Caffeine And Phentermine-Topiramate

Caffeine is the most popular drug that stimulates the nervous system. This is also what phentermine, a weight loss drug, does and how it reduces appetite. Due to this, combining caffeine and phentermine can increase the risk of side effects. How bad is it to combine phentermine and caffeine? Does topiramate, a combination drug prescribed with phentermine, change the interaction of caffeine and phentermine? This blog will address these common questions.
Klara Hatinova

Klara Hatinova

Klara is postgraduate researcher in experimental psychology at the
University of Oxford.

A blue image with text saying "Caffeine And Phentermine-Topiramate"

How Does Phentermine Work?

Phentermine is a prescription drug that belongs to a class of medications known as anorectics, meaning it suppresses appetite and promotes weight loss. It was first discovered in the 1960s and has been approved for the treatment of obesity together with topiramate since 2012. It should primarily be used in overweight or obese individuals with one or more obesity-related conditions, such as hypertension, high blood pressure, or musculoskeletal difficulties[1, 2].

Phentermine interacts with neurotransmitter transporters in the brain. It primarily interacts with dopamine and norepinephrine transporters, increasing the release of these neurotransmitters [3]. Dopamine is associated with feelings of pleasure and reward, which could potentially reduce the desire to eat. This was demonstrated in a mouse study, where mice treated with phentermine learned a reward association quicker when on phentermine [4].

Norepinephrine is a stress hormone that often leads to the 'fight or flight' response by increasing the activity of the sympathetic nervous system. The sympathetic nervous system counteracts the activity of the parasympathetic nervous system, which is linked to resting and digesting. Hence, increasing sympathetic activity can suppress appetite [5].

Phentermine also increases serotonin levels, a neurotransmitter that regulates mood and appetite. This adds to its anorexigenic properties [6].

Phentermine also has weaker activity at the serotonin transporter and negligible activity towards it [6]. Serotonin is a neurotransmitter that can affect mood and appetite.

Since phentermine acts on dopamine, the brain can quickly develop a tolerance to its effects, requiring higher and higher doses. This is why it is critical to only use phentermine for short periods of time [2].


In some countries, such as Germany, phentermine approval has been withheld, particularly for its abuse potential.

How Does Topiramate Work?

We know much more about how topiramate works in the brain than about how phentermine works in the brain.

Topiramate is a neuromodulator that can stabilise brain activity by acting on ion channels that regulate excitation-inhibition, such as voltage-activated sodium and calcium ion channels and glutamate receptors [7].

Because it can block sodium channels and inhibit excitation, topiramate has been used for managing seizures and migraine, meaning it has anticonvulsant efficacy [7, 8].

Animal models indicate that topiramate can also inhibit brain activity by potentiating the effects of GABA [9], but these studies have not been replicated in humans [10]. One study found that topiramate increased levels of GABA in the brain, demonstrating whether or not GABA activity is increased remains to be confirmed.

How Does Caffeine Work In The Brain?

According to the British Coffee Association [11], about two million cups of coffee are consumed worldwide daily, making caffeine a frequent stimulant. Understanding its neurobiology is critical to establishing whether caffeine interacts with phentermine since not many studies have directly investigated their combination.

Caffeine And Neurotransmitters

One of the primary ways caffeine works is by antagonizing adenosine receptors, specifically A1 and A2A adenosine receptors. This antagonistic effect increases neuronal activity and constriction of blood vessels in the brain [12].

Adenosine is a neurotransmitter that promotes sleep and relaxation when it binds to its receptors, A1 and A2A. Caffeine can mimic the structure of adenosine, enabling it to bind to adenosine receptors. Critically, caffeine can sit in the receptor without inducing the effects of adenosine, thereby blocking adenosine’s sleep and relaxation effects [13].

Caffeine also impacts other neurotransmitter systems, which is critical for interacting with phentermine. By increasing calcium levels and different signalling molecules, caffeine can increase the formation of long-range connections in the brain and re-structure cortical networks. It can additionally reduce the effects of GABA, which counteracts some of the plausible mechanisms of topiramate action. [14].

Caffeine And Cognition

Caffeine affects areas of the brain that facilitate attention, processing speed, and memory. For example, caffeine increases the activity in the frontal cortex during cognitive tasks, which is associated with improved performance on demanding tasks [12]. Similarly, in memory-dependent tasks, increased activation was found in regions supporting memory and flexibility, such as temporoparietal regions and the anterior cingulate cortex [15].

Peripheral Effects Of Caffeine

Caffeine has effects relevant to phentermine-topiramate’s weight loss activity outside the brain. For example, caffeine also increases heart rate and blood pressure, likely through its effects on constricting blood vessels and increasing sympathetic arousal. Despite this, caffeine is considered neuroprotective, which may indicate the benefits of combining caffeine and phentermine [16].

A recent study highlights the bimodal effects of caffeine on glucose regulation, which can also be relevant to the goals of taking phentermine. In the short term, caffeine hampered glucose regulation, but in the long term (above two weeks), drinking coffee had a favourable effect on glucose regulation [17]. Hence, taking caffeine long-term could improve one's ability to regulate sugar levels and thereby supplement some of the effects of phentermine and weight loss.

Can You Combine Phentermine And Caffeine?

As discussed above, phentermine and topiramate are two medications that have been approved in combination for managing obesity. Caffeine also has some appetite-suppressing properties and benefits for cardiovascular, cognitive, and glucose regulation.

To date, little evidence supports or prevents the combination of caffeine and phentermine. Both substances are, however, stimulants, which could reduce one's ability to fall asleep, increase blood pressure, and accelerate heart rate. These effects should be carefully considered, especially in patients with pre-existing hypertension and arrhythmias, even more so when phentermine is prescribed for obesity-related comorbidity.

Phentermine And Caffeine Interactions With Other Drugs

Research has shown that caffeine can interact with various medications, including those used for occipital neuralgia, OCD, ADHD and Parkinson’s Disease. For instance, caffeine has been found to influence the efficacy of antiepileptic medications, including topiramate [18]. This is because caffeine and topiramate have different effects on inhibitory GABA activity.

On the other hand, caffeine has been shown to enhance the activity of certain antidepressants [19, 20]. However, these studies did not specifically investigate the interaction between caffeine and phentermine, although phentermine is similar to some antidepressants, such as Wellbutrin.

It's important to note that the National Library of Medicine advises patients to inform their doctors about all the medications, vitamins, nutritional supplements, and herbal products they are taking or plan to take before starting a regimen of phentermine and topiramate [21]. Certain substances could interact with these medications, potentially leading to side effects or reduced efficacy.

Summary: Caffeine and Phentermine

In conclusion, caffeine and phentermine-topiramate are both stimulants that can suppress appetite and aid weight loss. However, you should combine them with caution due to potential heightened side effects, such as increased blood pressure and heart rate. The independent actions of phentermine in enhancing monoamine release, topiramate’s stabilizing effects on brain activity, and caffeine’s antagonism of adenosine receptors collectively suggest complex neurobiological interactions. Due to limited research on their combined use, you should consult healthcare professionals before mixing these substances, mainly if you have been prescribed phentermine for weight loss with pre-existing health conditions.

Related Posts

Klara Hatinova

Klara Hatinova

Klara is a postgraduate researcher in experimental psychology at the University of Oxford. She has worked across a spectrum of hot topics in neuroscience, including her current project measuring reinforcement learning strategies in Parkinson’s disease. Previously, she studied the efficacy of psilocybin as a therapy for critical mental health conditions and examined molecular circadian rhythms of migraine disorders. She completed her undergraduate degree in Neuroscience at the University of Glasgow and participated in a year abroad at the University of California, where she worked on a clinical trial for spinal cord injury.