Through ketamine fields
Viana Chaves, Tharcila
DOI:10.33612/diss.107955714
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Viana Chaves, T. (2019). Through ketamine fields: pain and afterglow. Rijksuniversiteit Groningen. https://doi.org/10.33612/diss.107955714
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Chapter 6
Overdoses and deaths
related to the use of
ketamine and its analogues:
a systematic review
By: Tharcila Chaves Zila M. Sanchez Bob Wilffert
Introduction
Ketamine is quickly opening its spot as a therapeutic option in the management of treatment-resistant depression, yet its abuse continues to be a worldwide issue (1-8). Because the duration of the antidepressant effect of ketamine is limited, re-dosing it after some weeks is necessary. If applying ketamine infusions either once or more often, clinicians need to consider the addictive potential and the risk of inducing psychosis-like symptoms (2).
Non-medical use of ketamine was recognized in the United States when the Food and Drug Administration (FDA) expressed concerns about it in 1979. In Europe, it came to public notice in the 1990s, following a seizure of almost 100,000 ketamine tablets in the United Kingdom; these carried a logo usually found on ecstasy tablets; some users suffering anxiety attacks were hospitalized after taking large doses of ketamine believing it to be ecstasy (9).
Ketamine recreational users are broadly divided into (a) hospital and veterinary-linked staff (and their friends) who have access to the drug and are more likely to inject the liquid, resulting in primarily psychedelic effects, and (b) users primarily linked with the dance culture who take ketamine powder by the intranasal route, resulting in more stimulant effects (10).
The use of ketamine analogues, such as phencyclidine (also known as PeaCe Pill, PCP, angel dust), methoxetamine (MXE) and dizocilpine (MK-801) is also a point of concern. In Sweden, Bäckberg et al. (2015) described that the use of methoxylated PCP analogues (3-methoxy-phencyclidine or 3-MeO-PCP and 4-methoxy-phencyclidine or 4-MeO-PCP) was noted starting in mid-2013. They have found that intoxications involving new psychoactive substances (NPS) and poly-substance use were common (11). Furthermore, Chong et al. (2017) described a ketamine analogue in the streets of Hong Kong: 2-Oxo-PCE (deschloro-N-ethyl-ketamine). Ketamine is one of the most prevalent drugs of abuse in Hong Kong; there is a suspicion about the substitution of ketamine for 2-Oxo-PCE in street supplies, possibly to evade detection (12).
Ketamine’s pattern of use has features in common with dance drug and cocaine abuse. Patterns of binge use are well described, as are the effects of acute intoxication (13-17). The most appealing aspects of ketamine for two-thirds of users studied by Muetzelfeldt et al. (2008) were a “melting into the surrounding” feeling, visual hallucinations, out-of-body experiences and giggliness (18).
The effects of ketamine are dose-dependent. At low doses, it gives a feeling of inebriation, euphoria, depersonalization, reduced pain perception and sympathetic stimulation. Nystagmus can also be present. Users also describe out-of-body
experiences, which can be frightening and lead to accidents. With increased doses, there are also agitation, physical inhibition, hypertension, tachycardia, hyperthermia and hyperreflexia. Severe intoxication can result in aspiration pneumonia, acidosis, rhabdomyolysis, epileptic seizures, respiratory depression and cardiac arrest (19). Another study performed in Hong Kong analysed 233 records of ketamine use. The most common symptoms of ketamine misuse were impaired consciousness (45%), abdominal pain (21%), lower urinary tract symptoms – LUTS (12%), and dizziness (12%). The most common abnormal physical findings were high blood pressure (40%), followed by tachycardia (39%), abdominal tenderness (18%), and white powder in the nostrils (17%) (20). Additionally, repeated use of ketamine for recreational or mind-exploring purposes affects prefrontal dopaminergic transmission. Repeated exposure to ketamine is associated with up-regulation of
D1 receptors in the dorsolateral prefrontal cortex. Thus, repeated use of ketamine
might be associated with detrimental effects on brain neurotransmission (21). In a review article about ketamine abuse, Bokor and Anderson (2014) reported that death from ketamine’s acute direct toxicity is rare, but it can happen from drug interactions or from accidents (22). Vroegop et al. (2007) also observed that there are few reports of deaths caused only by ketamine (19). It is noteworthy that poly-substance use is very usual among ketamine and NPS users (11, 23). For instance, in a study with 100 ketamine users, Dillon et al. (2003) noticed that ketamine appeared to be added to an already extensive drug use repertoire of a well-educated and informed sample of drug users (24).
The aim of this systematic review is to outline the cases of overdoses and deaths related to the use of ketamine and/or its analogues reported in the scientific literature.
Method
Data collection for this systematic review was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statements (25).
Search strategy
Searches were performed in the PubMed, EMBASE and CINAHL databases, in July 2019. Keywords regarding ketamine and its analogues (“ketamine”, “esketamine”, “phencyclidine”, “methoxetamine”) and deleterious and fatal effects (“substance-related disorders”, “addictive behaviour”, “death”, “mortality”, “overdose”, “toxicity”) were applied for data collection.
Inclusion and exclusion criteria
Articles describing cases of overdose and/or death associated with ketamine and/or its analogues were included.
The exclusion criteria were: (1) articles not available in English, Portuguese, Spanish, French or Dutch; (2) studies performed in non-human animals.
Study selection
Discrepancies between the two reviewers regarding study eligibility were solved through consensus. Figure 6.1 shows the PRISMA flowchart for data selection and inclusion process. The search strategy yielded 3105 results. After the removal of duplicates, this number dropped to 1753 articles. Their titles were screened and 298 were selected for full-text analysis, which resulted in the 34 articles included in this review.
Excluded: - articles not in English, Spanish, Dutch or Portuguese - studies not performed with humans Records identified through database searching
(n = 3105) Id en tif ic at io n Sc re eni ng
Records after removal of duplicates (n = 1753) E lig ib ili ty
Full-text articles selected for eligibility (n = 298)
Records excluded after title analysis (n = 1352) Records screened (n = 1753) Inc lud ed
Articles included in this systematic review (n = 34)
T ab le 1 : D ea th s r el at ed t o t he u se of k et am in e a nd i ts a na lo gu es St ud y M oz ay an i e t a l., 2 00 3 (2 6) A da m ow ic z a nd Z ub a, 2 01 5 (2 7) B re it m ei er e t a l., 2 01 2 (2 8) C hi ap pi ni e t a l., 2 01 5 (2 9) N um be r o f c as es 1 1 1 8 Lo ca tio n U ni te d St at es Po la nd G er m any Un ite d K in gd om D em og ra ph ic s 45 -y ea r-ol d m ale 29 -y ea r-ol d m ale 28 -y ea r-ol d m ale 7 m ale s + 1 f em ale m ed ia n a ge: 2 7 y ea rs o ld K et am in e a na lo gu e in vo lv ed M K-80 1 MX E ke ta m ine MX E C au se o f d ea th A cu te t ox ic ity r el at ed to th e c om bi ne d co ns um pt io n of be nz od ia ze pi ne , M K-80 1 an d et ha no l. A cu te t ox ic ity r el at ed t o M X E. A ut oe ro tic acc id en t. 7 d ie d f ro m d ro w ni ng o r fr om s ub sta nc e a bu se . T he g ag a nd t he d ru g-in du ce d r es pi ra to ry de pr es sio n c om bi ne d w ith c er eb ra l o ed em a ca us ed i na dequ at e ox yg en at io n, r es ul tin g in c en tr al p ar al ys is le ad in g t o f at al a sp hy xi a. O ne d ie d f ro m i sc ha em ic he ar t d ise as e.
6
T ab le 1 : C ont in ue d D in is -O liv ei ra et a l., 20 10 ( 30 ) EM C D D A *, 2 00 2 ( 9) La lo nd e a nd W al la ge , 20 04 ( 31 ) M itc he ll-M at a e t a l., 2 01 7 (3 2) W ie rg ow sk i e t a l., 2 01 4 (3 3) 1 3 2 2 1 Po rt ug al 2 i n I re la nd C an ad a U ni te d St at es Po la nd 1 i n F ra nc e 29 -y ear -o ld m an 2 I ris h p eo ple 26 -y ea r-ol d m ale 21 -y ea r-ol d m ale 31 -y ea r-ol d m ale on e 1 9-ye ar -o ld F re nc h m ale 20 -y ea r-ol d m ale 52 -y ea r-ol d m ale ke ta m ine ke ta m ine K et am in e 3-M eO -P C P MX E Su ic id e b y h an gi ng . K et am in e w as n ot co ns id er ed t o b e t he c au se of de at h i n t he I ris h c as es . 26 -y ea r-ol d m ale : k et am in e in to xic at io n A cu te i nt ox ic at io n d ue t o po ly -d ru g co ns um pt io n M ul ti-or ga n d ys fu nc tio n sy nd ro m e c au se d b y M X E an d a m ph et am in e u se . U nd er t he i nfl ue nc e of ke ta m in e a nd a lc oh ol . Ec sta sy a nd L SD w er e a lso fou nd i n t he b od y of t he Fr en ch m ale . 20 -y ea r-ol d m ale: a sth m a. K et am in e w as c on sid er ed an i nc id en ta l fi nd in g. *E ur op ea n Mo ni to rin g C en tr e f or D ru gs a nd D ru g A dd ic tio n
T ab le 1 : C ont in ue d T he of el e t a l., 2 01 9 ( 34 ) W ik st rö m e t a l., 2 01 3 ( 35 ) T ao e t a l., 2 00 5 ( 36 ) Li ca ta e t a l., 1 99 4 ( 37 ) 1 1 1 1 G er m any Swe de n C hi na Ita ly 52 -y ea r-ol d m ale 26 -y ea r-ol d m ale 34 -y ea r-ol d f em ale 18 -y ea r-ol d m ale 2-O xo -P C E MX E ke ta m ine ke ta m ine T he c om bi na tio n of 2 -O xo -P C E w ith v en la fa xi ne . A cu te i nt ox ic at io n w ith M X E, al th ou gh t he p re se nc e of 3 sy nt he tic c an na bi no id s m ay h av e co nt rib ut ed t o t he d ea th . C hr on ic k et am in e p oi so ni ng M as siv e p ul m on ar y o ed em a ca us ed b y k et am in e o ve rd os e. T he c ou rt i nv es tig at io n r ev ea le d th at s he w as p oi so ne d b y h er hu sba nd o ve r a p er io d of 1 y ea r i n an a ct o f h om ic id e. It w as a h om ic id e f or h om os ex ua l en ds .
6
T ab le 1 : C ont in ue d G ill a nd S ta jíc , 2 00 0 ( 38 ) G ai lla rd a nd P ép in , 1 99 8 (3 9) M oo re e t a l., 1 99 7 ( 40 ) Pe yt on et a l., 1 98 8 ( 41 ) Sc hi fa no e t a l., 2 00 8 ( 42 ) 87 1 1 2 23 U ni te d St at es Fr anc e U ni te d St at es U ni te d St at es Un ite d K in gd om N on -h os pi ta l d ea th s (n =1 5) : 1 1 m ale s + 4 fem al es be tw ee n 2 5 a nd 3 0-ye ar s-ol d f em ale 32 -y ea r-ol d m ale (1 ) 3 1-ye ar -o ld f em ale 19 m ale s + 4 f em ale s H os pi ta l d ea th s ( n= 72 ): n ot m ent io ne d (2 ) 4 6-ye ar -o ld m ale 19 - 4 9 y ea rs o ld ke ta m ine ke ta m ine ke ta m ine ke ta m ine ke ta m ine N on -h os pi ta l d ea th s (n =1 5) : 1 2 d ue t o a cu te m ul tid ru g i nt ox ic at io ns , 2 du e t o p hy sic al i nj ur y a nd 1 d ue t o s ar co id os is. A cu te i nt ox ic at io n c au se d by t he c om bi na tio n of he ro in , c oc ai ne , c an na bi s, th io pe nt al , k et am in e a nd ch lo ro fo rm . A cc id en ta l k et am in e a nd et ha no l i nt ox ic at io n. (1 ) A cc id en ta l k et am in e in to xic at io n. In 4 c as es : k et am in e in to xi ca tio n ( 3 a cc id en ta l + 1 s ui ci de ) H os pi ta l d ea th s ( n= 72 ): 54 a cu te t ra um at ic d ea th s th at h ad e m er ge nt s ur ge ry + 1 8 b ur n a nd p ae di at ric / ob ste tr ic s ur gi ca l d ea th s. (2 ) G un sh ot v ic tim w ho w as g iv en k et am in e du rin g s ur ge ry . In t he r em ai ni ng c as es : 1 7 m ul tid ru g i nt ox ic at io n, 1 d ro w ni ng a nd 1 s ta b w ou nd t o c he st.
ab le 2 : O ve rd os es r el at ed t o t he u se of k et am in e a nd i ts a na lo gu es St ud y B ob o a nd M ill er , 20 02 ( 43 ) N og ué e t a l., 2 01 5 ( 44 ) B on ne t, 2 01 5 (4 5) B ow m an e t a l., 20 19 ( 46 ) C ap ap é e t a l., 20 08 ( 47 ) C og er , 2 01 6 ( 48 ) N um be r o f ca se s 1 3 1 1 1 1 24 -y ea r-ol d m ale D em og ra ph ic s 20 -y ea r-ol d m ale 20 -y ea r-ol d f em ale an ae sth et ic n ur se 2-ye ar -o ld f em ale 3-ye ar -o ld m ale 49 -y ea r-ol d m ale 23 -y ea r-ol d f em ale Lo ca tio n U ni te d St at es Spa in G er m any U ni te d St at es Spa in U ni te d St at es K eta m in e an alo gu e in vo lv ed ke ta m ine M X E a nd k et am in e K et am in e ke ta m ine ke ta m ine ke ta m ine B ri ef de sc ri pt io n A cc id en ta l lo ra ze pa m a nd ke ta m in e ove rd os e. T he 2 4-ye ar -o ld m ale re fe rr ed a fte r a n ep iso de of se iz ur es a sso ci at ed w ith br ai n i nj ur y. H e h ad u se d ke ta m in e, c oc ai ne a nd al co ho l b ef or e t he ep iso de . U se of k et am in e to se lf-tr ea t de pr es sio n. Fo r s ed at io n, 2 3 m g o f k et am in e w as o rd er ed . By m ist ak e, 2 30 m g wa s a dm in ist er ed . Fo r s ed at io n, 45 m g o f k et am in e w as o rd er ed . By m ist ak e, 45 0 m g wa s a dm in ist er ed . Fo r pa in c on tr ol af te r a s ur ge ry , i t w as a llo w ed t he ad m in ist ra tio n of 5 to 30 m g p er h ou r. By m ist ak e, t he pa tie nt r ec eiv ed a do se s uffi ci en t t o in du ce a na es th es ia . T he f em ale s cl ai m ed t ha t th ey h ad b ee n s ex ua lly as sa ul te d u nd er t he i nfl ue nc e of a c he m ic al s ub m iss io n. La bo ra to ry a na ly sis co nfi rm ed t he p re se nc e of M X E i n t he ir s am pl es . D ue t o to ler an ce , th e do se in cr ea se d f ro m 50 m g o nc e a w ee k t o 2 g d ai ly .
6
T ab le 2 : C ont in ue d G re en e t a l., 1 99 9 ( 49 ) M ar sh m an e t a l., 1 97 6 (5 0) M as ke ll e t a l., 2 01 6 ( 51 ) N i e t a l., 2 01 8 ( 52 ) St oc ka rd e t a l., 19 76 ( 53 ) 9 3 1 22 1 20 -y ea r-ol d m ale ch ild re n 18 -y ea r-ol d f em ale 29 -y ea r-ol d m ale m ale s a nd f em ale s f ro m al l a ge s 25 -y ea r-ol d m ale 26 -y ea r-ol d m ale U ni te d St at es C an ad a U ni te d St at es U ni te d St at es U ni te d St at es ke ta m ine PC P MX E ke ta m ine PC P T hr ee p at ie nt s r ec eiv ed 5 tim es t he i nt en de d d os e; 5 p at ie nt s r ec eiv ed 1 0 tim es t he i nt en de d d os e; 1 pa tie nt r ec eiv ed 1 00 t im es th e i nt en de d d os e. M ul tip le d ru g a bu se i n al l c as es . U se of M X E f or its an al ge sic e ffe ct s t o t re at ch ro ni c f oo t p ai n f ro m a su rg er y o ne y ea r p rio r. H e ha d i ng es te d u p t o 1 0 m g ev er y 4 h ou rs f or 5 d ay s be fo re b ei ng f ou nd b y t he po lic e l yi ng i n f ro nt o f on co m in g t ra ffi c. 20 ou t of 22 us ed ke ta m in e w ith o th er d ru gs . T he e le ct ro en ce ph al og ra ph ic fin di ng s w er e s im ila r t o t ha t of de ep a na es th es ia w ith ke ta m ine .
T ab le 2 : C ont in ue d T an g e t a l., 2 01 8 ( 54 ) W ar ne r a nd S m is ch ne y, 20 18 ( 55 ) W ei ne r e t a l., 2 00 0 ( 56 ) W oo d e t a l., 2 01 2 ( 57 ) Y in -C he un g, 2 01 2 ( 8) 56 1 20 3 18 8 36 m ale s f ro m 2 4 t o 5 2 ye ar s o ld 65 -y ea r-ol d m ale 11 m ale 28 - 4 2 y ea rs o ld m ale p re do m in an ce 20 f em ale s 9 f em ale m ajo rit y f ro m 1 0 t o 3 9 ye ar s o ld H on g Ko ng U ni te d St at es U ni te d St at es Eng lan d H on g Ko ng 2-O xo -P C E ke ta m ine K et am in e MX E ke ta m ine In 3 1 c as es , o th er d ru gs of ab us e w er e d et ec te d. I n 25 c as es , 2 -O xo -P C E w as us ed a lo ne . By m ist ak e, t he p at ie nt re ce iv ed 9 50 m g in ste ad of th e i nt en de d 9 5 m g. Ele ve n p at ie nt s s ta te d th at t he i nj ec te d d os e w as be tw ee n 1 00 a nd 2 00 m g. T he y p re se nt ed a t t he em er ge nc y d ep ar tm en t o n un re lat ed o cc as io ns . N in et y c as es p re se nt ed w ith n eu ro lo gi ca l f ea tu re s, su ch a s c on fu ns io n a nd dr ow sin ess . T hr ee p at ie nt s r equ ire d in te ns iv e c ar e. Tw o p at ie nt s a dm itt ed t he co nc om ita nt u se of L SD an d m et ha m phe ta m in e. O th er d ru gs w er e d et ec te d in t he ir b lo od . Si xt y c as es h ad l ow er ur in ar y t ra ct s ym pt om s co m pa tib le w ith ke ta m in e cys tit is.
6
Results
With a sample of 34 articles, eighteen describe fatal cases and sixteen describe overdoses. Importantly, some cases of over-sedation (i.e. cases that were not connected to drug abuse) were included as overdose cases. Tables 1 and 2 give an overview about each article.
Ketamine analogues mentioned in the selected articles were: MK-801, 2-Oxo-PCE, 3-MeO-PCP, MXE and PCP. Poly-substance use was mentioned in 56% of the selected articles (18/32).
The remarkable majority of cases were males and the variety of ages was broad: from two to 65 years old.
From Asia, three articles were included (9% of the sample): two from Hong Kong describing overdoses cases and one from China portraying a fatality. The sample also contains fifteen European articles (44%) and sixteen North American publications (47%).
A total of 312 overdose cases were reported. With large sample sizes (when compared to the other studies included in this review) two publications from Hong Kong portray 188 overdose cases involving ketamine (8) and 56 overdose cases involving 2-Oxo-PCE (54). Among all the overdose cases ketamine was predominant (246 cases = 79%), followed by 2-Oxo-PCE (56 cases = 18%), MXE (6 cases = 2%) and PCP (4 cases = 1%). Over-sedation of children was described in three publications (46, 47, 49), where three cases received five times the intended dose of ketamine, seven cases received ten times the intended dose and, impressively, one case received 100 times the intended dose. In all cases, the over-sedation was closely monitored and it produced no sequelae. Another over-sedation case occurred with an elder patient: he received 10 times the intended dose. After ketamine was administered, there were no signs of any problem until the wake-up appeared to be unusually prolonged. Despite this, the patient did not demonstrate any systemic effect (55).
The development of tolerance was reported by Bonnet (2015), in a case where a nurse was self-injecting 50 mg of ketamine intramuscularly once a week to cope with her depression. Due to a gradually developing tolerance to ketamine’s antidepressant action, she increased the dose and frequency of injections, reaching 2 g daily over six months. Fourteen weeks after the beginning of her abstinence from ketamine, she presented normal condition without any sequelae (45).
In the articles about deaths, 138 cases were reported in total, from which 87 came from one single publication (38). Ketamine was the preponderant drug in this group (123 cases = 89.1%), followed by MXE (11 cases = 8%), 3-MeO-PCP (2 cases = 1.5%), MK-801 (1 case = 0.7%) and 2-Oxo-PCE (1 case = 0.7%).
The only MK-801 case involved a man who bought it in an attempt to treat a self-diagnosed depression (26). An interesting case related to ketamine was an autoerotic accident involving a fatal combination of asphyxia by suffocation and intoxication with self-administered intravenous ketamine (28). Also interesting, a case from Portugal described a suicide by hanging under the influence of ketamine and alcohol (30). Besides that, two non-intentional and non-hospital cases were included, more specifically, two homicides. One involved a chronic ketamine poisoning of a woman by her husband (36). The other involved a teenager who was found dead in a car (37). The other fatal cases were mostly associated with regular recreational use of ketamine and/or its analogues in combination with other drugs.
Ketamine and/or its analogues were considered the exclusive cause of death in only nine cases (6.5%): one with MXE (27) and the eight others with ketamine (31, 36, 37, 41, 58). Acute intoxication caused by poly-substance abuse was the cause of death in one third of the cases (9, 26, 29, 32, 33, 38-40, 58-60). In the other two thirds, ketamine and/or its analogues were present, but the causes of death were diverse, for example: asphyxia (28), heart disease (29), suicide by hanging (30), asthma (31), trauma that had emergent surgery (38), sarcoidosis (38), and drowning (58). In two cases the cause of death was not mentioned in the article (9).
Discussion
In 1964, the first experiment with ketamine on human subjects was performed with 20 volunteers from a prison population. It was the first investigation describing the multiple pharmacological effects of ketamine, including anaesthetic, analgesic, and antidepressant effects. That is when the term “dissociative anaesthetic” was suggested to describe the mental state produced by ketamine, because it was observed that the subjects got sort of disconnected from their environment under ketamine’s effect (61, 62). Outside the medical setting, ketamine and its analogues have been used for recreational and psychonautic (i.e. exploration of altered states of consciousness) purposes since the 1960s (16).
The intensity of the effects caused by ketamine and its analogues depends on the dose consumed. Low to moderate doses can cause high blood pressure, agitation, numbness, nausea and, chronically, kidneys toxicity. The higher the dose, the worse the damage. Chronic use of high doses can cause risky changes in blood pressure, panic, loss of consciousness, delirium, psychotic behaviour, cognitive damage, and bladder removal (5, 63). Both the acute and chronic effects of dependence-forming
drugs, such as ketamine, have been associated with deficits in various aspects of reward-processing (64).
An excessive and dangerous dose, i.e. an overdose, seem to be well managed with the administration of benzodiazepines and time (46, 47, 49). However, considering the popularity in mixing drugs for recreational purposes, it is essential to keep in mind that a patient experiencing a ketamine overdose might have used other drugs concomitantly. More than half of the cases (56%) included in this study mentioned the simultaneous consumption of several drugs (also known as poly-substance use), which increases the risks for severe and unpredicted consequences. This investigation corroborates the concerns around these risks. Ketamine and its analogues were rarely used alone and the danger of having accidents while one is under the influence of drugs is ever present (e.g. the autoerotic accident described by Breitmeier et al., 2012) (28).
From 2005 to 2013, 317 new illegal psychoactive products were identified in Europe (65). Some NPS, such as MXE, are marketed as a “bladder safe” derivative of ketamine (57). In an article from 1979, Sidoff (1979) stated that “phencyclidine is the most dangerous drug to hit the street in the decade or so since the experience with LSD”. PCP was released for veterinary use under the trade name Sernylan®. It appeared illicitly in 1967, marketed as the PeaCe Pill (hence PCP) in San Francisco, United States (66). Since then and up to now, several ketamine analogues are emerging from the underground culture.
During data collection, a significant number of studies was found about ketamine abuse and its deleterious effects performed in Hong-Kong (67-69). Ketamine has been the commonest abusive substance used by Hong Kong teenagers since 2005. It is also the fourth commonest poison encountered in the Hong Kong Poison Information Centre data from 2010 (8). Further in Asia is remarkable the amount of studies about ketamine and its harmful effects on the lower urinary tract, causing ketamine-related cystitis and many other LUTS (7, 70-73). In China, ketamine is an increasingly popular drug of abuse and, consequently, the number of dependence cases is rising. To improve the management of ketamine dependence, Fan et al. (2015) developed a checklist of short and long-term symptoms associated with ketamine dependence, with a classification of its psychological effects (74). Moreover, a Spanish team of researchers elaborated and validated the Severity of Dependence Scale in a sample of 264 recreational ketamine users (75).
Ketamine is a street drug, but the abuse of ketamine is also present among professionals who have access to the drug, constituting an occupational hazard. For example, in India, Bhad et al. (2016) describe a case of a veterinary officer who injected ketamine via the intramuscular route for four years before seeking
treatment. He presented withdrawal symptoms which responded well to naltrexone (76). Several other articles describe the abuse of ketamine by medical professionals (77, 78).
It is not a surprise that naltrexone has effects on managing ketamine dependence. Ketamine has an entourage effect, presenting direct and/or indirect effects on several receptors in the brain. In addition to NMDA antagonism, it produces mu-opioid receptor agonism and causes dopamine reuptake inhibition, together with actions
on sigma, nicotinic acetylcholine, D2, cannabinoids, serotonin and GABA
(gamma-Aminobutyric acid) systems (10, 79-87)
It is also found that addictive patterns of behaviour were a concern, considering that the majority of frequent users reported using the drug without stopping until supplies ran out (binging) and the mean increase in dosage in this group was six-fold from initiation to current use (drug tolerance) (18). Existing evidence suggests that a disruption of the oxytocin system is involved in the development of addiction. Huang et al. (2018) performed a study with 65 ketamine-dependent patients and 65 controls. They found a distinctively reduced oxytocin level in the ketamine-dependent group, and this level did not normalize after early abstinence (88). Furthermore, there are reports of discontinuation symptoms in cases of ketamine dependence (14). There are no guidelines for the management of withdrawal symptoms, such as irritability, tremulousness, sweating, restlessness, sleep disturbances, and cravings. However, the use of naltrexone has shown to achieve successfully the remission of these symptoms (89). Additionally, several studies highlight the potential that the chronic use of ketamine has in causing depression. The so-called “breakthrough antidepressant” can cause withdrawal-related depression (90, 91).
A limitation of this study is given by the definition of “deaths related to the use of ketamine and its analogues”. The fact that a drug was detected postmortem does not necessarily imply that it contributed directly to the death. Moreover, the studies included in this systematic review have methodological limitations. Most of them have a cross-sectional nature, which reduces the inference of causal associations. Since they are not experimental studies, it is not possible to measure the association between the consumed dose of ketamine and pharmacological interactions with other drugs.
There is legitimate concern about the risks involving the use of ketamine and its analogues. Their dissociative effect increments vulnerability and recklessness, leaving its users more exposed to accidents and/or misguided decisions. Their abuse and chronic use can produce an assortment of symptoms: neurotoxicity, cognitive impairment, urinary tract damage, dependence and withdrawal issues. On the other hand, ketamine as a medicine is considered safe and it is listed as an essential
medicine by the World Health Association. The over-sedation cases described in this study ratify the fact that dying from an exclusive ketamine overdose is not easy neither common. Although prescribers must remain vigilant, this should not deter appropriate prescribing, just like heroin abuse should not deter the adequate use of morphine. Finally, prevention based on drug education and harm minimisation campaigns are needed to alert people about the potential damages caused by the acute and chronic use of ketamine and its analogues.
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