Recreational substance use and neurotransmitters

Nervous system imbalances can lead to cravings, such as the desire to abuse recreational substances.   However, engaging in recreational substance use can also lead to changes in nervous system function and ultimately nervous system imbalances.

A number of neurotransmitters have been implicated in patients who engage in recreational substance use.   Glutamate, dopamine, serotonin, acetylcholine and norepinephrine have all been shown to contribute to cravings and urges through their respective roles in the pleasure and reward pathways of the nervous system.

It is important to recognize that recreational substance use can impact neurotransmitters, and psychological and physiological effects of recreational substance use are mediated by changes in the nervous system.  A brief overview of  some of the effects on neurotransmitter systems is listed here and additional resources can be found below.


  • Binds GABA receptors as an agonist
  • Blocks glutamate receptors ( antagonist)
  • Increases dopamine release

Cannabis (marijuana)

  •  THC (tetrahydrocannabinol) binds to cannabinoid receptors and interferes with neurotransmitter systems
  • Decreased compensatory neurotransmitter release and leads to increased dopamine release


  • Strong central nervous system(CNS) stimulation through inhibition of catecholamine (dopamine, norepinephrine, epinephrine) reuptake
  • Dramatically increases extracellular dopamine concentrations
  • Interferes with serotonin and norepinephrine reuptake


  • Metabolizes to morphine and interacts with opioid receptors
  • Prevents compensatory control of dopamine resulting in increased dopamine release
  • Reduces norepinephrine release


  • Blocks NMDA (N-methyl-D-aspartate) glutamate receptor (antagonist)
  • May activate opioid receptors
  • Increases CNS glutamate levels
  • Increases norepinephrine and dopamine activity and prevents dopamine reuptake
  • Inhibition of cholingeric transmission


  • Binds serotonin receptor as a partial agonist
  • Binds dopamine and norepinephrine receptor as an agonist
  • Increases central norepinephrine release

MDMA (Ecstasy)

  • Taken up by serotonin transporters and alters transporter function
  • Increases synaptic serotonin
  • Neurotoxic to serotonin-producing neurons
  • Mild stimulatory effect by inhibiting reuptake of serotonin, dopamine, and norepinephrine


  • Increases synaptic dopamine, norepinephrine, and serotonin levels
  • Resembles dopamine and is taken up through reuptake transporters forcing high amounts of dopamine out of the cell and into the synapse

For more information on how recreational substance use can impact the nervous system, please view these helpful links:

Mouse Party (

Drugs and Human Performance Fact Sheet (

U.S. Department of Justice, DEA 2008 Annual Report (

National Institute on Drug Abuse:  The Science of Drug Abuse and Addiction  (

National Survey on Drug Use and Health:  Findings  (

MedLinks MIT Student Health Pharmacology Reference (

Additional References
Schobel S. Chaudhury N.H. Khan U.A.  Paniagua B. Styner M.A. Asllani I. Inbar B.P.  Corcoran C.M. Lieberman J.A. Moore H. Small S.A.  Imaging patients with psychosis and a mouse model establishes a spreading pattern of hippocampal dysfunction and implicates glutamate as a driver.  Neuron. 2013;78:81-93.
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3 Responses to Recreational substance use and neurotransmitters

  1. Thanks for the info! I’m curious — if cocaine blocks reuptake of norepi and serotonin, does it increase or decrease the overall levels of norepi/serotonin? Cymbalta (also a norepi/serotonin reuptake inhibitor) is “supposed to” increase the availability of norepi/serotonin by blocking reuptake. But it is used for hyperadrenergic postural orthostatic tachycardia syndrome, where norepi levels are sky high. Is it possible that by blocking reuptake, there are less “recycled” ingredients for the neurotransmitters, resulting in an overall reduction of norepi/serotonin? Thanks so much for answering this question which has puzzled me for years.

    • Britt Sager says:

      There is some evidence to suggest that use of re-uptake inhibitors may hasten the depletion of neurotransmitter stores. This of course is dependent on a number of other factors: dietary intake of precursors and co-factors, levels of stress (thus neurotransmitter demand), and genetics. Typically, reuptake inhibitors are used to increase synaptic levels rather than depleting presynaptic stores. More information about neurotransmitter depletion can be found in the Pharmacology module of the NEI Certification program offered through NeuroScience, Inc. This is a complimentary educational curriculum available to providers who have an account with NeuroScience, Inc.

      Other potential mechanisms offer additional insight.

      Preventing the reuptake of any neurotransmitter increases the possibility of activating presynaptic auto-receptors, which may down-regulate neurotransmitter release into the synapse by the presynaptic neuron. Reuptake inhibitors are used to increase synaptic levels and thus neurotransmission at the postsynaptic neuron, but the presence of non-responders and adverse responders to natural and pharmaceutical reuptake inhibitors suggest there may be other mechanisms.

      Many norepinephrine reuptake inhibitors have a profound effect in the locus coeruleus, a noradrenergic brain region. This region helps to regulate the autonomic nervous system (ANS), providing balance between the adrenal sympathetic response and the neural sympathetic response. Perhaps the use of an SNRI in patients with elevated norepinephrine is an attempt to restore locus coeruleus control to the ANS, while the addition of the SSRI helps to offset the stimulation that can potentially take place with increased synaptic norepinephrine. Anecdotal reports of improved adrenal hormone levels have been seen with both SNRI and SSRI use, suggesting that the brain regions they impact are playing a regulatory role within the ANS. Certainly interesting connections, although more research is warranted to fully address your question. Some of our previous blog posts highlight the role of the locus coeruleus in maintaining nervous system balance.

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