A releasing agent (RA), or simply releaser, is a drug that induces the release of a neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs use neurotransmitter release to exert their psychological and physiological effects, namely the amphetamines and related compounds. Virtually all currently known releasing agents affect the monoamine neurotransmitters serotonin (5-HT), norepinephrine (NE), and/or dopamine (DA), and as such, they are often referred to more formally as monoamine releasing agents (MRAs).
Mechanism of action 
Releasing agents cause the release of monoamine neurotransmitters by a complex mechanism of action. First, they enter the presynaptic neuron primarily via membrane transporters, including the dopamine transporter (DAT), norepinephrine transporter (NET), and/or serotonin transporter (SERT). Some, such as amphetamine and methamphetamine, can also diffuse directly across the cell membrane to varying degrees. Next, they inhibit vesicular uptake of the neurotransmitter by interfering with a vesicular transporter such as vesicular monoamine transporter 2 (VMAT2) (via binding or pH-gradient), and thus inhibit the repackaging of the neurotransmitter(s) from the cytoplasm into vesicles. Finally, releasing agents reverse the action of monoamine reuptake transporter(s) via a process known as phosphorylation, allowing the neurotransmitter(s) to flow out from the cytoplasm into the nerve terminal or synapse. The result is increased monoaminergic neurotransmission. The postsynaptic effect is enhanced due to the agents' interaction with reuptake transporters; one method by which the action of monoamines is terminated is via reuptake into the presynaptic neuron, and disruption of this process causes further increases in extracellular monoamine concentration.
Releasing agents act to varying extents on serotonin, norepinephrine, and dopamine. Some induce the release of all three neurotransmitters to a similar degree, like MDMA, while others are more selective. As examples, methamphetamine is a potent releasing agent of norepinephrine and dopamine but only a very weak releaser of serotonin (~30- and 60-fold less than dopamine and norepinephrine, respectively) and MBDB is a fairly balanced releaser of serotonin and norepinephrine but a weak releaser of dopamine (~6- and 10-fold lower for dopamine than norepinephrine or serotonin, respectively). Even more selective include agents like fenfluramine and ephedrine, which are selective releasing agents of serotonin and norepinephrine, respectively.
As of present, no selective dopamine releasing agents are known. This is because it has proven virtually impossible to separate DAT affinity from NET affinity and retain releasing efficacy at the same time. Accordingly, no known selective serotonin and dopamine releasing agents are known either; though, UWA-101, a serotonin-dopamine reuptake inhibitor, is an amphetamine derivative as well as analogue of MDMA and could possess some releasing efficacy.
Release efficacies of selected compounds 
|Compound||NE (Release)||DA (Release)||5-HT (Release)|
The values above are expressed as equilibrium dissociation constants (EC50 (nM)). Lower values correspond to higher binding at the site, or in other words, less is more. NE, DA, and 5-HT correspond to the abilities of the compounds to induce the release of norepinephrine, dopamine, and serotonin, respectively. All compounds listed are racemic unless noted otherwise.
Many releasing agents, notably many of those derived from amphetamine, have been found to be neurotoxic to serotonin and/or dopamine neurons via damage to axons and dendrites, enzymes, mitochondria, DNA, plasmalemmal and vesicular transporters, and the cell membrane, ultimately causing cell death or apoptosis as a result. Examples include amphetamine, methamphetamine, MDMA, fenfluramine, and PCA, among others. In contrast, piperazine, aminoindane, aminotetralin, and oxazoline releasing agents, as well as those from various other chemical families, are considered to be either significantly less toxic, or fully non-toxic in comparison, depending varyingly on the compound in question.
The neurotoxicity of some of these drugs is believed to be caused by oxidative stress induced by the generation of reactive oxygen species or free radicals, highly reactive particles that rip apart proteins and induce chain reactions of destruction. The free radicals are thought to be generated as byproducts when either the base compound or one or more of its metabolites are broken down by the enzymes monoamine oxidase (MAO-B) and/or cyclooxygenase (COX), among others, from within the presynaptic cell. Hyperthermia and simultaneous serotonin and dopamine release may play a major role in augmenting the damage as well. Monoamines themselves can be seen neurotoxic due to oxidative metabolism. This means even if a releasing agent is non-neurotoxic, the caused flood of monoamines that are then metabolized by monoamine oxidase generate oxidative stress.
These observations are supported by the facts that antioxidants such as ascorbic acid, MAO-B inhibitors like selegiline, drugs that induce hypothermia such as 5-HT2, D2, β-adrenergic, and NMDA receptor antagonists, as well as GABAA and GABAB receptor agonists, and serotonin reuptake inhibitors and dopamine reuptake inhibitors, respectively, are neuroprotective, and can help reduce damage caused by neurotoxic releasing agents.
List of releasing agents 
- Cathine (found in Catha edulis (Khat))
- Cathinone (found in Catha edulis (Khat))
- Ephedrine (found in Ephedra sinica (Ephedra))
- Phenylethylamine (Has NDRA actions) 
- Pseudoephedrine (Sudafed) (found in Ephedra sinica (Ephedra))
- Amphetamine (Adderall, Dexedrine; "Speed")
- Benzphetamine (Didrex)
- Chlorphentermine (Apsedon, Desopimon, Lucofen)
- Diethylcathinone (Tenuate)
- Ethylamphetamine (Apetinil)
- Fenfluramine (Pondimin, Fen-Phen, Redux)
- Levomethamphetamine (Vicks Vapor Inhaler)
- Lisdexamphetamine (Vyvanse)
- Methamphetamine (Desoxyn; "Meth", "Crank", "Crystal")
- Methylphenidate (Ritalin, Concerta, Focalin)
- Norfenfluramine (metabolite of fenfluramine)
- Phentermine (Fastin, Fen-Phen)
- Phenylpropanolamine (PPA; Acutrim, Dexatrim)
- Selegiline (L-Deprenyl; Eldepryl, Zelapar, Emsam)
- 4-Fluoroamphetamine (4-FA)
- 4-Fluoromethcathinone (4-FMC; Flephedrone)
- 4-Methoxyphenylpiperazine (MeOPP; Paraperazine)
- 4-Methylaminorex (4-MAR; "Ice", "EU4EUH")
- 4-Methylmethcathinone (4-MMC; Mephedrone)
- 4-Methylthioamphetamine (4-MTA)
- 5-(2-aminopropyl)benzofuran or 1-benzofuran-5-ylpropan-2-amine (5-APB)
- 6-(2-aminopropyl)benzofuran or 1-benzofuran-6-ylpropan-2-amine (6-APB or Benfamine)
- 5-(2-Aminopropyl)indole (5-API, 5-IT)
- 5-Methoxyalphaethyltryptamine (5-MeO-AET)
- 5-Methoxyalphamethyltryptamine (5-MeO-AMT)
- β-Keto-Methylbenzodioxolbutanamine (bk-MBDB; Butylone)
- Benzodioxylbutanamine (BDB)
- Benzylpiperazine (BZP)
- meta-Chlorophenylpiperazine (mCPP)
- Methylbenzodioxolbutanamine (MBDB; "Eden")
- Methylbenzylpiperazine (MBZP)
- Methylenedioxyamphetamine (MDA)
- Methylenedioxybenzylpiperazine (MDBZP)
- Methylenedioxyethylamphetamine (MDEA; "Eve")
- Methylenedioxyethylcathinone (MDEC, bk-MDEA; Ethylone)
- Methylenedioxymethamphetamine (MDMA; "Ecstasy", "Adam")
- Methylenedioxymethcathinone (MDMC, bk-MDMA; Methylone)
- Methylenedioxymethoxyamphetamine (MMDA)
- Methylhexanamine (Geranamine; 1,3-Dimethylamylamine)
- para-Fluorophenylpiperazine (pFPP; Fluoperazine)
- para-Methoxyamphetamine (PMA)
- para-Methoxyethylamphetamine (PMEA)
- para-Methoxymethamphetamine (PMMA)
- para-Methoxymethcathinone (bk-PMMA; Methedrone)
- Trifluoromethylphenylpiperazine (TFMPP)
- 2-Aminodilin (2-AD)
- 2-Aminoindane (2-AI)
- 2-Aminotetralin (2-AT)
- 4-Benzylpiperidine (4-BP)
- 4-Methylamphetamine (4-MA)
- 4-Methylmethamphetamine (4-MMA)
- 5-Aminopropyldihydrobenzofuran (5-APDB)
- 5-Carboxamidotryptamine (5-CT)
- 5-Methoxytryptamine (5-MT)
- 8-Hydroxydipropylaminotetralin (8-OH-DPAT)
- Ethyltrifluoromethylaminoindane (ETAI)
- Indanylaminopropane (IAP)
- Methoxymethamphetamine (MMA)
- Methoxymethylaminoindane (MMAI)
- Methylenedioxyaminoindane (MDAI)
- Methylenedioxymethylaminoindane (MDMAI)
- Naphthylaminopropane (NAP; PAL-287)
- para-Bromoamphetamine (PBA)
- para-Chloroamphetamine (PCA)
- para-Iodoamphetamine (PIA)
- Trifluoromethylaminoindane (TAI)
See also 
- Question: Is release restricted to MAs only?
- Rothman RB, Blough BE, Baumann MH (2007). "Dual dopamine/serotonin releasers as potential medications for stimulant and alcohol addictions". The AAPS Journal 9 (1): E1–10. doi:10.1208/aapsj0901001. PMC 2751297. PMID 17408232.
- Johnston TH, Millar Z, Huot P, et al. (February 2012). "A novel MDMA analogue, UWA-101, that lacks psychoactivity and cytotoxicity, enhances l-DOPA benefit in parkinsonian primates". FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology 26 (5): 2154–63. doi:10.1096/fj.11-195016. PMID 22345403.
- Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI et al. (2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin.". Synapse 39 (1): 32–41. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID 11071707.
- Rothman RB, Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates.". Curr Top Med Chem 6 (17): 1845–59. doi:10.2174/156802606778249766. PMID 17017961.
- Rothman RB, Vu N, Partilla JS, Roth BL, Hufeisen SJ, Compton-Toth BA et al. (2003). "In vitro characterization of ephedrine-related stereoisomers at biogenic amine transporters and the receptorome reveals selective actions as norepinephrine transporter substrates.". J Pharmacol Exp Ther 307 (1): 138–45. doi:10.1124/jpet.103.053975. PMID 12954796.
- Rothman RB, Blough BE, Woolverton WL, Anderson KG, Negus SS, Mello NK et al. (2005). "Development of a rationally designed, low abuse potential, biogenic amine releaser that suppresses cocaine self-administration.". J Pharmacol Exp Ther 313 (3): 1361–9. doi:10.1124/jpet.104.082503. PMID 15761112.
- Wee S, Anderson KG, Baumann MH, Rothman RB, Blough BE, Woolverton WL (2005). "Relationship between the serotonergic activity and reinforcing effects of a series of amphetamine analogs.". J Pharmacol Exp Ther 313 (2): 848–54. doi:10.1124/jpet.104.080101. PMID 15677348.
- Nakamura, Ishii, Nakahara (1998). "Characterization of β-phenylethylamine-induced monoamine release in rat nucleus accumbens : a microdialysis study". European Journal of Pharmacology 349 (2–3): 163–9. doi:10.1016/S0014-2999(98)00191-5. PMID 9671094.
- Krebs KM, Geyer MA (1993). "Behavioral characterization of alpha-ethyltryptamine, a tryptamine derivative with MDMA-like properties in rats". Psychopharmacology 113 (2): 284–7. doi:10.1007/BF02245712. PMID 7855195.
- Nagai F, Nonaka R, Satoh Hisashi Kamimura K (March 2007). "The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain". European Journal of Pharmacology 559 (2-3): 132–7. doi:10.1016/j.ejphar.2006.11.075. PMID 17223101.
- Marsden CA (November 1979). "Evidence for the release of hippocampal 5-hydroxytryptamine by alpha-methyltryptamine [proceedings]". British Journal of Pharmacology 67 (3): 438P–439P. PMC 2043998. PMID 497560.
- Yamaguchi T, Ohyama M, Suzuki M, et al. (September 1998). "Neurochemical and behavioral characterization of potential antidepressant properties of indeloxazine hydrochloride". Neuropharmacology 37 (9): 1169–76. doi:10.1016/S0028-3908(98)00009-4. PMID 9833647.
- Driessen B, Reimann W (January 1992). "Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro". British Journal of Pharmacology 105 (1): 147–51. doi:10.1111/j.1476-5381.1992.tb14226.x. PMC 1908625. PMID 1596676.
- Bamigbade TA, Davidson C, Langford RM, Stamford JA (September 1997). "Actions of tramadol, its enantiomers and principal metabolite, O-desmethyltramadol, on serotonin (5-HT) efflux and uptake in the rat dorsal raphe nucleus". British Journal of Anaesthesia 79 (3): 352–6. doi:10.1093/bja/79.3.352. PMID 9389855.
- Reimann W, Schneider F (May 1998). "Induction of 5-hydroxytryptamine release by tramadol, fenfluramine and reserpine". European Journal of Pharmacology 349 (2-3): 199–203. doi:10.1016/S0014-2999(98)00195-2. PMID 9671098.
- Baumann MH, Clark RD, Budzynski AG, Partilla JS, Blough BE, Rothman RB (October 2004). "Effects of "Legal X" piperazine analogs on dopamine and serotonin release in rat brain". Annals of the New York Academy of Sciences 1025: 189–97. doi:10.1196/annals.1316.024. PMID 15542717.
- Eriksson E, Engberg G, Bing O, Nissbrandt H (March 1999). "Effects of mCPP on the extracellular concentrations of serotonin and dopamine in rat brain". Neuropsychopharmacology 20 (3): 287–96. doi:10.1016/S0893-133X(98)00070-0. PMID 10063489.
- Baumann MH, Ayestas MA, Dersch CM, Rothman RB (May 2001). "1-(m-chlorophenyl)piperazine (mCPP) dissociates in vivo serotonin release from long-term serotonin depletion in rat brain". Neuropsychopharmacology 24 (5): 492–501. doi:10.1016/S0893-133X(00)00221-9. PMID 11282249.
- Wölfel R, Graefe KH (February 1992). "Evidence for various tryptamines and related compounds acting as substrates of the platelet 5-hydroxytryptamine transporter". Naunyn-Schmiedeberg's Archives of Pharmacology 345 (2): 129–36. doi:10.1007/BF00165727. PMID 1570019.
- Schönfeld CL, Trendelenburg U (April 1989). "The release of 3H-noradrenaline by p- and m-tyramines and -octopamines, and the effect of deuterium substitution in alpha-position". Naunyn-Schmiedeberg's Archives of Pharmacology 339 (4): 433–40. doi:10.1007/BF00736058. PMID 2500604.