Potentially addictive substances prohibited by international law used in psychiatric therapy

SUMMARY                                                                                                                                                 

Psychoactive substances called “drugs” are most often associated with addiction, being subject to a special legal regime in most countries of the world. In the context of criminalizing the use of these substances, research on their potential beneficial effects in psychiatric therapy, which began in the 1950s, was, therefore, most often stopped. In recent years, however, we have witnessed a resumption of research with encouraging results. The paper aims to present recent developments in this field. If the research results so far are to be confirmed, some of the addictive substances could bring significant benefits to the therapy of psychiatric disorders.

Key words: forbidden psychoactive substances; addiction; research; psychiatric therapy.

A significant number of psychoactive substances are controlled by both national and international legislation. The purpose of the legislative measures is to reduce the use of these substances due to the harmful effects they produce, even if some of them can also be useful at therapeutic level.

In most countries, legal control of psychoactive substances originates in three United Nations acts: the Single Convention on Narcotic Drugs (1961), the Convention on Psychotropic Substances (1971) and the Convention against Illicit Traffic in Narcotic Drugs and Psychotropic Substances (1989).

In Romania, the legal act regulating the use of these substances is Law 143 of July 26, 2000 (with subsequent additions). In the text of the law, there are annexed tables I-IV, which contain substances under national control, drugs and precursors. High risk drugs are listed in Tables I and II, risk drugs in Table III, and precursors (described as substances frequently used in drug manufacture) in Table IV [1].

In the USA, the first act to classify these substances was published in the 1970 (Comprehensive Drug Abuse Prevention and Control Act). In its Section 202, this document mentions the division of substances into 5 categories starting with Schedule I, which includes, according to the definition, drugs or substances with high potential for abuse, being unacceptable for medical treatment and lacking safety criteria for use under medical supervision [2].

In the United Kingdom, the Misuse of Drugs Act became effective in1971, which classifies drugs into Class A, B and C, where Class A drugs are considered the most harmful, and Class C, the least harmful [3]. In 2001, the Misuse of Drugs Regulations appeared, completing the Act of 1971 and classifying the substances into 4 categories, according to the American model [4].

Indeed, many of the substances mentioned by legislators generate physical and / or psychological dependence, where physical dependence involves increased tolerance (the user is looking for higher doses of substance to achieve the same effect), intense desire, urgency to use the drug and the withdrawal syndrome which is a cluster of symptoms that occur for 1-2 weeks when a person stops taking an addictive drug, while the psychological dependence involves intense emotional need for the presence of the drug, but without tolerance or withdrawal syndrome resulting from the use or interruption of its use [5, 6].

The study of addictions allowed two rankings, where the intensity of addiction decreases:

Psychological dependence: heroin – cocaine – tobacco – methadone – barbiturates – benzodiazepines

alcohol and amphetamines – ketamine, cannabis and 4-MTA (4-methyl-thio-amphetamine)-buprenorphine-methylphenidate-MDMA (ecstasy) and solvents; Physical dependence: heroin-methadone-tobacco-benzodiazepines and barbiturates-alcohol-

buprenorphine-cocaine-amphetamines, GHB

(gamma-hydroxybutyrate); methylphenidate-cannabis and 4-MTA (4-methyl-thio-amphetamine); MDMA (ecstasy) [7].

In Romania, drug use is on the increase. The 2017 country report for Romania by the “European Monitoring Centre for Drugs and Drug Addiction” mentions the following percentages of drug use for the 15-34 age group: Cannabis 3.3%; MDMA 0.3%; Cocaine 0.2%; Amphetamine 0.1%. The report has a special mention for the 15-24 age group: Cannabis 3.4%; Cocaine and MDMA 0.4%; Amphetamine

0.1% [8].

The top 5 drugs confiscated by authorities in Romania give heroin a first place, followed by cannabis, cocaine, cannabis (resin) and amphetamines [8].

In Romania, for most drugs, the prevalence of use is similar to that in other European countries, except cannabis, where, although there is an increase in consumption concerning the 15-16 years age group compared to the situation in the year 1999, compared to the average data provided by the “European School Survey Project on Alcohol and Other Drugs (ESPAD) – 2015” (which takes over data from 35 European countries), it represents only half of the consumption in all European countries [9].

Against this background, what comes next is likely to be risky. However, in the present case, we start from the premise that it is often desirable to find a middle way between the ban and the possibility to conduct research. We believe that research into the potentially beneficial effects of some of these substances in the face of the real addictive potential, as well as the perception of the public on drugs as being totally harmful, together with the existence of legislation and the penalties provided by the law, the research into the potentially beneficial effects of some of such substances has suffered.

Looking closely, it is noteworthy that the current situation raises many dilemmas, for example, there is no homogeneity among classifications. According to the legislator, depending on the country, the placement of some substances differs. For example, cannabis, considered a class B drug in the UK (otherwise not so dangerous), was included in the Misuse of Drugs Regulations 2001 (in the same country) in Schedule I (extremely dangerous drug). In the US, although listed in Schedule I, cannabis with medical use was used legally until the end of June 2017 in 29 US states (including the District of Columbia) [10].

In the UK, heroin is listed in Schedule II, although, in the United States, it is introduced in Schedule I [2]. In this context, in the UK, a researcher could study heroin more easily than cannabis. LSD was included in Schedule I in 1970, although at that time there were numerous studies conducted in the 1950s and 1960s showing its beneficial effects in the anxiety related to the terminal phase of cancerous disease, in the therapy of alcoholism and of other addictions. A recent meta-analysis (2016) of 19 studies performed from 1949 to 1973 on patients with emotional disorders showed the presence of improvement in 78% of these patients [11]. However, among so many uncertainties, it was expected to delay the studies on the potential benefits which some of these substances, otherwise considered very dangerous, could bring to patients, on condition that the drugs be used under medical supervision.

In this paper we will analyse three of these substances: dextromethorphan, ketamine and MDMA. Dextromethorphan is an antitussive with molecular mechanisms of action still unclearly defined. In the Romanian pharmaceutical market, it can be found under the names Tussin, Robitussin, Rofedex, Humex or Humisec. Used for the first time in 1954 [5], it was approved in the USA by the FDA in 1958, which considered it, from the toxicity point of view, to be the safest antitussive. Initially available without a prescription, in 1975 it was included in the category of prescription drugs, as it was increasingly used for recreational purposes, without being placed on the lists of the “Controlled Substances Act” [12]. As a sigma-1 receptor agonist (meaning that, potentially, it has an antidepressant effect) and as NMDA receptor antagonist, it has a pharmacodynamic effect similar to that of ketamine or phencyclidine. However, its action on serotonin and noradrenaline transporters (acting as a re-uptake inhibitor) is noteworthy [13]. A study from the year 2000 shows that dextromethorphan, as a glutamate antagonist, produces a psychotropic effect similar to that of alcohol [13]. In 2009, 5 cases of dead adolescents were reported in the USA, in 3 different incidents, following increased consumption of dextromethorphan. Until 2010, 5 cases of dextromethorphan dependence were described in the literature [5], but the frequency of use is increased, especially among adolescents and young adults, with percentages ranging from 4 to 8%, being noted not only in North America (in the USA, the use of this substance is called “robo-tripping”) but also in Europe, Australia, and Asia. In 2006, an epidemiological investigation related to its use among high school students in the USA indicated a percentage of 5.4% [14]. In Romania, it was initially used (15-20 years ago) in the form of tablets (Tussin forte-20 mg tablets), more recently it is met in high school students, most of it being consumed in the form of syrup (Rofedex- 100 ml medicine bottle, at a concentration of 15 mg / 5 ml) [15]. Effects obtained vary with dose: between 100-200 mg, mild psychomotor stimulation; between 200-400 mg, euphoria and hallucinations; between 300-600 mg, distorted visual perception and loss of motor coordination, and between 500 and 1500 mg, dissociative sedation [14]. Beyond these aspects, its action on sigma-1 and NMDA receptors has led to the idea that it could be used as an adjuvant in the treatment of a depressive disorder. At present, there is a completed trial in which the effects of the use of dextromethorphan in association with quinidine (the experimental product is called AVP-786) were followed [13]. The use of a substance with anti-arrhythmic properties in combination with dextromethorphan has started from the fact that the latter is metabolized by the cytochrome CYP2D6. In combination with quinidine, which inhibits CYP2D6 activity, the bioavailability of dextromethorphan increases, thus allowing for more intense action on NMDA receptors [13, 16]. The attempt to increase its bioavailability, together with the desire to avoid one of the known effects in cardiology, called the “proarrhythmic effect of antiarrhythmic drugs”, has led to the development of another association: dextromethorphan and bupropion. The association, called AXS-05, is currently undergoing a Phase III research study, related to treatment-resistant therapy of depressive disorder [13].

Neurology is another area of interest for the use of dextromethorphan. Also used in combination with quinidine in the therapy of pseudo-bulbar syndrome (with the approval of FDA in 2010 and of the European Medicine Agency in 2013), there is more recent benefit from using the combination (dextromethorphan 30 mg / quinidine 10 mg twice daily) in the treatment of psychomotor agitation in patients with Alzheimer’s disease (Phase II study in 2015) [17, 18].

MDMA (3-4 methylenedioxymethamphetamine) was synthesized in 1914 by Merck in order to diminish appetite, although there was never any commercial interest in it on the part of the company [19]. In the 1950s, in a study conducted by the American Army investigating the effects of psychedelic substances on humans and animals, MDMA toxicity to animals was noted. In 1973 its behavioural effects were studied and in 1978 its use as an adjunct in psychotherapy was suggested. In 1977 it was declared illegal in the UK, and since 1985 it has been temporarily restricted by the Drug Enforcement Administration because it has been found that it was used frequently for recreational purposes, noting at the same time that it has no medical utility, an opinion which was disputed at the time by a number of researchers [7]. Since 1988 it has been introduced into Schedule I.

MDMA is also known as “Ecstasy” [20]. Used as a drug in clubs, often utilised in “rave” parties, it has found widespread use with adolescents and young adults [21]. Older studies (1998) showed that US usage rates were 1.8% for young people over 12, increasing to 5.4% for those aged 18-25. Recently, it has been considered the second most common stimulant used in the UK, with a 1.5% use rate mentioned in the Crime Survey for England and Wales for the years 2015/2016, the prevalence rate remaining stable in the last 10 years. In the Netherlands, the frequency of use in the age group 15-24 years is 7.1%, slightly decreasing in the age group 25-34 years (6.1%) [23]. In Romania, the latest available data are from 2013. They describe a very low consumption compared to Western countries, with 0.4% for the 15- 24 age group and 0.2% for the 25-34 years age group [8]. As an overview, at the level of the European continent, the results of the project carried out in association with the SCORE group and the EU Drug Agency, which analyzed the waste water in several European cities, showed a significant increase in the presence of MDMA in 2016 compared to 2011, either due to the increased purity of the delivered product or due to the increased consumption [24].

Most often, tablets delivered for consumption are not pure. They may contain, besides MDMA and MDA (3,4-methylenedioxyamphetamine), MDEA (3,4-methylenedioxyethylaminophetamine), amphetamines and methamphetamines plus, often caffeine and paracetamol. They are manufactured in different geometric shapes, having different colors, thus making them more appealing to young people [25]. Ingested, the effects begin at about 30 minutes after ingestion, often lasting up to 12 hours. The use of ecstasy produces increased euphoria and sociability while also providing a feeling of increased energy [26, 19].

The analysis of studies on 220 volunteers shows that the subjective effects of MDMA are the same, regardless of subjects (), but the objective effects are also the same: increased heart rate and increased values of the blood pressure [27].

In a study from 1992 involving 20 psychiatrists who received MDMA, it has been found that they reported the following subjective experiences (with percentages ranging from 50 to 90%): altered perception of time, increased ability to communicate, low defensiveness, decreased fear, less sense of alienation in relation to the others, changes in visual perception, increased perception of emotions, diminished aggressiveness. As side effects, the majority reported a decrease in the desire to resolve mental or physical tasks (70%), decreased appetite (65%) and trismus (50%) [28].

At the cerebral level, MDMA stimulates the release of monoamines (serotonin, noradrenaline and dopamine) by inhibiting the reuptake, having a stronger effect on serotonin and noradrenaline. MDMA modulates glucocorticoids, acting on the adrenal-pituitary-hypothalamic axis, thus contributing to learning and memory. Through serotonin, MDMA also works on oxytocin, increasing its plasma concentration. MDMA decreases the activity at the level of tonsil and hippocampus and increases prefrontal cortex activity. It also acts on the “brain derived neurotrophic factor” (BDNF), thus promoting neuroplasticity [29]. This multitude of neuro-hormonal interactions, result in the beneficial effects of using MDMA.

Most likely, through oxytocin, which appears to be a candidate for mediating the empathic and prosocial effects of MDMA (in rats, the administration of oxytocin antagonists leads to decreased social interaction), significant benefits are gained in psychotherapy. MDMA has thus been used as an adjunct in psychotherapy in the therapy of post-traumatic stress disorder (PTSD), social anxiety (in adults with autism), to reduce fear and anxiety (as an adjunct in psychotherapy in patients with anxiety related to the presence of a terminal illness -including cancer).

Neural plasticity promoted by MDMA through BDNF, associated with the readjustment of the Hypothalamic-Pituitary-Adrenal-Axis HPA Axis) (the posttraumatic stress disorder is characterized by disorders of the HPA axis and hypersensitivity to glucocorticoids), allow action on learning and memory, which are rehabilitated in a psychotherapeutic context, all the more so as the recovery from the posttraumatic stress disorder and the extinction of the learning of the fright are dependent on BDNF, which controls the reconstitution of memory after re-stimulation in the amygdala – hippocampus circuit [29,36]. The use of cerebral functional imaging techniques has brought additional data about the mechanism by which MDMA has beneficial effects in psychotherapy [29]. MDMA administration has been found to affect in a differentiated manner the ability to correctly decode the social facial stimuli, depending on the valence of the stimulus. In a cheerful (party) setting, the use of MDMA can improve the correct reading of positive facial expressions (functional imaging shows that there is a reaction at the level of the ventral striatum in this context) [29] combined with extraversion and positive affects, thus leading to behavioural approach and to a higher sociability [31,27]. In contrast, misinterpretation of negative social information as neutral or positive may lead to engaging in risk behaviours (MDMA attenuates the response to tantalizing faces in the tonsil and increases the response to cheerful faces in the ventral striatum) [29]. MDMA reduces the accuracy of identifying negative feelings especially in women, reducing the acknowledgement of fear [26]. When MDMA is administered during psychotherapy for posttraumatic stress disorder, the change induced with the aim of a better perception of positive emotional stimuli may facilitate the therapeutic alliance [31]. There are improvements in coping strategies and emotion adjustment. The objective measurements that have been made support the mitigation of the impact of social rejection as well as the diminished response to angry or frightening faces. This, the objective evaluations using the Multifaceted Empathy Test (MET) and Face Emotion Recognition Task (FERT) showed increased empathy and prosocial behaviour, mainly observed in male patients, which, quantified, was considered equivalent to the same type behaviour seen in women in the study but who received placebo. It has also been noticed that MDMA tends to increase the preference for fairness, reflected by a tendency to aversion to inequality [26].

In psychotherapy, MDMA has been used in a controlled manner. Initially, in the 1980s and early 1990s, doses ranging from 50 to 200 mg (ordinarily between 100-150mg) were used for psychotherapy, and at the time when the effect of the first dose appeared to be extinguished, another dose of 50-75 mg was added. Typically, the psychotherapy sessions took place every second week [54]. More recently, the administration of medication is preceded by preparatory sessions, followed by psychotherapy sessions that support the integration of therapeutic change into everyday life. Thus, sessions in which MDMA is administered alternate with sessions without MDMA administration. The doses were unique and their administration required medical supervision, being performed 2 or 3 times a month.

Studies have shown that MDMA may be useful in the treatment of disorders associated with attachment insecurity, including depression, anxiety-depressive disorder, PTSD (mentioned above), obsessive-compulsive disorder. In Phase II studies related to PTSD, after a 2-month dosing of 3 doses of MDMA, 55% of subjects no longer met the PTSD criteria, and 66% were in remission for a long time (12 months) after MDMA . Apparently, the onset of action is fast and the effects seem to be long lasting [32].

Neuroplasticity promoted by BDNF under MDMA and the benefits to date have led to the initiation of a study that aims to use MDMA associated with psychotherapy in the treatment of alcoholism.

But there are also difficulties in associating MDMA with psychotherapy. First of all, those related to the general health of the patients. As mentioned above, because of tachycardia and elevated blood pressure, the use of MDMA is contra-indicated in people with cardiovascular problems [27]. Secondly, the fact that serotonin reuptake inhibitors (SSRIs) act as serotonin transporter antagonists (SERT), results (by competition) in the absence of MDMA effects when administered concomitantly with them. Potentially, the use of MDMA in depressive disorder therapy would mean to discontinue the administration of SSRI. On the other hand, the benefit of administering MDMA is the rapid effect of action. If the SSRI takes about 6 weeks until favourable effects are achieved, the MDMA effect is almost instantaneous [33]. Thirdly, the gender of the patients should be considered. When MDMA is administered, women show more acute effects than men, but also more long-term adverse effects [26]. Fourthly, the presence of mental disorders that could be generated by MDMA consumption cannot be neglected. However, it was noted that, often, mental suffering was preceded by the use of MDMA and consequently MDMA functioned as a way to reduce pre-existing discomfort. A study on this topic shows that in 80.4% of users, mental illness was pre-existing at the moment MDMA was administered. A Dutch study on 14-year-old children and adolescents using MDMA notes that they previously had criteria specific to depression and anxiety diagnoses. Another study, conducted in patients with major depressive disorder, showed that 44.5% of patients who were taking ecstasy had been diagnosed with depressive disorder prior to the consumption of the drug [33].

MDMA has moderate potential for abuse, studies showing that, in the long run, the use tends to cease when conditions that have favoured the onset of use disappear [32].

The doses necessary to cause serious side effects are high. Those used in posttraumatic stress disorder studies are small and, to date, there are no studies to prove their neurotoxicity. When deaths occur, they are caused by the uncontrolled use of MDMA in combination with other substances.

Ketamine was developed as an anaesthetic agent in 1962 and introduced into public use in 1970. It is used in pain therapy, commonly employed in emergency departments, even for young people (children aged over one year). It is a dissociative anaesthetic, the meaning of the term “dissociative” being initially linked to the production of the disconnection of the thalamo – neocortical and limbic systems, and used later to describe the sensation of detachment of the body from the mind felt by those to whom ketamine was administered [34].

It is commonly used to induce and maintain anaesthesia, causing analgesia, sedation and amnesia, but without having a significant impact on cardiovascular and pulmonary systems [34]. The administration is either intravenous or intramuscular. Dissociation occurs at 1-1.5 mg / kg body weight at IV administration, respectively at 4-5 mg / kg body weight, when administered IM. In about 30% of the patients who received it, hallucinations and alteration of sensory functions occurred [34].

Recreational use was recorded for the first time in the USA in 1971 and it has been widely used for recreational purposes since the mid-1990s. In the 1980s it was used frequently in clubs, being also used as a drug with the ability to induce sexual attacks (due to its sedative and dissociative properties). But the main reason for using it is that, at subanaesthetic doses, it produces derealization and depersonalization, hallucinations, synaesthesia, altered body perception, and concern with unimportant sounds. At higher doses, “out of body experience” occurs, implying a loss of the sense of space and time. It reduces consciousness and environmental monitoring in the user through lack of coordination of movements, blurred vision and temporary paralysis [34,35]. Available initially only as an injection, it is also present in powder form, capsules or tablets and is often associated with other stimulants and alcohol, being inhaled, smoked, drunk or injected.

Ketamine is one of the most widespread abuse drugs around the world. In countries such as Vietnam, Taiwan and China, it is the third most commonly used drug [35]. In the United States, the frequency of ketamine use increases from 8th grade children (0.8%) to 12th grade children (1.7%) [27]. In Hong Kong, in 2005, a study showed that it was one of the most commonly used drugs under the age of 21 [36]. In Indonesia, it is used by 1.8% of youths of high school age [34]. It is used in Denmark for recreational purposes, more frequently after the year 2000, with a street price of approximately 60-70 euros / 1 gramme of ketamine (the same price as that of 1g of cocaine) [27].

If the number of users in the general population is small (1%), the percentage of users who attend clubs may reach 10% [27].

Consequently, there have been regulations relating to the use of ketamine in many countries, such as the USA (since 1999 it is considered a controlled substance under Schedule III), South Korea, Great Britain, Mexico or Canada [35]. In Denmark, it has become illegal since 2008. In Malaysia and Singapore, people who are discovered in possession of ketamine are imprisoned or punished by repeated strikes, and, if the offense is repeated it is sentenced to death in Malaysia [36]. Instead, in the Netherlands its use is not regulated, being considered just medicine [35]. The ketamine addiction profile involves physiological dependence, with a withdrawal syndrome characterized by psychotic phenomena.

The full mechanism of action of ketamine has not been fully understood yet. We know about ketamine that acts on the ionotropic receptors of glutamate (an NMDA excitatory neurotransmitter), NMDA and AMPA (non-NMDA type glutamate receptors) [37,38]. It blocks NMDA receptors, resulting in the inhibition of gamma-aminobutyric acid, and consequently there is a significant increase of glutamate at the synaptic level, allowing the activation of AMPA receptors (transmembrane receptors for glutamate), thus inducing synaptic plasticity, by increasing the translation and secretion of Brain-Derivated Neurotrophic Factor (BDNF) and by inhibiting glycogen synthase kinase-3 (GSK-3) [39]. Ketamine acts on mu and sigma opioid receptors and on type A receptors of gamma-aminobutyric acid. Inhibition of GSK-3 in the hippocampus and prefrontal cortex appears to be essential (studies on animals) to obtain a rapid antidepressant effect [40]. As for the dissociative effects, most probably, the electrophysiological dissociation produced between the limbic system and the thalamo-neocortical system is the basis for them and determines the state that can be likened to a cataleptic type trance [35]. Mechanisms of action (possibly a molecular cascade that promotes synaptic plasticity and maturation of dendritic structures in critical regions of the brain) still need to be investigated as long as the significant difference between the short halving time of ketamine after intravenous administration (11 minutes) and its long efficacy time [40]. It is assumed that the effect is prolonged and amplified by the action of a metabolite of ketamine, (2R-6R) -hydroxynorkethamine, which directly stimulates AMPA.

In 2014, Thomas Insel, former director of the National Mental Health Institute in the USA, said that obtaining the results of intravenous treatment with ketamine is the most important discovery of antidepressant treatment in decades [41]. The statement came at a time when enough studies were being carried out to support this view. Thus, a sub-anesthetic dose of ketamine administered intravenously resulted in marked antidepressant effects (rapid relief of symptoms within hours), with effect duration of 7-14 days. The dose to be administered in depressive disorder, used since 2006, was 0.5 mg

kg bodyweight administered intravenously in 40 minutes [40]. The dose was considered safe since the one used in anesthesia is 3 mg / kg body weight. Given the difficulties encountered in the intravenous route (the need for the venous approach, the discomfort caused to the patient to maintain it, the need for needles, etc.), other ways of administration were attempted, choosing the nasal route [40,42].

In a study investigating the efficacy of this route of administration and the duration of beneficial effects of ketamine, it was found that intranasal administration of 50 mg compared to placebo (saline solution) has significantly favourable effects at 24 hours but disappears at 72 hours [43]. Another (Phase II) study using esketamine (a racemic S-enantiomer of ketamine) administered 4-fold in 2 weeks intranasally at different doses (28.56.84 mg) indicated significant reduction in depression scores (patients with severe depression, resistant to treatment) [44].

Nine meta-analyses of randomized trials of acute phase have shown statistically significant advantages of ketamine versus placebo or active control conditions (i.e., versus the standard treatment used in that particular disease). Overall, they showed the benefit of ketamine as a maximum at 24 hours after administration (onset in just a few hours), with remanence of effect up to 7 days and few adverse effects during this period. From day 14 after administration, the advantages comparative to the control sample are statistically insignificant. It was observed that the rate of response to repeated administration of ketamine was better than in single administration, with the average relapse time being 18-19 days [43].

In general, studies mainly followed patients with severe depressive disorder resistant to conventional treatments. The response rate in the studies ranged between 50 and 70%. Moreover, a 2011 study, following patients undergoing electroconvulsive therapy without improvement in depressive symptomatology, showed favourable results after IV administration of ketamine, 0.5 mg / kg body weight [39].

Several important factors have been observed as predictors of treatment success. Thus, the effects appear to be longer in those with anxiety-depressive disorder and depressions from families with a history of alcoholism [40]. The higher the neurocognitive performance in treatment-resistant depressive disorder, the higher the response rate to ketamine. When neurocognitive effects occur following ketamine administration (usually, low dose ketamine is associated with minimal neurocognitive effects 40 minutes after administration), they have poor prognosis (reported low antidepressant response at administration) [45]. Having a large body mass index appears to be a good indicator of ketamine response. If the patient does not respond favourably to a second intravenous ketamine infusion, s/he is unlikely to respond in the future. A meta-analysis of 8 randomized, double-blind controlled trials comparing ketamine (administered intravenously or intranasally) to placebo (saline solution or midazolam) showed both clinical response and improvement at 7 days, showing greater effects in unipolar depression in comparison with bipolar disorder [43].

Generally, it was found that the magnitude of the antidepressant effect appears to be significant in patients with major depressive disorder compared to those with bipolar disorder, and even intensely administered treatment leads to an incomplete response to the latter [40,43].

The favourable results of using ketamine have stimulated research in the field. There are currently 5 trials in the USA related to ketamine administration in the 0-17 year age group in all phases (recruitment, completed, finalised) to major depression, major depression associated with anxiety disorder, unipolar depression and bipolar depression. The results of the only completed study have not yet been made public at the time of writing (August 2017) [44]. One of these, NCT02078817 – Phase II study evaluates boys and girls aged 12 to 18 years with a treatment-resistant depressive disorder following the efficacy of ketamine in subanaesthetic doses and the sustainability of a single dose response over a 4-week period, as well as the study of the neurobiological mechanisms involved in the ketamine response. The assumption of the initiators of the study is that, given the ongoing neurodevelopment processes at the age of adolescence due to neuroplasticity, the obtained therapeutic response will last longer [46].

The long-term remission of the major depressive disorder using ketamine is the subject of multiple controversy. From the data obtained so far, it seems to result from a combination of ketamine administration and the use of electroconvulsive therapy [47].

Perhaps one of the most spectacular results of ketamine administration is found in people with suicidal ideation and suicide attempts [48]. Suicide is the second most common cause of death in adolescents, and 40% of those who attempted do not respond to the first line of treatment. Another half does not respond to multiple trials with other antidepressants coupled with psychotherapy, often leading to the latest solution currently available – electroconvulsive therapy [49]. However, the disappearance of suicidal ideation requires weeks (with the exception of clozapine and lithium, standard therapies for major depressive disorder and bipolar disorder were not accompanied by clear anti-suicidal benefit) and up to 6 electroconvulsive therapy sessions (conducted over a period of 2 weeks). Nevertheless, studies in 2009, 2011 and 2012 have shown that the IV use of ketamine at doses of 0.5 mg / kg (or even 0.2 mg / kg) body weight significantly and constantly reduces the suicidal ideation [47]. The last dose mentioned here is supported by the results of a study that followed the administration of ketamine in the emergency room to 14 patients with unipolar depression with suicidal ideation at doses of 0.2 g / kg body weight in 1-2 infusion minutes. The results show the significant decrease in the Montgomery-Åsberg Depression Rating Scale (MADRS), a state which was maintained for 10 days, and during this period the conventional treatment was administered. Also, the score on suicide-related items in the Hamilton Depression Rating Scale decreased 6 at hours after ketamine treatment [47]. Another analysis of 7 trials has shown that ketamine use significantly decreases suicidal ideation at 24 hours and 3 days post-administration but not at 7 days post-administration [40].

Of course, not all results are consistent with the duration of the ketamine infusion benefit, but the importance of relief for these patients is noteworthy. Furthermore, a post hoc analysis of four studies of ketamine use showed that its effect on suicidal ideation seems to be independent of its effect on anxiety and depression [47].

The mechanism by which this effect is obtained is not clearly understood. Initially, it was considered that in the suicidal ideation there is an abnormal glutamate-glutamine-GABA cycle, which ketamine alters [50]. More recently, it is believed that the intention of suicide appears to be related to inflammatory status in which tryptophan and its metabolic products play an essential role [47]. Tryptophan, an essential amino acid, is metabolized in two ways: one that leads to serotonin formation; the other (dominant) results in the occurrence of kynurenin, typically producing oxidation of tryptophan into N-formyl-kynurenine. In the presence of inflammation, the tryptophan metabolisation is triggered by tryptophan pyrolase (which is induced by proinflammatory stimuli and cytokines such as gamma interferon, interleukin 6 or tumour necrosis factor), resulting in the augmentation of kynurenin in the brain. This is, in turn, metabolised into quinolonic acid (which is an NMDA receptor agonist) and kyrunenic acid (which is an NMDA receptor antagonist). In suicides, the amount of quinolonic acid and the ratio of the cyanuric acid in the cerebrospinal fluid are increased, showing the presence of an NMDA receptor stimulation in these individuals. Quinolonic acid is particularly high in those with suicidal attempts by violent means and with high scores when using Suicide Intent Scale.

Within this mechanism, the ketamine effect of diminishing the suicidal ideation is related to its role as an antagonist of NMDA receptors – which results in blocking the effects of quinolonic acid on them.

Taking into account the results and the pathophysiological mechanisms, ketamine was also used in patients with another type of pathology. Thus, benefits have been reported following administration of ketamine to patients with posttraumatic stress disorder. There were benefits after administration of ketamine in mourning when it became complicated due to duration and form of manifestation (an Indian study noted significant improvement after IV administration of ketamine in the context of the previous presence, during the mourning period, of catatonic symptoms while maintaining remission over the next 3 months) [42]. It has also been shown to be useful in obsessive-compulsive disorder. Thus, ketamine infusion of 0.5 mg / kg body weight in patients with obsessive-compulsive disorder produces rapid, one-week, anti-obsessional effects that lasted for a week [39]. The most probable favourable effect is determined by the action of ketamine on glutamate, as it is known that the obsessive-compulsive disorder reveals elevated levels of glutamate in cerebrospinal fluid, and due to cerebral imaging it has been observed that, in paediatric patients, it increases the production of glutamatergic products in the caudal lobe and decreases their concentration in the anterior cingulate cortex.

Obviously, repeated administration also allowed adverse effects to be recorded, too. Ketamine is a racemic mixture of S-ketamine and R-ketamine and, apparently, significant side effects are caused by S-ketamine, while the use of R-ketamine does not produce psychomimetic side effects nor does it have any potential for abuse [52].

The most common adverse events reported in patients receiving ketamine were increased heart rate and blood pressure, dry mouth [35], headache, anxiety, and dissociation disorder being present during the 40-minute infusion and shortly thereafter, generally disappearing within 2 hours from the completion of IV treatment with ketamine. Therefore, the rate of dropout of the study was low – 7%. The reduction in side effects appears to be significant if the infusion is given within 100 minutes instead of 40-60 minutes (the usual duration of administration). On the other hand, 833 ketamine infusions in sub-anesthetic doses showed no serious adverse effect, the participants being individuals of whom some were receiving concomitant psychotropic medication [39]. The attempt to use ketamine on alternative routes of administration (comparing intravenous, intramuscular and subcutaneous options) shows the reduction of side effects by the subcutaneous route compared to the other routes of administration. It has also been observed that repeated administration of ketamine appears to diminish dissociative side effects. At the same time, the use of lamotrigine in combination with ketamine resulted in a significant decrease in perceptual disorders associated with ketamine, while amplifying its antidepressant effect [37]. Data related to long-term medical use of ketamine are almost non-existent. Those who use it for recreational and long-term purposes have cognitive and cystic deficits (although they usually also administer themselves other substances, too). Studies have reported the presence of lower urinary tract symptoms in one third of users (dysuria, suprapubic pain, hematuria), and regular use can also lead to so-called “K-cramps”

• ranging from diffuse pain to to intense abdominal colic [53].

Nevertheless, it should be noted that no class of antidepressants modulates the glutaminergic system like ketamine, and even if ketamine is to be discarded, it would still be the prototype of developing another product that could maintain its benefits and would diminish its adverse effects [54].

BIBLIOGRAFIE

1. http://www.ana.gov.ro/legislatie%20nationala/L%20143%20AC-TUALIZATA.pdf
2. https://www.gpo.gov/fdsys/pkg/STATUTE-84/pdf/STATUTE-84-Pg1236.pdf
3. http://www.legislation.gov.uk/ukpga/1971/38/contents
4. The Misuse of Drugs Regulations 2011:http://www.legislation. gov.uk/uksi/2001/3998/pdfs/uksi_20013998_en.pdf
5. Marckgraf, C.G.; Introduction to Tolerance,Physical Dependence and Withdrawal; https://www.safetypharmacology.org/AM2012/ am12presentations/Markgraf_IntroPhysicalDependenceWD.pdf
6. Mutschler, J.; Koopmann, A.; Grosshans, M.; Hermann, D.; Mann, K.; Kiefer, F.; Dextromethorphan Withdrawal and De-pendence Syndrome; Deutsches Ärzteblatt International, 2010; 107[30]: 537–40;
7. Nutt, D.J.; King, L.A.; Nichols, D.E.; Effects of Schedule I drug laws on neuroscience research and treatment innovation; Nature Reviews Neuroscience ,Vol 14, August 2013; 577-585
8. European Monitoring Center for Drugs and Drugs Addiction: Romania-Country Drug Report 2017; http://www.emcdda.euro-pa.eu/system/files/publications/4507/TD0116919ENN.pdf
9. European School Survey Project on Alcohol and Other Drugs [ESPAD]-2015 http://www.espad.org/report/home
10. https://medic almar ijuana . procon . org/vie w. resource . php?resourceID=000881
11. Carhart-Harris, R.L.; Goodwin, G.M.; The Therapeu-tic potential of Psychedelic Drugs: Past, Present and Future; Neuropsychopharmacology,April 2017,1-9;
12. Schwartz, J.; Murrough, J.W.; Iosifescu, D.W.; Ketamine for treat-ment-resistant depression: recent developments and clinical appli-cations; Evid Based Mental Health May 2016 Vol 19 No 2; 35-38;
13. Ionescu, D.F.; Papakostas, G.I.; Towards new mechanisms: an update on therapeutics for treatment-resistant major depressive disorder; Molecular Psychiatry [2015], 20, 1142-1150;
14. h t t p : / / w w w . w h o . i n t / m e d i c i n e s / a r e a s / q u a l i t y _ safety/5.1Dextromethorphan_pre-review.pdf
15. https://www.anm.ro/nomenclator/medicamente
16. Ionescu, D.F.; Papakostas, G.I.; Experimental medication treat-ment approaches for depression; Translational Psychiatry [2017], 1 – 8;
17. Corbett, A.; Ballard, C.; Dextromethorphan and quinidine are suitable for off-label short-term treatment of agitation in people with Alzheimer’ s disease following first line non-drug approaches; Evidence Based Medicine,Feb 2016,Vol 21,Number 1,25;
18. Cummings, J.L., Lyketsos, C.G.; Peskind, E.R. et al. Effect of dextromethorphan-quinidine on agitation in patients with Alzhe-imer disease dementia: a randomized clinical trial. JAMA 2015; 314:1242–54
19. Stahl, S.M.; Dextromethorphan-quinidine–responsive pseudobul-bar affect [PBA]: psychopharmacological model for wide-ranging disorders of emotional expression?; CNS Spectrums [2016]; 21; 419-423;
20. Brandis,A.;Current Trends in Teen Drug Abuse;https://www. atlantapsych.com/files/Current%20Trends%20in%20Teen%20 Drug%20Abuse.pdf
21. Cottler, L.B.; Womack, S.B.; Compton, W.M.; Ben-Abdallah, A.; Ecstasy abuse and dependence among adolescents and young adults:applicability and reliability of DSM-IV criteria; Human Psychopharmacology,2001,16,599-606;
22. United Kingdom-Drug Situation 2016: http://www.nta.nhs.uk/up loads/2905931ukdrugsituation2016webaccessible.pdf
23. European Monitoring Center for Drugs and Drugs Addiction:Netherlands -Country Drug Report 2017: http:// www.emcdda.europa.eu/system/files/publications/4512/ TD0616155ENN.pdf_en
24. European Monitoring Center for Drugs and Drugs Addiction; In-teractive Wastewater Analysis Tool Zooms in on City Drug Use; News Release, No 12/2016;
25. Bora,F.; Ylmaz,F.; Bora,T.; Ecstasy [MDMA] and its effects on kidneys and their treatment:a review; Iran J Basic Med Sci, Vol. 19, No. 11, Nov 2016;1151-1158;
26. Hysek, C.M.; Schmid, Y; Simmler, L.D.; Domes, G; He-inrichs, M.; Eisenegger, C.; Preller, K.H.; Quednow, B.B.; Liechti,M.E.;MDMA enhances emotional empathy and prosocial behavior;SCAN [2014] 9,1645-1652;
27. Nutt, D.J.; King, L.A.; Saulsbury, W.; Blakemore, C.; Develop-ment of a rational scale to assess the harm of drugs of potential misuse; The Lancet,vol 369,1047-1053;March 24,2007
28. Barceloux,D.G.; Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants;Wiley,2012,137-138; https:// books.google.ro/books
29. Wit, H.; Bedi, G.; Phan, K.L.; Angstadt, M.; Effects of MDMA on sociability and neural response to social threat and social reward;Psychopharmacology [Berl]. 2009 November; 207[1]: 73–83.
30. Young, M.B.; Andero, R.; Ressler, K.J.; Howell, L.L.; 3,4-Methylenedioxymethamphetamine facilitates fear extinction learning;Translational Psychiatry [2015], 1 – 8;
31. Hysek, C.M.; Domes, G.; Liechti, M.E.; MDMA enhances “mind reading” of positive emotions and impairs “mind reading” of nega-tive emotions; Psychopharmacology [2012] 222:293–302;
32. Yazar Klosinski B.B.; Mithoefer, M.C.; Potential Psychiatric Uses for MDMA; Clinical Pharmacology &Therapeutics,Vol 101, No 2, February 2017; 194-196;
33. Patel, R.; Titheradge, D.; MDMA for the treatment of mood disorder:all talk no substance?; Therapeutic Advances in Psychopharmacology; 2015, Vol. 5[3] 179–188
34. Higgins, S.S.; Baron, D.; Juarez, G; Esmaili, N.; Gold, M.; A Re-view of Ketamine Abuse and Diversion;Depression and Anxiety 33:718-727 [2016];
35. Han, E.; Kwon, N-JFeng L-Y.; Li, J-H.; Chung, H. Illegal use pat-terns, side effects, and analytical methods of ketamine; Forensic Science International, 268 [2016] 25-34;
36. Zhang, M.V.; Harris, K.M.; Ho,R.C.; Is Off-label repeat prescrip-tion of ketamine as a rapid antidepressant safe?Controversies, ethi-cal concerns, and legal implications.BMC Medical Ethics [2016] 17:4;1-8.
37. Howland, RH; Ketamine for the Treatment of Depression; Journal of Psychosocial nursing • Vol. 51, no. 1, 2013;11-14;
38. Kirby, T.; Ketamine for depression: the highs and lows; Lancet Psychiatry, Vol 2, No 9, 2015, 783-784;
39. Rodriguez, C.I.; Kegeles, L.S.; Levinson, A.; Feng, T.; Marcus, S.M.; Vermes, D.; Flood, P.; Simpson, H.B.; Randomized Con-trolled Crossover Trial of Ketamine in Obsessive-Compulsive Di-sorder: Proof-of-Concept; Neuropsychopharmacology [2013] 38, 2475–2483
40. Sayar, G.H.; Ozten, E; Savas, H.A.; Ketamine Infusion in Treat-ment Resistant Depression:A Case Report and Brief Review of Literature; Journal of Mood Disorders 2015; 5[2]:78-82
41. https://www.nimh.nih.gov/about/directors/thomas-insel/ blog/2014/ketamine.shtml
42. Gowda, M.R.; Srinivasa, P.; Kumbar, P.S.; Ramalingaih, V.H.; Muthyalappa, C.; Durgoji, S. Rapid Resolution of Grief with IV Infusion of Ketamine: A Unique Phenomenological Experience; Indian Journal of Psychological Medicine;Jan – Feb 2016; Vol 38; Issue 1; 62-64;
43. https://clinicaltrials.gov/ct2/results?cond=Depressive+Disorder&term=ketamine&cntry1=&state1=&Search=Search&age=0

44. Murrough, J.W.; Wan, L-B.; Iacoviello, B.; Collins, C.A.; Solon, C.; Glicksberg, B.; Perez, A.M.; Sanjay, J.M.; Charney, D.S.; Iosi-fescu, D.V.; Burdick, K.E.; Neurocognitive effects of ketamine in treatment-resistant major depression: association with antidepre-ssant response; Psychopharmacology [2014] 231:481–488; https://clinicaltrials.gov/ct2/show/NCT02078817

45. Price, R.B.; Sanjay, J.M.; Does Ketamine Have Anti-Suicidal Pro-perties? Current Status and Future Directions; CNS Drugs. 2015 March ; 29[3]: 181–188.
46. Murrough, J.W.; Soleimani, L.; DeWilde, K.E.; Collins, C.A. et al.; Ketamine for rapid reduction of suicidal ideation: a randomi-zed controlled trial; Psychological Medicine,Vol 45,Issue 16,3571-3580;
47. Turban, J.;The Ketamine Breakthrough for Suicidal Children; Sci-entific American,Vol 317,1,July 18,2017;
48. Reinstatler, L.; Nagy, A.Y.; Ketamine as a Potential Treatment for Suicidal Ideation: A Systematic Review of the Literature;Drugs in R&D 2015 Mar; 15[1]: 37–43;
49. Feder, A.; Parides, M.K.; Murrough, J.W.; Perez, A.M.; Morgan, J.E.; Saxena, S.; Kirkwood, K.; Lapidus, K.A.D.; Wan, L-B.; Io-sifescu, D.; Charney, D.S.; Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder.A Randomi-zed Clinical Trial;Jama Psychiatry,2014,71 [6],681-688;
50. Hashimoto K., R-ketamine: a rapid-onset and sustained antide-pressant without risk of brain toxicity; Psychological Medicine [2016], 46, 2449–2451;
51. Wood, D.; Dargan, P.; Novel Psychoactive Substances: Classifica-tion, Pharmacology and Toxicology, Academic Press, 2013, p 305; https://books.google.ro/books
52. White, T.P.; Caddy, C.; Giaroli, G.; Shergill, S.S.; Tracy, D.K.; Ketamine as the prototype glutamatergic antidepressant: pharma-codynamic actions, and a systematic review and meta-analysis of efficacy; Therapeutic Advances in Psychopharmacology; [2013] 0[0] 1–25;
53. Taylor,C.P.;Traynelis,S.F.;Siffert,J.;Pope,L.E.;Matsumoto,R. R.;Pharmacology of dextromethorphan: Relevance to dextro-methorphan/ quinidine [Nuedexta] clinical use;Pharmacology & Therapeutics 164 [2016] 170–182;
54. https://clinicaltrials.gov/ct2/results?cond=&term=mdma&cntry1=&state1=

56. https://www.palliativedrugs.com/news/november/ketamine-and-s-ketamine-now-schedule-2-controlled-drugs.html
57. Green, S.M.; Roback, M.G.; Kennedy, R.M.; Krauss, B.; Clinical Practice Guideline for Emergency Department Ketamine Dissoci-ative Sedation: 2011 Update; Annals of Emergency Medicine,Vol 57, No 5, 449-461, May 2011;
58. Ravn, S.; Demant, J.; Prevalence and perceptions of ketamine use among Danish clubbers: a mixed-method study; Nordic Studies on Alcohol and Drugs; 29, 2012, 397-412;
59. Spangler, D.C.; Loyd, C.M.; Skor, E.E.; Dextromethorphan: a case study on addressing abuse of a safe and effective drug; Sub-stance Abuse Treatment, Prevention, and Policy [2016] 11:22;
60. Steele, T.D.; McCann, U.D.; Ricaurte, G.A.; 3,4-Methylenedio-xyimethamphetamine [MDMA, „Ecstasy”]: pharmacology and toxicology in animals and humans; Addiction [1994] 89, 539-55;
61. Tasman, A.; Kay, J.; Lieberman, J.A.; First, M.B.; Riba, M.B.; Psychiatry, Fourth Edition,Blackwell-Wiley, 2015,Vol 2, Chapter 76,p 1494; https://books.google.ro/books.