Author: luca davicco
Date: 30/07/2014


A cura di Alessandra PUGLIESE e Luca DAVICCO


Drug abuse is not just about street drugs. Besides marijuana, legal medicines are the most commonly abused drugs in the U.S and Europe.

Dextromethorphan and Benzydamine are easily-found ingredients of over-the-counter (OTC) and prescription drugs, used as antitussive (DM) and anti-inflammatory (BZ) agents; they can produce neurobehavioral effects if the dose is increased above the therapeutic threshold.
The widespread and easy access makes these drugs particularly appreciated for their abuse-recreational use.

Our purpose is to study the mechanisms and the clinical effects of commonly OCT-drugs abuse, like BRONCHENOLO TOSSE (Dextromethorphan) and TANTUM ROSA (Benzydamine).


Dextromethorphan (DM) is a common ingredient of more than 100 cough and cold remedies available since 1954 as an antitussive agent; DM has a strong safety and efficacy profiles without sedative or addictive properties at the recommended doses.(1)

It has now been recognized that DM could also be used as an analgesic in the treatment of pain associated with cancer if administered at higher doses than typically prescribed for the treatment of cough with a mechanism that appears to be related to a N-methyl-D aspartate (NMDA) receptor blocking effect (low-affinity, non-competitive NMDA receptor antagonist).(2)

The abuse of this substance, easily found in cough medicines among children and adolescents has been well documented for decades.(3)


DM is the D-isomer of the codeine analogue, levorphanol. As morphinans family, it’s a polycyclic compound with a four-ring skeleton with three condensed sixmember rings forming a partially hydrogenated phenanthrene moiety, one of which is aromatic while the two others are alicyclic.

IUPAC NAME: (+)-3-methoxy-17-methyl-(9α,13α,14α)-morphinan

Even if similar, in contrast to its L-isomer and others MOP opioids-agonists:
- it has no effect on the opioid receptors;(4)
- its effect is not suppressed by naloxone-antagonism;(4), (5), (6)
- does not possess analgesic or addictive properties at recommended doses; (7)
- does not have major opioid-like respiratory or hemodynamic side effects, neither histamine released-complications or classical addictive properties;(8)


The currently recommended adult doses for the therapeutic action are 10-30 mg orally, three to six times daily; a bigger dose (100-600mg) is required to obtain neurobehavioral effects.


DM is a prodrug: dextrorphan is the active metabolite that produces neurobehavioral effects in reason of a greater affinity to NMDA receptors, while DM does not reach the same efficacy.
The hepatic conversion to dextrorphan is an important determinant of the abuse potential.(9)


Antitussive action is not well understood; however DM is a low-affinity, non-competitive NMDA receptor antagonist and the capacity of binding and antagonize the NMDA receptor is probably due to a structural architecture common to the family of dissociative agents, as Ketamine and Phencyclidine.(10)

According to other studies (in animals), DM shows also:
- an agonist action to the opioid sigma 1 and sigma 2 receptors;
- an antagonist action to alpha3/beta4 nicotinic receptor;
- targets the serotonin reuptake pump;(11)

The relationship of these receptor binding sites and the pharmacological mechanism of the antitussive effects of dextromethorphan is not well known; however, coupling these observations with the inability of naloxone to antagonize the antitussive effects of DM, studies suggest that cough suppression can be achieved by different mechanisms.(12)


Dextromethorphan has equal antitussive effects as codeine, so it is wildly appreciated as antitussive agent. It is clear that it increases the cough threshold, but the pharmacological mechanism and the specific central sites upon which it exerts its effect are still uncertain. It is postulated that the action could be direct on the cough center in the medulla brain, with a multi-mechanism probably distinct from those of opioids.

Dextromethorphan is also used recreationally as a dissociative hallucinogen thanks to his antagonist action on NMDA receptor. Laboratory studies suggest that dissociative drugs, including PCP, ketamine, and DM, cause their effects by disrupting the actions of glutamate receptors who plays a major role in cognition (including learning and memory), emotion, and the perception of pain.(13), (14)
There is evidence that the effects of ketamine and PCP to cause alteration in sensory perception and dissociative anaesthesia are largely attributed to non-competitive antagonism of NMDA receptor.(15)

With key roles in essential brain functions ranging from the basics of excitatory neurotransmission to the complexities of learning and memory, the N-methyl-D-aspartate (NMDA) receptor can be considered one of the fundamental neurotransmitter receptors in the brain; it has a critical role in excitatory synaptic transmission, plasticity and excitotoxicity in the CNS.(16)

The NMDA receptor belongs to the family of ionotropic receptors for the excitatory amino acid glutamate and is characterized by high affinity for glutamate, a high unitary conductance, high calcium permeability, and a voltage-dependent block by magnesium ions;16 the involvement of NMDARs in mentioned processes reflects their unique features, in particular voltage-sensitive block, a high permeability to Ca2+ and unusually slow ‘activation/ deactivation’ kinetics.(17)

Otherwise, activation of NMDA receptors by the glutamate requires glycine as an essential coagonist; two of each are required for the maximal activation, by binding different subunits of the receptor; this characteristic has been exploits in the research of competitive agonists and antagonists.(16)

The NMDA receptor subunit has similar structural characteristics as other members of the ionotropic glutamate receptor family, with an extracellular N-terminus, intracellular C-terminus and a re-entrant transmembrane domain.

Over the past decade, a variety of NMDAR subunits have been identified: the ubiquitously expressed NR1 subunit; a family of four distinct NR2 subunits (A, B, C and D); and two NR3 subunits; there is general agreement that glutamate molecules bind with high affinity to the NR2 subunits of the NMDAR while glycine molecules bind to the NR1 subunits.(17)

The most obvious subunit dependent properties of NMDARs are their single-channel conductances and their block by extracellular Mg2+. Thus, diheteromeric NMDARs containing NR2A or NR2B subunits generate ‘high-conductance’ channel openings with a high sensitivity to block by Mg2. (17)

Returning to primary function, during excitatory neurotransmission, presynaptic release of glutamate activates glutamate receptors in the postsynaptic membrane, resulting in the generation of an excitatory postsynaptic potential (EPSP).(17)
The NMDA receptor functions as a modulator of synaptic response and a co-incidence detector. At resting membrane potentials, NMDA receptors are inactive. This is due to a voltage dependent block of the channel pore by magnesium ions, preventing ion flows through it. Sustained activation of AMPA receptors by, for instance, a train of impulses arriving at a pre synaptic terminal, depolarises the post-synaptic cell, releasing the channel inhibition and thus allowing NMDA receptor activation.(18)

These receptors are permeable to sodium, calcium and potassium ions, following the direction of their natural gradient: l’activation leads to the opening of ion channel, resulting in the influx of Na+ and Ca++ ions and efflux of K+ ions.(16)
NMDA receptors can contribute significantly to the amplitude of unitary evoked postsynaptic potentials plasticity and the entry of calcium into the postsynapse permits coupling of electrical synaptic activity to biochemical signaling via activation of Ca++-dependent enzymes and downstream signaling pathways.(16)

The following pathways are implicated with NMDA Calcium-influx (18)
- activation of CaMKII and phosphorylation of the GluA2 AMPA receptor subunit resulting in LTP (HFS)
- activation of PICK1 to drive the PKC-dependent synaptic insertion of AMPA receptors during LTP
- activation of hippocalcin, a Ca2+-binding protein that recruits AP2 to the GluA2 AMPA receptor subunit prior to internalisation during LTD (LFS)
- activation of PI3K/Akt/GSK3 to modulate LTP

DM has been shown to reduce and regulate the influx of intracellular calcium through the NMDA receptor-gated channels. (19)
The blockage of NMDA receptors by DM and metabolites result in production of specific neurobehavioral findings such as dissociative, “out-of-body” experiences, like ketamine mechanism of dissociative anesthesia (9). A further aspect that can be considerate, DM bind D2 receptors leading to psychoses, visual hallucinations and manic symptoms (such as restlessness, insomnia, irritability, and racing thoughts).(20)


The 2013 annual US Drug Use and Health report, revealed that in 2006 around 3.1 million people in the United States aged 12–25 used OTC cough and cold medicine to “get high’’(21); in addition, dextromethorphan misuse and abuse among children and adolescents has been well documented for decades with evidence of plateau occurred since 2006.(3)
The 29th Annual Report of the AAPCC National Poison Data System published in December 2012, documents 74,995 exposures to cold and cough preparations. This accounts for 2.73% of all exposures called into United States poison centers and ranks “cold and cough preparations” number eleven on the list of top 25 substance categories most frequently involved in human exposures. Over 9,400 (12.5%) of the exposures to cough and cold preparations were the result of intentional abuse or misuse.(3)

The dose of ingested dextromethorphan determines the neurobehavioral effects which begin within 30–60 minutes from ingestion and persist for approximately 6 hours.
The first plateau (100 and 200 mg) is a mild stimulant effect similar to that of methylenedioxymethamphetamine.
The second plateau (200 and 400 mg) is described as similar to a combination of concurrent ethanol and marijuana intoxication, although some users describe hallucinations as occurring at this stage.
The third level (300 and 600 mg) is a dissociative, “out-of body” state, like that produced by a low recreational dose of ketamine, and the fourth plateau (600–1,500 mg) is a fully dissociative condition similar to that produced by ketamine intoxication. (22), (23)

The clinical presentation of dextromethorphan intoxication therefore depends on the ingested dose: minimally intoxicated persons may develop tachycardia, hypertension, vomiting, mydriasis, diaphoresis, nystagmus, euphoria, loss of motor coordination, and giggling or laughing; in addition to the above findings, persons with moderate intoxication may demonstrate hallucinations and a distinctive, plodding ataxic gait that has been compared with “zombie-like” walking (34). Severely intoxicated individuals in a dissociated state may be agitated or somnolent (24), (25), (26), (27).
Extremely agitated patients may develop hyperthermia and metabolic acidosis.

Although dextromethorphan is not thought to have addictive properties, susceptible individuals may develop craving and habitual use of the drug. An abstinence syndrome may be associated with cessation of dextromethorphan abuse that is characterized by dysphoria and intense cravings. Toxic psychosis and cognitive deterioration may arise from chronic use of the drug (9).

Drug interactions exist between dextromethorphan and other substances, the best characterized of which is serotonin syndrome. This condition typically occurs from the interaction between dextromethorphan and selective serotonin reuptake inhibitors or monoamine oxidase inhibitors, but concurrent administration of antibiotics (eg, linezolide), opiate analgesics (eg, meperidine and tramadol), or drugs of abuse (eg, Syrian rue) could precipitate the condition (28).

Expectorants, like Guaifenesin, a ubiquitous expectorant found in OTC cough medicines, has minimally toxic effects limited to mild gastrointestinal irritation. It can be considered a safer alternative for use in patients with addiction to or dependence on other antitussives with high abuse potential.


Benzydamine has analgesic and anti-inflammatory activities, particularly when applied topically (29). Its preparations are used throughout the world for the symptomatic treatment of oropharyngeal and gynaecological conditions.
In Italy, for example, benzydamine is marketed as mouthwash or tablets for oral use (ex. TANTUM VERDE o OROSAN, GOLA ACTION), or as vaginal wash (ex. TANTUM ROSA, now renamed as GINETANTUM).

We focused on this last product of benzydamine, because it figure also among the substances of abuse with hallucinogenic effects and sensory alteration.


IUPAC NAME: 1-benzyl-3–3-(dimethylamino) propoxy-1H-Indazole
DRUG CLASS: indazol class of Non Steroidal AntiInflammatory Drugs (NSAIDs)

It was synthesized in Italy in 1964 and marketed in 1966.
Benzydamine was the first NSAID to appear as a vaginal solution for local application in the symptomatic treatment of non-specific vaginitis (30) and vulvovaginitis, and it is indicated in children, adolescents and adults. (31)


1 or 2 vaginal irrigations with benzydamine hydrochloride / daily.
It is marketed as GINETANTUM, sachets of 500 mg granules for cutaneous solution to external genitalia. The vaginal douche is prepared by dissolving 500 mg of the powder formulation in one liter of water. (32)


After topical application, such as dermal cream or vaginal douche, systemic absorption of benzydamine is limited, with and without vaginitis. In these cases, it has been demonstrated that the drug concentrates in the mucosa and is gradually absorbed, reaching blood levels insufficient to express systemic pharmacological effects.
On the other hand, benzydamine is well absorbed after oral administration (mean systemic availability = 87%). 64% of an oral dose is absorbed by 1 hour, and absorption is complete in 4–6 hours. The elimination half-life is 13 hours.
Approximately 55% of the dose is excreted unchanged in the urine and the rest is metabolized by oxidation, conjugation and dealkylation. (33), (34)
Because of this difference in the absorption, commercially the dosages are lower in products for oral use and higher in products for different use. However, if you take orally the vaginal douche, you can reach blood concentrations sufficient to give systemic effects, even on the CNS.


If used as topical anti-inflammatory, benzydamine does not behave like a classic NSAIDs, because it does not inhibit cycloxygenase or lipoxygenase, and is not ulcerogenic.
At therapeutic concentrations, in inflamed tissue:
- Stabilizes the membrane;
- Stabilizes the small blood vessels, making them more resistant to pro-inflammatory mediators;
- Prevents the release of pro-inflammatory enzymes by leukocytes.
At higher concentrations inhibit the synthesis of certain prostaglandins (PGF2, PGD2 and TXA2) involved in the inflammatory process, with:
- Reduced capillary permeability, and reduced formation of edema and exudate;
- Antiplatelet activity on platelets and erythrocytes;
- Stabilization of lysosomal membranes and cellular, so as to reduce the release of lysosomal enzymes and the formation of free radicals.
- analgesic activity thanks to its myorelaxants properties on striated muscle, and antispasmodic on smooth muscle.

If used as a subsance of abuse, the most likely hypothesis to explain the effects of benzydamine is that it can act, just like classic psychedelics, as an agonist of 5-HT2A receptors present in certain areas of the CNS.(35)
The benzydamine’s molecule has a structural affinity with serotonin, because in its structure is present an indazol (in the circle in fig.1) similar to the indole compound (in the circle in fig.2) present in serotonin. Thanks to this structural similarity benzydamine can act as serotonin, by activating the 5-HT2A receptors, and can cause hallucinations.

Fig. 1 - Benzydamine

Fig.2 - Serotonin

This same mechanism of action has already been detected for other indole compounds, such as diethylamine in lysergic acid (LSD), DMT or DiMethylTriptamine and psilocin (fig.3-4-5), which can promote hallucination by activating the same receptor.

Fig. 3 - LSD

Fig. 4 - DMT

Fig. 5 - Psilocin

The receptor involved, 5-HT2A , is a subtype of the family of 5-HT2 receptors of serotonin.
The serotonin receptors (5-HT) are divided in seven families and, with the exception of 5- HT3, are all G protein-coupled receptors (GPCRs). The G proteins involved are different in the various 5-HT receptor, and the response produced can be either excitatory or inhibitory.(36)

5-HT2A receptor is considered the main excitatory receptor subtype among the GPCRs for serotonin, although it may also have an inhibitory effect (on certain areas, such as
the visual cortex and the orbitofrontal cortex).
It is a transmembrane receptor, coupled to Gq/G11 proteins, which uses as second messengers IP3 e DAG when activated.

Even if its natural ligand is serotonin, it was first studied just as the target of psychedelic drugs, such as LSD previously mentioned.
Later it was found that it mediate, at least partly, also the action of many antipsycotic drugs, especially the atypical ones. The same receptor can have opposite effects because psychedelic drugs act as agonists, whereas those antipsychotic as antagonists.
In this context it is of our interest to study the mechanism of action that explain the effects of the classic psychedelics drugs, because it can be the same used by benzydamine to cause its hallucinogenic effects.

The “classic” psychedelics - like LSD, psilocin and mescaline - act as full or partial agonists at this receptor (they represent the three main classes of 5-HT2A agonists, the ergolines, tryptamines and phenethylamines respectively). To mediate their hallucinogenic activity, these agonists must activate in particular 5-HT2A receptors located on the apical dendrites of pyramidal cells within regions of the prefrontal cortex.
Newer findings reveal that their psychoactive effects are mediated not by a monomeric 5 HT2A receptor but by an heterodimer 5-HT2A–mGlu2.

ABUSE - Effects after an oral ingestion of a vaginal douche

Clinical signs or symptoms reported, when present, were mainly gastrointestinal (48% of symptomatic patients) followed by neurological (31%) or both (21%).
The most common symptom was nausea (32.8% of symptomatic patients) followed by vomiting (27.9%), dizziness (20.1%), hallucinations (15.3%), abdominal pain (13.4%), and esophageal irritation and agitation (10.5%, each). Six of 68 children (mean age 6.2, range 3–11 years) had hallucinations. A severe case was that of a 4-year-old child who had convulsions caused by the unintentional ingestion of benzydamine.
Hallucinations were mainly visual and auditory in only one occasion. The patients complained, especially when asked, about images of zoomorphism (spiders, dogs), death people, Walt Disney comics, falling walls, or lights and colors.
They were described only in patients older than 5 years old and the lowest dose at which hallucinations appeared was 500 mg (7.1 mg/kg in a 70 kg-weight adult and 20 mg/kg in children) (37).
In most cases it is an accidental intake, as documented by the following studies:
- a spanish study shows that, in a studied population of 724 people, in 85.9% cases benzydamine was ingested because it was mistaken for an oral preparation or for an oral antiseptic.
The rest were unintentional exposures in children (13.8%) or suicidal attempts (0.3%);37
- in Italy, the Milan and Pavia Poison Centres have identified 50 cases of inappropriate benzydamine ingestion between December 2009 and January 2010, and attibuted this misuse to an allegedly misleading television advert. (38)
However, the most recent increase in benzydamine misuse reports in Italy were associated with a parallel increase in level of online information regarding the potential misuse of the molecule.
The recreational misuse of benzydamine is a well-known phenomenon in Brazil (39) and in some EU countries as well, notably in Poland (40) and Romania. And online it is possible to find reports that explain how to take in the drug and its possible effects.


1 Bem and Peck 1992
2 Siu and Drachtman 2007
3 Bronstein AC, Spyker DA, Cantilena LR, Rumack BH, Dart RC. 2011 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 29th Annual Report. London: Informa Healthcare; 2012.
4 Benson WM, Stefko PL, Randall LO. Comparative pharmacology of levorphanol, racemorphan and dextrorphan and related methyl ethers. J Pharmacol Exp Ther 1953
5 Klepstad P, Maurset A, Moberg ER, Oye I. Evidence of a role for NMDA receptors in pain perception. Eur J Pharmacol 1990
6 Craviso and Musacchio 1983
7 Carr BC. Efficacy, abuse, and toxicity of over-the-counter cough and cold medicines in the pediatric population. Curr Opin Pediatr. 2006
8 Bem JL, Peck R. Dextromethorphan. An overview of safety issues. Drug Saf 1992
9 Antitussives and substance abuse, Jarrett M Burns, Edward WBoyer2013
10 Boyer EW. Dextromethorphan Abuse. Pediatr Emerg Care. 2004
11 Hernandez SC, Bertolino M, Xiao Y, Pringle KE, Caruso FS, Kellar KJ: Dextromethorphan and its metabolite dextrorphan block alpha3beta4 neuronal nicotinic receptors. J Pharmacol Exp Ther. 2000
12 Dextromethorphan Pre-Review Report, Expert Committee on Drug Dependence Thirty-fifth Meeting Hammamet, Tunisia, 4-8 June 2012
13 Morgan, C.J.; Curran, H.V.; and Independent Scientific Committee on Drugs. Ketamine use: A review. Addiction 2012
14 Morris, B.J.; Cochran, S.M.; and Pratt, J.A. PCP: From pharmacology to modelling schizophrenia. Curr Opin Pharmaco 2005.
15 Oye N, Paulsen O, Maurset A. Effects of ketamine on sensory perception: evidence for a role of N-methyl-Daspartate receptors. J Pharmacol Exp Ther
16 NMDA Receptor Function and Physiological Modulation K Zito, University of California at Davis, Davis, CA, USA V Scheuss, Max- Planck-Institute for Neurobiology, Martinsried, Germany
17 NMDA receptor subunits: diversity, development and disease, Stuart Cull-Candy*, Stephen Brickley and Mark Farrant
18 NMDA Receptors -
19 Church et al. 1991
20 Achamallah 1992; Bostwick 1996; Drachtman et al. 2002
21 Substance Abuse and Mental Health Services Administration, 2008
22 Boyer EW. Dextromethorphan Abuse. Pediatr Emerg Care. 2004
23 White W. DXM FAQ, 1995. Available at:
24 Graudins A, Ferm R. Acute dystonia in a child associated with therapeutic ingestion of a dextromethorphan-containing cough and cold syrup. J Toxicol Clin Toxicol. 1996
25 White W. DXM FAQ, 1995. Available at: Accessed June 19, 2013
26 Banerji S, Anderson I. Abuse of Coricidin HBP cough and cold tablets: episodes recorded by a poison center. Am J Health Syst Pharm. 2001
27 Kirages T, Sule H, Mycyk M. Severe manifestations of coricidin intoxication. Am J Emerg Med. 2003
28 Bowdle T. Adverse effects of opioid agonists and agonist-antagonists in anaesthesia. Drug Saf. 1998
29 Cioli V, Corradino C, Scorza Barcellona P. Review of pharmacological data on benzydamine. Int J Tissue React 1985; 7:205–213
30 Levy G. Value of benzydamine, the first anti-inflammatory vaginal solution. Rev Fr Gynecol Obstet 1989; 84:779–781
31 Cisternino M, Cammaresi V, Cattaneo E, Berbenni A, Lorini R, Severi F. Benzydamine for the topical treatment of vulvovaginitis in children and adolescents. Int J Tissue React 1985; 7:241–247
33 Baldock GA, Brodie RR, Chasseaud LF, Taylor T, Walmsley LM, Catanese B. Pharmacokinetics of benzydamine after intravenous, oral, and topical doses to human subjects. Biopharm Drug Dispos 1991; 12:481–492
34 Koppel C, Tenczer J. Metabolism of benzydamine. Arzneimittelfors- chung 1985; 35:634–635
35 E. S. Opaleye; A. R. Noto; Z. Sanchez; Y. Gonçalves de Moura; J.C. Fernandes Galduróz; E. Araújo Carlini. Recreational use of benzydamine as a hallucinogen among street youth in Brazil Rev. Bras. Psiquiatr. vol.31 no.3 São Paulo Sept. 2009.
36 Cook EH, Fletcher KE, Wainwright M, Marks N, Yan SY, Leventhal BL (August 1994). "Primary structure of the human platelet serotonin 5-HT2 receptor: identity with frontal cortex serotonin 5-HT2A receptor". J. Neurochem.
37 S, Ballestreros, M. F. Ramon, and R. Martinez-Arrieta. Ingestions of benzydamine-containing vaginal preparations Benzydamine vaginal preparations ingestion. Clinical Toxicology (2009) 47, 145–149
38 Davanzo, L. Settimi, F. Sesana, G. Milanesi, P. Maiozzi, E. Urbani, L. Cossa, M. L. Casini, F. Ferrazin e A. L. Rivolta. Assunzione per via orale di lavande vaginali prima e dopo l'avvio di una campagna di promozione televisiva. Le osservazioni effettuate dal CAV di Milano
39 Mota, D. M.; Costa, A. A.; Teixeira, C. D. S.; Bastos, A. A.; Dias, M. F. (2010). "Use abusive of benzydamine in Brazil: An overview in pharmacovigilance". Ciencia & saude coletiva (in portuguese) 15 (3): 717–724
40 Anand, J. S.; Lukasik–Glębocka, M.; Korolkiewicz, R. P. (2007). "Letter to the Editor: Recreational abuse with benzydamine

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