cites European Monitoring Centre for Drugs and Drug Addiction, 2012Not checked yet

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• cites Kampman, 2019Not checked yet

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• cites Kranzler & Soyka, 2018Not checked yet

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Dysregulation of the dopamine system contributes to the addicted state, both as a predisposing factor and as a consequence of chronic substance use.

“dysregulation of the dopamine system is thought to contribute (as a predisposing factor and/or a consequence of chronic substance use) to the addicted state”

• cites Volkow, Michaelides, et al., 2019Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Many smokers try to quit without medication or support, and the failure rate is 95-98%.

“Despite the available treatment options, many smokers attempt to quit without medication or support, with a failure rate of 95-98% (Prochaska & Benowitz, 2016).”

• cites Prochaska & Benowitz, 2016Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The dark side theory of addiction contends that impulsivity, compulsivity, and negative urgency derive from stress during withdrawal or the negative affect stage, even months into abstinence.

“'The dark side' theory of addiction contends that impulsivity, compulsivity and negative urgency are derived from stress experienced during withdrawal or 'negative affect stage', even several months into abstinence.”

• cites Zorrilla & Koob, 2019Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Dopaminergic neurons from the VTA project to the NAc, amygdala, hippocampus and prefrontal cortex, while dopamine neurons from the substantia nigra project to the dorsal striatum.

“Dopaminergic neurons emerging from the VTA project to the NAc, amygdala, hippocampus and prefrontal cortex, and dopamine neurons emerging from substantia nigra (SN) project to the dorsal striatum”

• cites Volkow et al., 2017Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Other central stimulants can raise synaptic dopamine through several mechanisms, including reuptake blockade, reverse DAT function and dopamine release.

“Other central stimulants can increase synaptic dopamine levels by several modes of action, for example, blockade of dopamine reuptake, 'reverse' DAT function and dopamine release”

• cites Lee et al., 2018Not checked yet

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May combine two claims.

Even when pharmacotherapy exists, long-term abstinence success rates are modest, which highlights an urgent need for new effective medications for SUD and AUD.

“Even when pharmacotherapy is available, success rates for achieving long-term abstinence are modest, highlighting the urgent need for new, effective medications against SUD and AUD (Kampman, 2019;Lee et al., 2018;Lyon, 2017; National Institute on Drug Abuse [NIDA], 2020; Volkow, 2020;Volkow, Jones, et al., 2019).”

• cites Kampman, 2019Not checked yet

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• cites Lee et al., 2018Not checked yet

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• cites Lyon, 2017Not checked yet

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May combine two claims.

One randomized clinical pilot trial of exenatide 2.0 mg once weekly with transdermal nicotine replacement reported increased smoking abstinence and reduced craving.

“one randomized clinical pilot trial has investigated the effects of exenatide, 2.0 mg once weekly, in combination with transdermal nicotine replacement therapy on smoking cessation.They have reported that exenatide increased smoking abstinence and reduced craving (Yammine et al., 2021).”

• cites Yammine et al., 2021Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Dopamine has a prominent role in the immediate reinforcing and rewarding effects of drugs, and dopamine dysregulation is thought to contribute to addiction as a predisposing factor and/or a consequence of chronic substance use.

“Dopamine plays a prominent role in the immediate reinforcing/rewarding effects of drugs-'the dopamine theory', and dysregulation of the dopamine system is thought to contribute to the addicted state as a predisposing factor and/or a consequence of chronic substance use (Volkow, Michaelides, et al., 2019).”

• cites Volkow, Michaelides, et al., 2019Not checked yet

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May combine two claims.

Other studies found unaffected DAT after exenatide treatment in rats or mice, or after genetic ablation of GLP-1 receptors in knockout mice.

“However, other studies reported unaffected DAT after exenatide treatment in rats (Fortin & Roitman, 2017), or mice (Jensen et al., 2020), or by genetic ablation of GLP-1 receptors, that is, knockout mice (Jensen et al., 2020).”

• cites Fortin & Roitman, 2017Not checked yet

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• cites Jensen et al., 2020Not checked yet

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May combine two claims.

GLP-1 receptor agonists do not appear to suppress baseline accumbal dopamine, unlike stimulated dopamine levels.

“GLP-1 receptor agonists do not seem to suppress baseline accumbal dopamine, as opposed to the modulation of stimulated levels”

• cites Egecioglu, Engel, & Jerlhag, 2013aNot checked yet

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• cites Fortin & Roitman, 2017Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

A blunted dopamine response compensating for glutamate or GABA deficits could also explain abnormal radiotracer imaging results.

“Another mechanism explaining the abnormal radiotracer imaging results could be a blunted dopamine response, compensating for other neurotransmitter deficits, that is, glutamate or GABA (Volkow et al., 2011).”

• cites Volkow et al., 2011Not checked yet

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May combine two claims.

Systemically injected liraglutide and exenatide attenuate alcohol-induced accumbal dopamine release.

“Systemically injected liraglutide (Vallöf et al., 2016) and exenatide (Egecioglu, Steensland, et al., 2013) attenuate alcohol-induced accumbal dopamine release”

• cites Vallöf et al., 2016Not checked yet

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• cites Egecioglu, Steensland, et al., 2013Not checked yet

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May combine two claims.

Different functional subtypes of GLP-1 receptors may exist, likely due to ligands showing different signalling bias for second messenger pathways, with expression varying by tissue.

“Thus, it may be appropriate to think of different functional subtypes of GLP-1 receptors, likely brought about by GLP-1 receptor ligands showing different signalling bias for different second messenger pathways, whose expression may vary by tissue (Fletcher et al., 2016;Zhang et al., 2015).”

• cites Fletcher et al., 2016Not checked yet

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• cites Zhang et al., 2015Not checked yet

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May combine two claims.

Rodents cannot vomit when nauseated, but nausea and malaise can be measured indirectly by pica, the consumption of kaolin clay.

“Rodents lack the ability of vomiting when nauseated, but nausea and malaise can be measured indirectly by pica, which is the consumption of the non-nutritive substance, kaolin clay (Kanoski et al., 2012).”

• cites Kanoski et al., 2012Not checked yet

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Based on rodent studies, GLP-1 receptor agonists vary in brain availability and in how discrete or extensive brain regions show GLP-1 receptor binding after systemic administration.

“Based on rodent studies, GLP-1 receptor agonists also vary with respect to brain availability and how discrete or extensive brain regions show GLP-1 receptor binding after systemic GLP-1 receptor agonist administration (Gabery et al., 2020;Salinas et al., 2018;Secher et al., 2014).”

• cites Gabery et al., 2020Not checked yet

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• cites Salinas et al., 2018Not checked yet

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• cites Secher et al., 2014Not checked yet

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Twelve days of exenatide treatment increased pica, while the pica response after liraglutide was more transient.

“Twelve days of treatment with exenatide has been reported to increase pica, but the pica response following treatment with liraglutide was more transient (Kanoski et al., 2012).”

• cites Kanoski et al., 2012Not checked yet

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May combine two claims.

Hypothalamic CRF neurons express GLP-1 receptors, and GLP-1 receptor stimulation enhances CRF signalling.

“The CRF neurons of the hypothalamus express GLP-1 receptors, and GLP-1 receptor stimulation has been shown to enhance CRF signalling (Kinzig et al., 2003;Larsen et al., 1997;Liu et al., 2017).”

• cites Kinzig et al., 2003Not checked yet

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• cites Larsen et al., 1997Not checked yet

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• cites Liu et al., 2017Not checked yet

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May combine two claims.

GLP-1 receptor agonists prevented relapse to binge-like alcohol drinking after deprivation and attenuated alcohol withdrawal-induced anxiety-like behaviour.

“GLP-1 receptor agonists prevented 'relapse' to binge-like alcohol drinking after deprivation and attenuated alcohol withdrawal-induced anxiety-like behaviour (Sharma et al., 2015b;Thomsen, Dencker, et al., 2017;Vallöf et al., 2016).”

• cites Sharma et al., 2015bNot checked yet

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• cites Thomsen, Dencker, et al., 2017Not checked yet

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• cites Vallöf et al., 2016Not checked yet

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May combine two claims.

In a Parkinson's disease trial, exenatide once weekly affected off-medication motor scores but had no significant effect on DAT availability after 48 weeks.

“investigating the effects of exenatide once weekly in patients with Parkinson's disease, where an effect on off-medication motor scores was reported, but no significant effect on DAT availability after 48 weeks of treatment (Athauda et al., 2017)”

• cites Athauda et al., 2017Not checked yet

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May combine two claims.

Chronic use of alcohol, central stimulants, nicotine and opioids increases CRF levels, and CRF antagonists reduce drug seeking.

“Thus, chronic use of alcohol, central stimulants, nicotine and opioids have all been shown to increase CRF levels, and CRF antagonists reduce drug seeking (Mantsch et al., 2016;Park et al., 2015).”

• cites Mantsch et al., 2016Not checked yet

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• cites Park et al., 2015Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Cocaine produces a GLP-1-dependent negative feedback loop through stress circuits including corticosterone, which limits cocaine intake.

“cocaine produces a GLP-1-dependent negative feedback loop through activation of stress circuits including corticosterone, limiting cocaine intake (Schmidt et al., 2016)”

• cites Schmidt et al., 2016Not checked yet

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May combine two claims.

GLP-1 systems regulate food and fluid intake, and GLP-1 receptor agonists can reduce food consumption at doses comparable to those that reduce alcohol intake.

“Because the GLP-1 systems regulate food and fluid intake, and GLP-1 receptor agonists can decrease food consumption at doses comparable with those that decrease alcohol intake”

• cites Dickson et al., 2012Not checked yet

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• cites Tang-Christensen et al., 1996Not checked yet

  Not checked in the free run.

May combine two claims.

Stimulation of GLP-1 autoreceptors in the NTS would be expected to reduce GLP-1 release to other brain regions, removing a tonic inhibitory modulation on reward and consummatory functions.

“A straightforward explanation for effects in the NTS could be that stimulation of GLP-1 autoreceptors in the NTS would be expected to reduce release of GLP-1 to other brain regions, removing a tonic inhibitory modulation on reward/consummatory functions.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Clinical observations in patients treated with GLP-1 receptor agonists for Type 2 diabetes suggest greater body weight reduction in those with higher baseline body mass index.

“Clinical observations from patients treated with GLP-1 receptor agonists for Type 2 diabetes suggest that GLP-1 receptor agonists may reduce body weight more in subjects with higher baseline body mass index (Niswender et al., 2013)”

• cites Niswender et al., 2013Not checked yet

  Not checked in the free run.

May combine two claims.

Brain GLP-1 receptors are heterogeneous and can exert inhibitory effects in CA3 hippocampus and lateral septum and stimulatory effects in CA1 hippocampus and hypothalamic nuclei at the cellular level.

“GLP-1 receptors in the brain are heterogeneous and can exert both inhibitory effects, as in the CA3 of hippocampus and lateral septum, and stimulatory effects, as in the CA1 of hippocampus and hypothalamic nuclei, at the cellular level (Liu & Pang, 2016).”

• cites Liu & Pang, 2016Not checked yet

  Not checked in the free run.

May combine two claims.

The GLP-1 receptor agonist-induced up-regulation of DAT availability may be species dependent, with no DAT-GLP-1 interaction in humans.

“Thus, it has been proposed that the GLP-1 receptor agonist-induced up-regulation of DAT availability might be species dependent, with no DAT-GLP-1 interaction in humans (Jensen et al., 2020).”

• cites Jensen et al., 2020Not checked yet

  Not checked in the free run.

May combine two claims.

Another study used both male and female mice to investigate GLP-1 receptor agonist effects on nicotine self-administration, but sex analyses were not reported and data were shown as sexes combined.

“Another study used both male and female mice to investigate the effects of GLP-1 receptor agonists on nicotine self-administration, but analyses of the sex variable were not reported, and data were only shown as sexes combined (Tuesta et al., 2017).”

• cites Tuesta et al., 2017Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based).

Individuals with obesity and individuals with addiction are suggested to have overlapping brain dysregulations.

“It is also suggested that individuals suffering from obesity and individuals suffering from addiction have overlapping brain dysregulations”

May combine two claims.

The precise mechanisms of GLP-1 receptor agonist actions on addiction-related endpoints have not been established, but the effects appear to be mediated centrally, at least partly through modification of dopamine signalling.

“The precise mechanisms of GLP-1 receptor agonists' actions on addictionrelated endpoints have yet to be established, but the effects seem to be mediated centrally, at least in part through modification of dopamine signalling.”

May combine two claims.

In that female-rat study, water intake was decreased, and alcohol preference may not have been decreased based on the relative effect sizes for water and alcohol intake.

“Water intake was decreased, and alcohol preference, although not reported, may not have been decreased based on the relative effect sizes for water and alcohol intake.”

• cites Abtahi et al., 2018Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Higher GLP-1 response after an oral glucose test has been reported in healthy women than in men.

“Higher GLP-1 response after an oral glucose test in healthy women than in men has been reported.”

• cites Faerch et al., 2015Not checked yet

  Not checked in the free run.

May combine two claims.

No clear well-defined circuit-level mechanism has been identified; GLP-1 appears to modulate brain circuits at multiple levels, and the relevant mechanisms may be species dependent.

“No clear and well-defined circuit-level mechanism has been identified yet, instead GLP-1 seems to modulate brain circuits at multiple levels, and the relevant mechanisms of action may well be species dependent.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Another study reported higher GLP-1 plasma levels in premenopausal women than in postmenopausal women, but this might be due to different microbiota compositions.

“Another study reported higher GLP-1 plasma levels in premenopausal women compared with postmenopausal women, but this might be due to different microbiota compositions (Santos-Marcos et al., 2018).”

• cites Santos-Marcos et al., 2018Not checked yet

  Not checked in the free run.