Pharmaco - Toxicological Aspects and Analysis of Phenylalkylamine and Indolylalkylamine Hallucinogens (Review)

32 Review articles

PHARMACO - TOXICOLOGICAL ASPECTS AND ANALYSIS OF PHENYLALKYLAMINE AND INDOLYLALKYLAMINE HALLUCINOGENS (REVIEW)

D. Obreshkova 1,6 , I. Kandilarov 2, V. T. Angelova 3 , Y. Iliev 4 , P. Atanasov 5 , P. S. Fotev 6

1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str, Sofia 1000, Bulgaria 2 Department of Pharmacology and Clinical pharmacology, Faculty of Medicine, Medical University of Plovdiv, 15A Vasil Aprilov Str., Plovdiv 4002,Bulgaria 3 Department of Chemistry, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str, Sofia 1000, Bulgaria 4 Department of Pharmacology and Drug Toxicology, Faculty of Pharmacy, Medical University of Plovdiv, 15A Vasil Aprilov Str., Plovdiv 4002, Bulgaria 5Clinic of Internal Diseases UMHATEM ”N. I. Pirogov”-Sofia, Bulgaria 6 College of Pharmacy, Medical University-Plovdiv, 15A Vasil Aprilov Str., Plovdiv 4002, Bulgaria

Abstract: The classical hallucinogens having an affinity towards 5HT2A receptors are discussed, along with their common behavioral effects, toxicity and psychiatric complications which could have long-term consequences on individuals. A survey has been done on the various analytical methods used for determination and quantification of hallucinogens: colorimetrical reactions (Marquis, Ehrlich tests), gas chromatography with mass spectrometry (when the substances are not thermo labile), tandem mass spectrometry, high-performance liquid chromatography with UV detection and IR spectroscopy. Methods most often used to analyze biological samples like urine, blood or plasma immunological methods for quick detection, which results are confirmed later by the other methods mentioned above have been also discussed.

Key words: hallucinogens, analysis, LSD, Mescaline, DMT

Introduction cannabinoids and N-methyl-d-aspartate Hallucinogens are substances which alter (NMDA) antagonists, which are not classified as thought, perception and mood without affecting hallucinogens and possess different mechanism memory, producing intellectual impairment or of action may produce similar and overlapping leading to addiction. They also have negligible effects. Therefore the definition was expanded autonomic side effects. This definition is often by Glennon (1996) who added that ‘the halluci- considered too limited because besides the two nogens are also agents that with an affinity for main hallucinogenic classes’ indolylalkyl the 5-HT2A receptors’[1] (Fig. 1). amines and phenylalkylamines other classes like Pharmaco - toxicological aspects and analysis... PHARMACIA, vol. 64, No. 1/2017 33

Fig. 1 Hallucinations arise from agonism at 5-HT2A receptors[1].

These drugs are also known as classical mine their molecular effect on the brain [4, 5]; or serotonergic hallucinogens [2]. Phenylalkyl- second, psychosis-associated diseases, which amines contain a phenetyl amine group similar commonly include hallucinations, are success- to endogenous neurotransmitters dopamine and fully treat using specific molecular approaches noradrenaline. Mescaline, 2,5-dimethoxy-4-me- as well as another diseases [6, 7]. Because of the thylamphetamine (DOM) and 2,5-dime- growing importance of the hallucinogens as thoxy-4-iodoamphetamine (DOI) are examples drugs of abuse, analytical methods are needed in of phenylalkilamines. Indolylalkylamines forensic and clinical toxicology, which allow possess an indole nucleus similar structurally to reliable screening and quantification of these 5-hydroxytryptamine or serotonin. They are substances in biological matrices [8]. divided into two subgroups – simple triptamines The aim of the current review is to sum- like N,N-dimethyltryptamine (DMT), bufotenin marize current information related to the analy- and psilocybin and ergolines like LSD [3]. The sis, pharmacology and toxicology of some clas- research into the psychopharmacology of hallu- sic hallucinogens with phenylalkylamine and cinations is conducted in two directions: first, indolylalkylamine structure. hallucinogenic agents are investigating to deter- D. Obreshkova, I. Kandilarov, 34 PHARMACIA, vol. 64, No. 1/2017 V. T. Angelova, Y. Iliev, P. Atanasov, P. S. Fotev

Results and discussion panic attacks, depression and “flashbacks” – a LSD recurrence of visions when the substance is Lysergic acid diethylamide or LSD is a absent. They appear most often after a “bad trip”. substance first synthesized in 1938 by Albert These complications are not lethal, however, Hofmann, who investigated the compounds of they increase the risk of suicidal reactions [9]. ergot – Claviceps purpurea in the Sandoz Labo- (Table 1) A reexamination of LSD’s potential as ratories (Fig. 2). The use of the hallucinogenic a treatment for addictions indicates that opti- drug LSD is prohibited. At doses greater than or mism, albeit cautious, may be appropriate [10]. equal to 25 µg LSD affects the behavior. A dose Although no teratogenic effects have been regis- of 25 µg usually leads to euphoria and facilitates tered after its use, the drug alters the expression introspection. The optimal dose of LSD which of genes within mammalian brain cells. Even a triggers a trip is within the 100-200 µg range. single dose of LSD has been demonstrated to The effects observed following the LSD intake alter gene expression patterns [11]. Genes that depend on the individual characteristics of the exhibit differential expression following treat- patient and on the specific environment, where ment with LSD include: c-fos, krox-20, NOR-1, the substance is taken. Calm and relaxing arc, IΚβ-α, sgk, and Ania3. Increased expression surroundings are more likely to trigger the of these genes, which are involved in a wide so-called “good trip”, while tense and hostile variety of cellular functions, alters synaptic plas- environment would cause a “bad trip”. There are ticity, glutamatergic signaling, cytoskeletal no documented cases of death after an LSD over- architecture, as well as communication between dose. Following the administration of LSD the the synapse and nucleus. psychiatric complications observed could be

Fig. 2 Chemical structures of Lysergic acid diethylamide (LSD) and natural analog - Lysergic acid amide (LDA)

LSD is a white crystalline substance, isomeric forms. The hallucinogenic effect is due odorless and tasteless with a melting point at to the right rotating isomer. LSD extraction is 80-85 °C. Tartrate salt melts at 198-200 °C and made with methanol-water 1:1 solution at 20 °C dissolves in water and ethanol to give clear and with the use of ultrasound. The substance can be odorless solutions. LSD is an unstable com- determined colorimetrically with Ehrlich test pound oxidized easily by air and light to form with para-dimethylaminobenzaldehyde to give a inactive products. The substance exists in three blue coloration [12]. The use of high perfor- Pharmaco - toxicological aspects and analysis... PHARMACIA, vol. 64, No. 1/2017 35 mance liquid chromatography (HPLC) with UV formation in the body and low concentrations in detector gives an absorption at 313 nm [13]. Gas blood and urine [15]. Its metabolites N-desmeth- chromatography with Mass spectrometry yl-LSD and mainly 2-oxo-3-hydroxy-LSD (GC-MS) and Infrared spectroscopy (IR) are (OH-LSD) (Fig. 3) have longer biological also an option for its analysis [14]. The detection half-life and are found at a 16-43 times higher and quantification of LSD in biosamples is diffi- concentrations in urine [16, 17]. cult due to low oral dose (50-250 μg), biotrans-

Fig. 3 Metabolites of LSD identified in human urine. The 2-oxo-3-hydroxy-LSD is the major metabolite Besides blood and urine, hair samples (RIA) gives a positive result in the content of also could be tested even at a low dose and after LSD in urine more than 0.5 ng/ml [20]. The a single administration of the substance[18]. The microplate enzymeimmunoassay (EIA) is more detection in body fluids is carried out by immu- sensitive and does not require the use of radioac- nological methods - RIA, CEDIA, EIA, Abu- tive materials, making it more accessible when it screen OnLineetc [19]. Radio-immunoassay can work with both urine and blood D. Obreshkova, I. Kandilarov, 36 PHARMACIA, vol. 64, No. 1/2017 V. T. Angelova, Y. Iliev, P. Atanasov, P. S. Fotev samples [21]. The results from these tests and and urine. They applied ultra-performance liquid quantification analysis could confirmed by GC chromatography (UPLC) combined with tandem or HPLC, combined with MS [22]. A combina- mass spectrometry (MS-MS). The relative retention of GC and MS is used to determine the pres- tion time and the ion ratios are used as identifica- ence and concentration of LSD and OH-LSD in tion parameters. The limits of detection are 5 urine with a limit of detection 0.5 ng/ml [23]. A pg/ml for LSD and iso-LSD, and 10 pg/ml for gas chromatography – ion trap tandem mass nor-LSD and OH-LSD in blood and 10 pg/ml for spectrometry method (GC-ion trap-MS-MS) all substances in urine. The limits of quantitation shows that m/z fragments of 2-oxo-3-hy- (LOQ) in blood and urine are 20 pg/ml for LSD droxy-LSD-bis-TMS are 309 and 499. The and iso-LSD and 50 pg/ml for nor-LSD and determination with GC, however, has its draw- OH-LSD [26]. Another method for analysis of backs, which result in an irreversible adsorption LSD, iso-LSD, nor-LSD and OH-LSD from hair of the substance in the column. LSD is a relative- was developed by Martin et al. The substances ly non-volatile substance and requires derivat- are extracted with HCL and methanol and quan- ization and obtaining of the volatile components tified by liquid chromatography coupled with - trifluoroacetyl (TFA) or trimethylsilyl electrospray tandem mass spectrometry [27]. (TMS)[23]. As GC works at higher tempera- tures, the results in losses are due to thermolabil- Mescaline ity [24].That leads to the development of differ- Mescaline (3,4,5-trimethoxyphenethyl- ent liquid chromatographical methods. The amine) is a well-known hallucinogen since method of HPLC with fluorescence detector ancient times (Fig. 4). It is a phenethylamine (HPLC-FLD) shows a wavelength of excitation compound which is a natural constituent of the at 315 nm and emission at 420 nm [22]. Bodin et peyote cacti – Lophophora williamsii, Cactace- al., used a combination of HPLC and MS to ae [28]. Found in the southwestern USA and determine the substance in urine with a limit for northern Mexico, the dried tops of this cactus has detection 0.02 ng/ml [25]. Chung et al.,validated been used by Native Americans in different a method for confirmation and quantification of religious ceremonies. Mescaline can be extract- LSD, iso-LSD, nor-LSD and O-H-LSD in blood ed from peyote or produced synthetically.

Fig. 4 Chemical structures of mescaline and modifications Pharmaco - toxicological aspects and analysis... PHARMACIA, vol. 64, No. 1/2017 37

Mescaline is used primarily as a recre- color [35]. Detection of mescaline could be ational drug and is also used to supplement vari- made with GC combined with MS [36, 37]. The ous types of meditation and psychedelic therapy. m/z top peak is 30, m/z 2nd highest is 182 and m/z The use of peyote is illegal and its consumption 3rd highest is 166. MS-MS peaks are m/z 180, m/z leads to a hallucinogenic effect similar to those 195 and m/z 179(35)(25).The quantification of of LSD, but 4000 times weaker although the mescaline is carried out by HPLC with UV duration of the trip is longer [29, 30]. Although detector. The UV absorbance maximum for mes- mescaline does not lead to addiction, it could caline is 205 nm [34]. Urine could be screened provoke a lot of adverse reactions like tachycar- for mescaline using biochip array immunoassay dia, hypertension, nausea, psychosis and para- as it is done by Battal et al. They validate noia [29]. Some death cases are reported after GC-MS by an electron impact ionization method the consumption of peyote but on extremely rare for quantification of the substance [38]. occasions. In one of them, a 32 year-old Native LC-MS-MS method was developed by Bjorns- American having drunk peyote tea died due to tad et al.,in order to confirm the presence of mes- Mallory-Weiss esophageal laceration caused by caline in urine samples. The limit of detection in vomiting which mescaline had induced a urine matrix is 3-5 µg/l. Separation is made on [31].With continued drug use, the long term a HyPURITY C18 column using methanol effects of mescaline take the form of addiction gradient in ammonium acetate buffer. The where a person’s lifestyle revolves around observed transitions in the MS-MS analysis are getting and using the drug. Mescaline interacts m/z 212.3 to m/z 180.3 for mescaline and m/z with the brain’s cognitive and emotion-based 221.3 to m/z 186.3 for the deutered internal stan- centers, oftentimes bringing users to vulnerable dard – mescaline-d9 [39]. Peyote tea, hair sam- and even helpless states of mind. With frequent ples and urine from boy suspected in mescaline drug use, the long term effects of mescaline can abuse were analyzed using GC-MS and compromise severely the psychological well-be- GC-MS-MS methods, validated by Gambelung- ing of a person (Table 1). he et al.,[40]. GC-MS analysis detected mesca- Mescaline is a white crystalline line in the tea but not in the urine (because it was substance with melting point of 35-36 °C, boil- already excreted) and GC-MS-MS analysis ing at 180 °C. It is moderately soluble in water found mescaline in the proximal segments of the and soluble in ethanol, chloroform and benzene hair where the substance accumulated for longer [32]. The usual dose of mescaline which periods. provokes a hallucinogenic reaction is within the range of 200 to 500 mg [30] (equals to 5-10 DMT peyote buttons) [33]. Mescaline could be detect- N,N-dimethyltryptamine (DMT) is a ed by a colorimetric test, e.g. Marquis test which psychoactive indolealkylamine which was found is used for alkaloids and amphetamines. The naturally in the human brain, in some animals reagent is a mixture of 100 ml of concentrated including mammals, and also in a broad range of sulfuric acid and 1 ml of 40 % solution of form- species of the plant kingdom (Fig. 5). DMT is a aldehyde dripped onto the tested substance. The potent, fast-acting hallucinogen with short dura- test is quick and does not require specific equip- tion in humans. It could be administrated via ment. Mescaline gives orange color and its limit different routes: inhalation 6-20 mg, intravenous of detection is 1 µg [34]. Froehde reagent could injection 0.7–3.1 mg, sublingual or intranasal also be used to identify mescaline. It consists of insufflation 10 mg, and oral administration 30 molybdic acid or sodium molybdate and concen- mg (only with MAO inhibitor like harmaline). trated sulfuric acid, mixed, heated and then 5-Methoxy-N,N-dimethyltryptamine added dropwise on the substance tested. If mes- (5-MeO-DMT) – a designer drug obtained from caline is available, it gives a greenish to brown DMT, produces psychedelic effects which D. Obreshkova, I. Kandilarov, 38 PHARMACIA, vol. 64, No. 1/2017 V. T. Angelova, Y. Iliev, P. Atanasov, P. S. Fotev start 3-4 min after insufflation, a peak about known to increase the systolic and diastolic 35-40 min, and an end around 60-70 min. It blood pressure, as well as the heart rate. Howev- distorts time perception and provokes visionary er, like LSD most adverse reaction is psychotic. and auditory changes. Those who take the DMT is capable of inducing psychological reac- substance often experience visions of mytholog- tions or transient psychotic episodes like the ical alien creatures [41, 42]. The data about appearance of unpredictable frightening images DMT toxicity is scarce, except from one argu- and thoughts that disappear shortly. Nausea and able report of a death case after drinking diarrhea, could also be observed after the admin- 5-MeO-DMT contained in an Ayahuasca prepa- istration of the substance [44] (Table 1). ration [43]. Intravenously administrated DMT is

Fig. 5 Metabolic pathways for N,N-dimethyltryptamine (DMT) in humans.

DMT is a white crystalline compound. It of DMT. The results show that the infrared spec- melts at 46 °C and boils at 60-80 °C. DMT is trum for DMT has peaks at 742, 809, 862, 1008, dissolved easily in diluted acetic and mineral 1031, 1110, and 1178 cm -1 . GC/MS demon- acids. The solubility in water is limited for the strates a peak at 21.2 min. The ions m/z 130 and base and good for the fumarate salt. It emits m/z 58 are selected for tandem mass spectrome- toxic fumes of nitrogen oxides when heated [45]. try but a mass spectrum is obtained only from DMT could be determined colorimetrically. m/z 130. After a direct insertion of the crystals Ehrlich’s reagent reacts with tryptamines into the mass spectrometer occur the molecular producing blue to purple color. The limits of ion peaks at m/z 188, and a base peaks at m/z 58 detection are 10-50 µg/ml [46]. Gaujac et al., [45]. These results are similar to the spectrum was applied different analytical methods to the provided in the NIST Mass Spectral Database: structural characterization and purity assessment m/z top peak is 58, m/z 2nd highest is 130 and Pharmaco - toxicological aspects and analysis... PHARMACIA, vol. 64, No. 1/2017 39 m/z 3rd highest is 188. The UV absorbance maxi- effect after an oral dose of 8-25 mg of psilocybin mum for DMT is at 280 nm [47]. Ishii at al.,[48] exhibits in 70-90 min., lasting about 360 min. It used GC with surface ionization detection (SID) changes perception by enhancing introspection, for identification and quantization of DMT in producing illusions and altering thought and whole blood and urine using gramine as an inter- time sense. Being low toxic psilocybin produces nal standard. Solid-phase extraction of the sam- no physical damage when used. However, it ples is carried out with Sep-Pak C18 cartrige could lead to many psychiatric complications before the analysis. The limit of detection of under uncontrolled conditions in individuals DMT is 0.5 ng/ml. The retention times are 7.9 who are emotionally vulnerable [53] (Table 1). min for gramine and 9.4 min for DMT. The It is a substance forming colorless crys- intensity of the peaks is similar, regardless of the tals soluble in water and methanol and insoluble different quantity - 500 ng for gramine and 10 ng in chloroform and benzene. Under acidic condi- for DMT thus the response of SID to DMT is tions it dephosphorylates into psilocin [54, 55]. higher [48]. Another method for the analysis of The colorimetrical determination of psilocin and designer triptamines and phenetylamines in psilocybin could be made by Marquis test giving blood and urine was developed by Vorce and a greenish-brown color for psilocin and orange Sklerov. They used a screening method based on color for psilocybin. Gas chromatography is not GC/MS with electrospray ionization (ESI), opti- useful for the determination of psilocybin due to mizing the separation of the substances. The its instability and dephosphorilation to psilocin retention time for DMT is 10.-14 min. The when heated. different drugs are identified of - by selected ion monitoring (SIM). The SIM ions for DMT is m/z 58.129 and 180 [49]. There are other analytical methods for identification and quantization of DMT as a component of the Ayahuasca preparation such as: analysis of plasma with GC with a nitrogen-phosphorus detection after liquid-liquid extraction with diphenhydramine as an internal standard [50]; or with n-pentane [51]; analysis of urine with LC-ESI-MS/MS [52].

Psilocybin and psilocin Psilocybin is a hallucinogenic tryptamine with chemical name - 4-phosphoryloxy-N,N-dimethyltryptamine. It was first isolated by the Swiss chemist Albert Hofman in 1957. The substance is a natural ingredient in Psilocybe mexicana distributed mainly in Central America. It is found also in many other mushroom species worldwide all known by the common name – “magic mushrooms”. They are one of the most common hallucinogenic used today. Psilocybin was first synthesized by Hofman in 1958. Phar- macokinetic studies show that after oral administration psilocybin is metabolized to psilocin in the liver (Fig. 6). Both substances produce simi- Fig. 6 Metabolic pathways for psilocybin in lar psychedelic effects. The hallucinogenic humans D. Obreshkova, I. Kandilarov, 40 PHARMACIA, vol. 64, No. 1/2017 V. T. Angelova, Y. Iliev, P. Atanasov, P. S. Fotev

HPLC could be used with retention time droxy-N,N-dimethylserotonin) is a hallucino- for psilocin – 6.08 min. and for psilocybin 7.61 genic substance, secreted in the parotoid glands min. [56, 57]. The UV maximum for detection is of Bufo toads, in mushrooms in the genus Ama- at 210 nm. Qualification could be performed nita and in the seeds of different Anadenathera with ultraviolet spectrophotometry; the absor- and Piptadenia species [60]. Its effects are simi- bance maximums when aqueous acid is used as a lar to DMT and 5-MeO-DMT. Structurally, solvent are at 266, 283 and 292 nm for psilocin bufotenine is an indole hallucinogen that is capa- and at 268 for psilocybin. Mass spectrum for ble of blocking the action of serotonin, which is psilocin shows highest pick at m/z 58, 2nd highest the indole amine transmitter of nerve impulses at m/z 204, 3rd highest at m/z 42. The values for and can be found in normal brain tissue (and in psilocybin are m/z 58 for the highest pick, m/z toad poison) [61]. Bufotenine also functions as a 204 for the 2nd highest pick and m/z 146 for the powerful constrictor of blood vessels, causing a 3rd highest pick[58, 59]. rise in blood pressure. However Bufotenine is unable to pass blood-brain barrier due to its low Bufotenine lipid solubility, thus its psychoactive effects is Bufotenine or Bufotenin (Fig. 7), controversial [62] (Table 1). 5-HO-DMT, N,N-dimethylserotonin, 5-hy-

Fig. 7 Chemical structures of Bufotenine

Color tests used for the determination of set at 210 nm and the retention time is 2.23 min. bufotenine are Marquis test – green brown and Capillary electrophoresis is also an option for Van Urqs test – violet to dark purple color. Other screening. Qualitative data could be obtained on screening methods are GC and HPLC [63]. GC a UV spectrophotometer. The absorbance maxi- is performed with a flame ionization detector mum is at 278 nm. Mass spectrum data is m/z 58 (FID). The retention time for bufotenine is 3.85 – highest pick and also m/z 146, 42 and 204[65]. min.[64] The HPLC method uses a UV detector Pharmaco - toxicological aspects and analysis... PHARMACIA, vol. 64, No. 1/2017 41

Table 1. Specifics of hallucinogens effect

e Pharmacology s)

an c Toxicological

rce ( Psychological Effects Acute Somatic Effects Lethal mm on u

o Data Neurocognitive s o C Subs t Effects A moderate dose (75–150 μg p.o.):  Decreases attention  Mild autonomic  Has no  NO  n euphoria, and concentration; changes of mydriasis, carcinogenic documented i

;  enhanced capacity for introspection,  thinking processes tachycardia, potential; human a

r e  hypnagogic experience and dreams, are can be also tachypnea,  LD50 for rabbit deaths from u

p  illusions, affected; hyperthermia, -0.3 mg/kg i.v. an LSD ;

s    pu r pseudo- hallucinations, intellectual functions hypertonia, and LD50 for rats overdose s  alterations of thinking and time are impaired; hyperglycemia; (16.5 mg/kg  eight rv o e ce p n experience;  psychomotor  rarely, some increase i.v.) individuals

v i a

a  

l “bad trips”; functions in body temperature; LD50 for mice had plasma C

yre i  flashback phenomena; (coordination and  respiration remains 46–60 mg/kg levels of – g

t  irrational acts leading to suicide or reaction generally unchanged; i.v. 1000–7000 o A r g s ] accidental death are extremely rare; time) are frequently  parasympathetic μg per 100 a 9 e r ng i

6 u  n - psychosis-like symptoms; impaired; stimulation: mL blood i c h 6 s f u ; 6  impaired time perception, distorted  memory was also diaphoresis and plasma and d [ s t ce p perception of the size and shape of affected. salivation are suffered v i am i a la n objects, movements, color, sounds, touch frequent, nausea may from l p LS D

C th y l f and the user’s own body image. occur, emesis is comatose ä o i s d exceptional, and states, - d flushing of the face is hyperthermi se e

n more frequent than a, vomiting, i

d paleness; light gastric n

u  temporary headache bleeding,

F o and near-syncope; and  slight unsteadiness of respiratory gait to full ataxia, problems German Lysergsäure positive Romberg’s n i sign, and mild tremor.

 Hallucinations/illusions, external  Short-lasting  Nausea, vomiting,  Has an  NO; hallucinations; tolerance; abdominal cramps, extremely low  Fatalities  prolonged and diarrhea; toxicity relative associated  shadow people, emotion enhancement, psychiatric  excessive yawning, to dose have been language suppression, addiction symptoms; drowsiness, dizziness,  the natural described, suppression;  paranoid lightheadedness, and levels of however  auditory, tactile, and visual experiences, lack of coordination; psilocybin these were hallucinations, analysis enhancement,  derealization;  pupil dilation, tearing, within magic not linked to catharsis, cognitive euphoria;  depersonalization; dry mouth, and facial mushrooms are direct  conceptual thinking, confusion, creativity  long lasting flushing much higher toxicity of enhancement, déjà vu, ego replacement, unpleasant  increased heart rate, than psilocin, psilocybin ego death, existential self-realization; experiences (bad blood pressure, and  Psilocybin - but most trips), including body temperature; LD for rats victims died  50 feelings of eternalism, of impending 

] frightening sweating followed by and mice is after s

2 doom, of interdependent opposites, of 7 m hallucinations; chills and shivering 280-285 jumping out - o predeterminism, of self-design, of unity 0  psychotic reactions  numbness of tongue, mg/kg, and for of the 7 r o [

h with the environment;

s and hallucinogen lips, or mouth; rabbits it is window or n u i  increased music appreciation, memory persisting perception  feelings of physical 12.5 mg/kg. committing suppression, personal bias suppression, p. M disorder (HPPD); heaviness or lightness  Psilocin - LD50 suicide; p s rejuvenation,spirituality enhancement;  attention and feelings of is significantly  fatality was e  subconscious communication, time disturbance, floating; lower for mice described  a nd Ps il o c distortion, wakefulness; distractibility,workin muscle relaxation, and rats 75 after

n g memory; weakness, and mg/kg and for ingestion of i Ps ilo cy b 

brighter colors, sharper visual definition;

n  delusions; twitches; rabbits 7 mg/kg an extreme i y b  d increased hearing acuity, synesthesia  associative deficits  changes in felt bodily dose n

u (melding of the senses: seeing music or  spontaneous tactile form; (psilocin

F o hearing colors); Ps il o c sensations;  changes in gravity; plasma level  difficulty focusing, maintaining attention,  a complete psychotic  frequent urination; was 4 μg/ml) concentrating, and thinking; episode of audio or  olfactory of Psilocybe visual hallucinations hallucinations; semilanceata  impaired judgment and preoccupation will occur, but may  perception of . with trivial. continue in users increased weight;  thoughts, experiences, or objects with additional  physical euphoria;  sense of detachment from body and mental illness.  runny nose; surroundings and loss of boundaries  salivation; between the two  watery eyes;   altered perception of space and time, coma, hyperthermia, inability to distinguish fantasy from and respiratory failure;  reality somatic toxicity.  melding of past experiences with present D. Obreshkova, I. Kandilarov, 42 PHARMACIA, vol. 64, No. 1/2017 V. T. Angelova, Y. Iliev, P. Atanasov, P. S. Fotev

 Visual hallucinations;  Increased risk of  Seizures;  LD50 for albino YES  radically altered states of consciousness; psychological  tremors; rat was found  often experienced as pleasurable and problems;  tachycardia; to be 370 illuminating but occasionally is  problems  hypertension; mgm./kgm ; i accompanied by feelings of anxiety or remembering;  nausea, vomiting;  LD50 for dog s i  

m revulsion; tolerance to the dizziness; was 68 mg/kg  produces “out-of-body” experiences or drug, meaning more  diarrhea;  LD50 for lli a i “trips”; must be used to get  vomiting; monkey 160 w p a   r

p lack of motivation; the same effects; headache; mg/kg s o h )   

] panic; psychosis; difficulty breathing; s u

74  terror;  ongoing paranoia;  incoherent speech ho p , p 3  hallucinations of death or frightening  anxiety; patterns; cer e 7 [ L o o experiences;  short attention span,  muscle stiffness; s e c h u i n  uncontrolled moods; inability to focus;  altered vision; i c t T r a l c a  psychosis;  psychological  dilated pupils; s ( ; e s i  altered perception of time; dependence on the  faster heart rate; t  floating sensation; drug.  increased blood Me s c ino p

Pey o 

inability to differentiate reality from pressure; m Ec h fantasy;  higher body o r

f  anxiety; temperature; e d

t  a distorted sense of time and space that  changes in motor a l persists long after using the drug; reflexes; s o I  inability to distinguish between past and  shaking hands or feet, present events; sweating;  psychotic-like episodes.  numbness  contractions of intestines or uterus.  Euphoria;  Numerous dramatic  Increased respiratory  LD50 of  YES -

s   i anxiety and dysphoria; cardiovascular rate; bufotenin in Death occurs eO c ti ve M  either geometric or arabesque patterns; effects;  heaviness in the chest; rodents has by

- ] r iu s 5 7    a auditory effects (usually high-pitched visual and purpling of the head been estimated respiratory 7 v - l

5 tinnitus and a much greater perceptive gastrointestinal and neck skin, like the at 200 to 300 arrest a an d syc ho a 7 o [ e f prominence of the auditory sense; effects; color of a diluted mg/kg. ; n e p u e i T h

B   n color hallucinations, exacerbation of eggplant;

t e n i M t t d

o   a

D visual hallucinations consisting of a play peripheral effects. nausea and vomiting; f o u

t of colors, lights, and patterns;  numerous dramatic b o te n secr e  o visual disturbance associated with color cardiovascular, visual ces t eser t Bu f n

d reversal and distortion; and gastrointestinal w e s ta n o  extreme anxiety; effects; h b T k n  a sense of imminent death.  visual disturbances. s u

 Hallucinogenic DMT trip;  coma and/or  Increased heart rate  LD50 in mice is  YES  altered perception of time and space; respiratory arrest and blood pressure; 47 mg/kg;  a median  feelings of intense joy; (reported in high  chest pain or  human LD50 lethal dose  visual and auditory hallucinations; doses). tightness; of 1.6 mg/kg of oral DMT  out-of-body experience;  for would be a  symptoms that agitation, dilated  perception of bright, intensified colors; pupils; administered total dose of

s would be present i  perceived insights or epiphanies (often  rapid rhythmic intravenous 560 mg for a d with other

r i believed to have come from aliens,  a total 70 kg neurological movements of the eye; ] V i divinities or other mystical beings);  intravenous individual. 9 dizziness, agitation; a

7 problems such as

r i   , itered perception of time and space  confusion; dose of 112 mg The average

8 brain tumors or

7  ho t feelings of intense joy.  for a typical 70 ceremonial

[ loss of muscle cerebrovascular kg person. dose of

T coordination;

Psy c accident (i.e., DMT is M  headache n ,

i stroke).

D about 27 mg d schizophrenia; n

u  hallucinations and

F o visual disturbances;  coordination problems;  nausea and vomiting (typically when taken in oral forms such as ayahuasca).

Conclusion toxicity but the risks of damaging mental health Most hallucinogens are found as natural or causing physical traumas during the halluci- ingredients in many plants, mushrooms or nogenic trips should not be underestimated. animals and have been known to man since Moreover, hallucinogenic substances are illegal ancient times. Nowadays with the discovery of in most countries worldwide, thus it is important novel synthetic and semi-synthetic substances, to know different sensitive analytical methods they are still used despite of the unpredictable for their determination and quantification in consequences that might occur as a result of their different biological matrices such as blood, application. Most of the substances exhibit low plasma, urine and hair. Pharmaco - toxicological aspects and analysis... PHARMACIA, vol. 64, No. 1/2017 43

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Corresponding author: V. T. Angelova Medical University of Sofia, 2 Dunav str., Sofia 1000, BULGARIA, Tel: +359 2 9236 586 E-mail address: [email protected]