June 2022

Medical Mass Spectrometry Vol. 6 No. 1

Review

Toxicological analysis on forensic investigation in drug related cases;
pharmacological information on 88 psychoactive substances in“Narcotics and Psychotropics Control Act” in Japan
Koutaro Hasegawa*, Osamu Suzuki
Department of Legal Medicine, Hamamatsu University School of Medicine,1‒20‒1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431‒3192, Japan
Abstract

Forensic toxicology is a ﬁeld dealing with applications of accepted scientiﬁc methods in investigating drug re-lated cases, analytical results of which can be issued and used in court. As unique aspects of forensic medicine/toxicology,
various specimens ranging from blood, urine, body ﬂuids to solid tissues can be dealt with in analysis. In addition, target
substances to be subjected can also be varied from medicines, abused drugs, chemicals, to daily used substances. In analysis, various high-sensitive instruments such as gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) are being employed throughout the world.
Thus, it should be taken into consideration that various phenomenon including postmortem distribution/redistributionof drugs in the body and matrix eﬀects on analysis can inﬂuence results of analysis, making the interpretation of analyticalresults very complex and diﬃcult in forensic investigations. In this review, we have presented comprehensive perspectives
on toxicological analysis and pharmacological information on 88 psychoactive substances in Narcotics and Psychotropics
Control Act in Japan, which should be of use in drug related cases. It is desirable for examiners to investigate and consider
the cause of death based on comprehensive medical perspective, keeping in mind that the results of toxicological analysis
are only one of factors in determining the cause of death. In addition, it is also quite important to record details of the samples and analytical procedures employed, so that the previous results can be veriﬁed later. These details on toxicologicalanalysis can provide chain of custody of the investigation.
Key words: Forensic Toxicology, LC-MS/MS, GC-MS(/MS), postmortem distribution/redistribution, chain-of-custody

Introduction

formed to clarify the cause of death itself, and the compre-

In the ﬁeld of forensic medicine, autopsies are performed

hensive understanding of each case. Regarding drug relatedcases including drug facilitated crimes (DFC), abuse, mis-

to investigate and determine the causes, or manners ofdeath in concerned cases. In addition to ﬁndings of autopsy,
various additional tests such as drug screening and micro-

use of drugs, homicide and even suicide using poisonous

scopic investigations on pathological ﬁndings are also per-analysis shall be performed to investigate the cases; thepresence or absence of the targets, the degree of contribu-

substances and/or various kinds of drugs, toxicological* Corresponding author

tion of involved substances in manner of death and also its

Koutaro Hasegawa

pharmacological potencies/eﬀects on the cases become

Department of Legal Medicine, Hamamatsu University Schoolof Medicine, 1‒20‒1 Handayama, Higashi-ku, Hamamatsu,

focuses of interest in the toxicological approach.
Forensic toxicology is a ﬁeld where dealis with applica-

Shizuoka 431‒3192, Japan
Tel: ＋81‒53‒435‒2239, Fax: ＋81‒53‒435‒2858

tions of accepted scientiﬁc methods in investigating drug

Received: January 31, 2022. Accepted: May 10, 2022.

used in court

related cases, analytical results of which can be issued andE-mail: 07484771@hama-med.ac.jp

1,2). In addition to analyzing samples collected,
seized or obtained by the police through their investiga-

Epub June 21, 2022.

tions, various complex samples including body ﬂuid sam-

DOI: 10.24508/mms.2022.06.007
2

June 2022

Medical Mass Spectrometry Vol. 6 No. 1

5‒7)

,

cially in forensic toxicological area. In addition, as fre-

and/orcollected at autopsies can also be sub-quently encountered drugs in ﬁeld of forensic toxicologicalinvestigation in Japan, 88 psychoactive substances in Nar-

jected to the toxicological analysis depending on each casecotics and Psychotropics Control Act with their pharmaco-

3)

ples such as blood , urine

4)

10)

even putrefactive eﬀusions
tissues samples
if necessary

14‒18), bile, vitreous humor

8,9)

11‒13)and solid organs

19,20). Therefore, it is of course very important inlogical information, which should be of practical use, were

investigations of the drug related cases to evaluate the con-dealt with in this paper.

tributions of drugs and/or poisonous substances to eachmanner of death through analysis, which is based on foren-

Samples in Forensic Toxicological Investigation

20)

sic toxicological perspectives and ﬁndings .

Various kind of human body specimens, or practically

In particular, the analysis for involved substances in vari-almost all kind of specimens, can be subject to analysis inous samples obtained from forensic autopsies should

forensic toxicological analysis . As one of unique aspects

require comprehensive understandings for them based onof forensic medicine/toxicology, which deals with various

19)

19)

and/or forensic medicine to evaluate

cases ranging from unnatural death, suicide to crime case,the analytical results correctly, because of unique characteristics and perspectives of forensic medicine and toxicology,

target substances to be analyzed can also be varied frommedicines, abused drugs, chemicals, to daily used sub-such as diversity of the target samples described above and20)
postmortem changes of the samples , which can give vari-stances, etc . Table 1 shows the target compounds likely to
be encountered in investigations and the samples to be col-ous inﬂuences over the whole process of analysis. In addi-

lected at autopsy for them . Also, Table 2 shows the pref-tion, there are still vast number of drugs and substances, thepharmacological eﬀects on the human body and the evalua-erable amount of each sample to be collected at autopsy forforensic toxicology

2)

19)

toxicological investigations.
In general, the distribution of substances in the humantion of toxicity and potency of which are unclear, making
evaluation of the analytical results of human samples, espe-

body can be greatly aﬀected by various factors such as

cially in intoxication cases, quite complex and diﬃcult.
In this review, we would like to discuss forensic toxico-

chemical characters of the substance (polarity, volume of26)
distribution, etc.) , manner/route of administration, gradi-

logical approaches in investigating causes of death basedent of concentration in the body, metabolism and of course

on results of analysis along with other ﬁndings such as

anatomical positions of organs . Thus, the above table
only show a kind of example in sample collection in foren-

21‒25)

27)

those of autopsies, describing on postmortem distribution/

sic autopsy; any kind of samples can be the subjects forredistribution of substances in the human body as a unique
phenomenon that should be taken into considerations espe-

investigations, in any volumes, regardless of the type ofTable 1. Kinds of target compound, and biological specimens often used in forensic toxicological investigations
Whole blood/plasma/serum
Organic solvent（inhalation）＋＋

Alcohols＋＋

CyanideCarbon-monoxide

＋＋

Urine

Gastric
contents

Liver

Brain

＋

＋

Kidney＋＋＋＋＋＋Hydrogen-sulﬁdeAnesthetics

Lung

＋＋
＋＋

＋＋

Heavy metals
Organic substances（oral）＋＋＋＋

Organic substances（injection）＋＋＋＋

Basic substances（injection）＋＋＋＋

Organic phosphorus agents＋＋

Parent drug

＋＋

＋/−

Metabolite(s)

＋/−

＋＋

＋＋

＋＋

＋＋

＋

＋

＋＋

＋＋
＋
＋＋

＋
＋＋
＋＋

＋
＋〜＋＋

＋＋: very suitable, ＋: suitable, ＋/−: possible/spare

3

＋＋

＋/−

＋

＋

＋/−

June 2022

Medical Mass Spectrometry Vol. 6 No. 1

Table 2.

Suitable amounts of matrices for forensic toxicological investigation at autopsy
Matrices/Volume

Gastric tissue

Matrices/Volume (area)
2

Suitably
20 mL*2

Dermal tissue

20 mL*210‒20 g*2

Bone (including mallow)

100 cm10‒20 g*2
10‒20 g*2

Hair

50 mg

10‒20 g*2
10‒20 g*2

Injection scar
Whole blood/plasma/serum

Around scar
20 mL*2Urine

20 mL*2

Nail

Gastric lavage residue

10‒20 g*2
10‒20 g*2
20 mL*2

Solid tissue specimens

Suitably
10‒20 g*2

Residue of vomit

As much as possible

Fluidal specimens

10‒20 mL*2

Gastric contents
Duodenum/intestinal contents
Brain
Lung
Liver
KidneySkeletal muscle

Adipose tissue* In living human cases, 10 mL of whole blood/plasma/serum and urine, 50 mL of gastric lavage residue should be collected.

drug or toxic substance involved.
In addition to simple judgement on presence or absence

sample, however, should be referred to in other studies andliteratures; it is impossible to present comprehensive analyt-of target substance and its concentration in each sample,

ical procedures for vast kinds of target substances in thisadditional various information on the target compound canreview because not only quite various substances but also
samples can be involved in forensic investigations. Regard-

also be obtained depending on kinds of tested sample. For
example, adipose tissue can store non-polar substances for aing forensic toxicological examination, analytical results onlong period and in relatively large amounts, so it may beauthentic human abuse cases will not only contribute to thepossible to detect substances from adipose tissue that could

investigation on cause of death in corresponding cases, but

not be detected in urine or blood samples

28, 29). With regard

also be able to provide reliable and of high reference value

to details of this case, we experienced a fatal multiple drug
abuse case where synthetic cannabinoids AB-CHMINACA,

data to other drug related cases.

Instrumental Analysis in Forensic Toxicological Investigations

5-ﬂuoro-AMB and diphenidine were involved. Although
AB-CHMINACA and 5-ﬂuoro-AMB could neither be
detected from any body ﬂuids including blood samples

Especially in the ﬁeld of forensic toxicology, high sensi-

even nor urine obtained at autopsy, they could be detected
and quantiﬁcated at 24.8±2.5 and 18.7±1.1 ng/g in the adi-

tivity and high speciﬁcity of instruments play an importantpose tissue, respectively, which could provide informativeclues to the investigation, showing evident results of inges-

xenobiotics and/or even their metabolites. In this ﬁeld, gas
chromatography-mass spectrometry (GC-MS) and liquidrole in the identiﬁcation and quantitative analysis of target

tions of drugs prior to the death .

chromatography-tandem mass spectrometry (LC-MS/MS)

In the analytical case of hair samples, it is possible toestimate the timing and even interval of ingestion of the tar-are usually/typically employed28)

get substances by detailed analysis of hair segments

30‒33)

34‒37)

throughout the world.

Recently, in addition to them, gas chromatography tandem
mass spectrometry (GC-MS/MS) has also been used in the;38)

Kuwayama et al. could successfully detect midazolam,which had been administrated in single dose (3 mg) intrave-ﬁeld of forensic toxicology .

nously 2 months before sample collecting, from well segmented (0.4 mm) hair samples using high-resolution quad-is fragmented into its constituent parts by each collisionrupole-Orbitrap

mass

quadrupole mass spectrometer according to their mass

spectrometry . Thus, as described before, it is possible for
examiners to obtain/provide useful clues and information

weights (m/z) , giving product ion mass spectrum
obtained from each compound. The qualitative identiﬁca-

on target compound(s) by analyzing various samples intion analysis of each substance is carried out by comparing

forensic toxicological investigations.

the mass spectrum of the target substance with reference
libraries and database, which are consisting of known com-liquidchromatography‒tandem

In mass spectrometry, the molecule of target compoundenergy for them, and these fragment ions are separated in a

33)

39)

Detailed analytical procedures for each substance and4June 2022

Medical Mass Spectrometry Vol. 6 No. 1

pounds . Quantitative analysis, on the other hand, is usu-

method.

ally carried out by examining the area of chromatogram of

Nowadays, GC‒MS/MS systems can be comparable tothose of LC‒MS/MS in selectivity, sensitivity and easiness40)

a speciﬁc m/z ion selected by selective ion monitoring(SIM) or multiple reaction monitoring (MRM) modes, opti-of handling them. In spite of such high analytical performance of instruments, the costs of GC‒MS/MS are usually

mized for respective targets; these SIM and MRM can also
41)
be used for high-sensitive qualitative analysis . Using

lower than those of LC‒MS/MS . In research laboratories
dealing with biomedical matrices, LC‒MS/MS and/or GC‒
38)

these technique, reliable qualitative and quantitative analy42, 43)

sis can be examined.

MS systems are now being widely employed. In addition tothem, when both LC‒MS/MS and GC‒MS/MS are avail-A lot of scientiﬁc literatures using LC-MS/MS and
GC-MS in forensic toxicological area have been reported soable as standard analytical instruments in the future, it isexpected that analytical possibilities in toxicological inves-

34‒37,44); these systems are now being widely employedfar

45‒47)

throughout the world for investigations. Their one oftigations shall be better than as is of nowadays.

advantages is that multiple ionization techniques including

Postmortem Distribution/Redistribution of
Xenobiotic Substances in Forensic Investigationelectrospray ionization (ESI) and atmospheric pressure
48‒51)

chemical ionization (APCI) are available in analysis,

according to kinds of target compounds.

It has been described above that distribution of substances in the human body can be greatly aﬀected by vari-

In GC systems, they could separate from gaseous mixture into individual substances by passing gas ﬂow throughous factors such as chemical characters of the substancea silica capitally column. Thus, the system is generallyrobust and have high speciﬁcity for analysis of various sub-26),

manner/route of administration (oral intake, inhalation via
the respiratory tract, intravenous injection, etc.), gradient of

stances; GC system is thought to be, so to speak, Goldstandard for either screening or determinating in investiga-

concentration in the body, metabolism and the course of

36,37). On the other hand, in GC techniques, target

excretion in human body. Furthermore, anatomical position

should be thermally stable and volatile substances, whichbrings limited utility for GC in forensic toxicological inves-and structure of organs can also contribute to distribution/
redistribution of drugs among samples, bringing about vari-tigations; laborious sample preparations such as derivatizations can be required in case of analyzing such not-suitableous concentration values of corresponding substancestion

substances for GC technique in analysis

34,35)

though the samples being collected from the same body.
With regard to such example, we experienced an intoxica-.

In LC systems, separation of target compounds from liq-tion autopsy case due to ingestion of methamphetamine inuid mixture can be carried out by passing the liquid throughour department. In the case, it was demonstrated that blooda column ﬁlled with various component particles (e.g. C18
and anion/cation exchange resins) and diameter size, as sta-samples obtained from various sites, including aortic arch,. They can be of wide utility for remark-artery, right pulmonary vein, superior vena cava, inferiorable vast range of analytes. Unlike GC, they can separate
39)
well even thermally unstable and not-volatile substances

vena cava, right iliac vein and right femoral vein, showed

through the separation; relatively simpler sample prepara-amphetamine among them; the highest and lowest values oftion than that in GC is required for LC analysis. However,methamphetamine were 911 and 268 ng/mL, in left heart

matrix eﬀects in instrumental analysis derived from target
sample matrices should be considered in LC analy-

and right femoral vein blood samples, respectively .

tionary phasesis

18,21‒24,52)

right heart ventricle, left heart ventricle, right pulmonary

34,35)

quite diﬀerent concentrations of methamphetamine and3)

In addition, such distribution of substances in a human, which are not remarkable in GC analysis inbody can occur not only prior to death, but also even in
6,53‒60). Regarding post-mortem distribupostmortem period

many cases.
Ultimately, both LC and GC system should be employedtion/redistribution of substances, in addition to the above

for sensitive and reliable analysis in forensic toxicologicalarea; it is also necessary for reliable identiﬁcation of target

factors, the period between the death and analysis for them,natural diﬀusion of the substance according to their concen-

substance(s) in qualitative analysis to be determined bytration , environment around the body, postmortem

multiple diﬀerent instrumental techniques, more than one

changes such as drying and decomposition of the body, and61)

5June 2022

Medical Mass Spectrometry Vol. 6 No. 1

62)even metabolism by microorganisms , can be involved

for interpretations for concerned cases. A number of relatedcases of them may be encountered very frequently in toxi-

and taken into consideration. These factors can make theinterpretation of analytical results very complex and diﬃ-

cological investigations especially in Japan, because allcult in forensic investigations on postmortem distribution/
21‒24); above methamphetredistribution of drugs in the body

psychoactive substances still being prescribed as medicine

amine case was autopsied about a week later his death,thus, of course post mortem time interval could also inﬂu-

the table; practically, the table 3 can be of use in, and deal
with every prescribed-psychoactive drugs related/concerned

ence distribution of targets and its analytical results in sam-cases in Japan.

for medical treatments nowadays in Japan are contained inples examined.

Postmortem distribution/redistribution of substances,

In other words, there is a possibility that the concentra-

however, could be concerned in investigations, as describedtions of target substances in samples collected at autopsy do

before. Therefore, it must be taken into consideration that

not always correctly reﬂect those at the time of poisoning

these data should be used with caution and suﬃcientknowledge about them according to each drug-related

22,61,63‒65)

or death, which should be essential and important

61)

case .

in toxicological investigations. The circumstances in which
concerned substances were exposed/involved and the con-

The listed 88 psychoactive substances are categorized
into 3 groups in Japan, according to pharmacological eﬃ-

ditions until analysis for them are quite diﬀerent in eachcase; no one drug-involved case has the same conditions

cacy and potency of each substance.

and background with those of another case in toxicological

Upon some substances listed in the table, it should beanalysis. Thus, the diﬃculty in evaluating the results ofsuch analysis has been described as a toxicological night-

taken into mind that not only psychoactive substances itself
as, so to speak, prodrugs and also its active metabolites arecontained as regulated substances. For example, cloraze-61)

mare .

pate, diazepam, ketazolam, medazepam, oxazolam andBlood-plasma Concentrations and Pharmacological Information of 88 Psychoactive Substances in Narcotics and Psychotropics Control Act

pinazepam are all precursors (prodrugs) of nordazepam(desmethyldiazepam), followed by producing oxazepam as
metabolite of nordazepam; oxazepam is also metabolite of113)

temazepam, which can be derived from diazepam

In Japan, 88 psychoactive substances including stimu-. Thesesuccessive metabolic series are of qualitative and analyticalimportance in determinations, especially from forensic toxi-lants, analgesics and sedatives are now being regulated andcontrolled strictly on their distributions among market, hos-cological perspective on the listed drugs; clorazepate, diaze-

pitals and laboratories, under Narcotics and Psychotropics

pam, oxazolam, pinazepam, nordazepam, temazepam and66)

Control Act law .
Blood-plasma concentration in therapeutic, toxic andoxazepam are all listed in the table and thus regulated byfatal level reported, half-life time, their supplemental infor-

drug related case where such drug(s) being suspected to bemation and references on the 88 psychoactive substances

involved, both targeted substance and its probable precursor
should be considered to be analyzed for appropriate deter-

Narcotics and Psychotropics Control Act

are listed in Table 3, which were found and collected from67‒69)

previous published literatures, drug label inserts and66). Therefore, inmination of involved drug(s) by analytical investigation.

available related data in our eﬀorts. Because xenobiotic
substances which can be involved in toxicological investi-(NPS) such as cathinone derivatives and synthetic cannabi-gations are of the quite vast number, thus comprehensive
reviewing on them does not seem to be possible in this liter-

noids, so to speak designer drugs and bath salt, are also
being a critical social problem in Japan. In addition to Nar-ature. Practically, it is appropriate and reasonable to refer tocotics and Psychotropics Control Act, blanket or genericscheduling system against them have also been imple-

Recent years, abuse of new psychoactive substance

related published data according to each concerned drug(s)involved, when toxicological investigation would be car-mented containing more than 2000 substances, evenried out in corresponding drug-related cases.
At least, in drug-related cases on above 88 psychoactive

increasing the number of regulated substances, by ministry

substances, listed data on them in the table 3 can be of help

such substances, nowadays.

of health, labour and walfare owing to wide distributions of6

7

ModaﬁnilPhenmetrazine

1-5

1-6

Methaqualone

1-3

Methylphenidate

Mecloqualone

1-2

1-4

Fenethylline

Stimulant

Stimulant

Stimulant

Sedative

Sedative

Stimulant

Type ofeﬃcacy0.02‒0.25

1‒1.7(3)0.01‒0.06

1‒3

n/a

0.04
(Cmax
at therapeutic
dose)

Therapeuticlevels0.5

2.1‒3.8, 13‒18

0.1‒0.5, 1

3‒5

n/a

n/a

Toxic levels

4, 1.1(0.1‒4.9)

n/a

2.3

5‒10

n/a

n/a

Fatal levels〇〇

Available
in Japan・Phenmetrazine is used as appetite suppressant, which could be metabolized from its analog phendimetrazine.
・In therapeutic use, adult oral dose is 25 mg at once, up to 3 times per day.
・A 75 mg administration gave peak plasma concentration averaging 0.14 (0.5‒0.24) μg/mL after 2 h, in
5 adults.

T1/2: 8 h・Modaﬁnil is psychostimulant agent, used for sleep disorders and narcolepsy.
・In therapeutic use, adult oral doses are 200‒400 mg in 1 portion.
・A 100 mg administration gave peak plasma concentration averaging 2.2 μg/mL after 2.1 h, in 12 adults.

T1/2: 10‒15 h, 9‒16 h

・Methylphenidate is phenethylamine derivative, which is used as medicine for depression and narcolepsy.
・In therapeutic use, child oral doses are 8.6‒40 mg, and 20‒100 mg for adult a day.
・Repeated oral administrations of 18 mg gave peak plasma concentration averaging 0.015 μg/mL after
4.5 h, in 48 adults.

T1/2: 1.4‒6.2 h, 2‒7 h・Methaqualone is quinazoline derivatives, having activity to GABA receptors.
・In therapeutic use, adult oral doses are 75‒300 mg as free base, and 200‒400 mg as hydrochloride salt,
in 1 portion.
・A 250 mg oral administration gave peak plasma concentration averaging 2.2 (1.0‒4.0) μg/mL after 2 h,
in 7 adults.

T1/2: 10‒40 h, 20‒60 h・Mecloqualone is methaqualone analog, also having activity to GABA receptors.
・Mecloqualone is ﬁrst synthesized in 1960, and no longer prescribed globally.

T1/2: n/a・Fenethylline is amphetamine analog, which consist of amphetamine structure linked to theophylline.
Thus, as metabolite of fenethylline, amphetamine can be produced in urine and blood.
・In therapeutic use, adult oral doses are 25‒100 mg per day for narcolepsy and depression.
・A 50 mg oral administration gave peak plasma concentration averaging 0.04 μg/mL after 1 h, in adults.

T1/2: 1.3 h

Supplemental information

Blood-plasma concentrations, and supplemental information of 88 psychoactive substances in Narcotics and Psychotropics Control Act in Japan

Name (synonym)

1-1

CategoryNo.

Table 3.

[67, 68][67, 68][72][67, 68][71][67, 68][67, 68]
[70]

[67]

Ref.

June 2022
Medical Mass Spectrometry Vol. 6 No. 1

8

Sedative

Stimulant

Butalbital

Cathine(d-norpseudoephedrine)

2-4

Analgesic

Sedative

2-3

Amobarbital

2-1

Antitussive

Buprenorphine

Zipeprol

1-8

Sedative

Type ofeﬃcacy2-2Secobarbital

Name (synonym)

1-7

No.

Category-around 0.07

1‒50.0005‒0.01

1‒5

0.1‒0.7

1.5‒5

Therapeuticlevelsn/a

10‒15

0.03‒0.1

5‒6, 10‒30

0.3‒1.0

7‒10

Toxic levels

n/a

15‒30

0.008‒0.029
0.0011‒0.029

13‒96, 29‒163

5.8, 10.6, 31

10‒15,
21(5‒52)

Fatal levels

〇

〇

〇

Available
in JapanSupplemental information

・Cathine is one of metabolites of pseudoephedrine, and natural stimulant agent contained in Khat leaves.
・As appetite suppressant agent, adult oral doses are 20‒60 mg per day.
・1 h chewing of Khat leaves containing 32 mg of cathine gave peak plasma concentration after 2.6 h,averaged 0.071 μg/mL, in 4 adults.

T1/2: 3‒8 h・Butalbital belongs to a barbiturate group, which have binding aﬃnity to GABA receptors.
・In therapeutic use, adult oral doses are 30‒100 mg at once, not to exceed 300 mg a day. Butalbital isoften used as combination with analgesic agents such as acetaminophen and aspirin.
・A 50 mg oral administration gave peak plasma concentration averaging 1.3 μg/mL after 0.9 h, in 15
adults.

T1/2: 30‒40 h, 35‒88 h

・In use of transdermal patch, plasma level of buprenorphine can be increased until 72 hours after administration.

・Buprenorphine has aﬃnity to opioid receptors (μ), and act as antagonist for them.
・For injection, 0.2‒0.3 mg doses are used at once; transdermal patches contain 5‒20 mg of them.

T1/2: 3‒5 h (i.v.), 18‒49 h (sublingual or transdermal)

・Amobarbital belongs to a barbiturate group as sedative drugs, which have binding aﬃnity to GABA
receptors.
・In therapeutic use, adult oral doses are 100‒300 mg once before bedtime, for insomnia.
・A 120 mg oral administration gave peak plasma concentration at 1.8 μg/mL after 2 h, in an adult.

T1/2: 8‒40 h, 15‒40 h・Zipeprol is antitussive agent, abuse of which can bring symptoms such as euphoria and hallucinations.
・In therapeutic use, adult oral doses are 150‒350 mg per day.
・A 175 mg oral administration gave peak plasma concentration ranging 0.02‒0.08 μg/mL after 1 h, in 2
adults.

T1/2: 1.2 hmuscular injection are also available.
・A 100 mg oral administration gave peak plasma concentration averaging 1.5 μg/mL after 1 h, in 15
adults.

・Secobarbital belongs to a barbiturate group as sedative drugs, which have binding aﬃnity to GABA
receptors.
・In therapeutic use, adult doses are 8‒250 mg in oral and rectal administration; intravenous and intra-

T1/2: 22‒29 h, 15‒30 h

Table 3. Continued[67, 68][67, 68][77][67, 68][76][67, 68][75][67, 68][74][67, 68]
[73]

Ref.

June 2022
Medical Mass Spectrometry Vol. 6 No. 1

Cyclobarbital

Flunitrazepam

Glutethimide

Pentazocine

Pentobarbital

Allobarbital

2-6

2-7

2-8

2-9

3-1

Name (synonym)

2-5

No.

Category-

9

Sedative

Sedative

Analgesic

Sedative

Sedative

Sedative

Type ofeﬃcacy1‒2, 2‒50.01‒0.2,
0.03‒12‒5
10

10‒19, 5‒10‒30

0.2‒5,
2‒12

1‒10

0.05

10

Toxic levels

0.005‒0.015

2‒6Therapeuticlevels

20‒30

15‒25

3

20‒50, 10‒80

30, 63, 84

20

Fatal levels

〇

〇

〇

〇

Available
in JapanSupplemental information

・Allobarbital is an intermediate acting barbiturate derivative, which act and used as sedative-hypnotic
agent.
・Allobarbital have not been used widely as other barbiturate derivatives so far, without some European
countries.

T1/2: 40‒48 h,・Pentobarbital is a short to middle acting barbiturate derivative, which used as sedative-hypnotic agent.
・In therapeutic use, adult oral doses are 15‒200 mg at once.
・A 100 mg oral administration gave peak serum concentration 1.2‒3.1 μg/mL after 0.5‒2 hours, in adults.

T1/2: 20‒40 h, 15‒48 h・Pentazocine is benzomorphan derivative used as analgesic agent and is also a weak narcotic antagonist.
・30 mg of pentazocine is used at once every 3‒4 h for subcutaneous, intramuscular and intravenous
injection in adults.
・A 45 mg intramuscular administration gave peak plasma concentration averaging 0.14 μg/mL after
15‒60 mins, in 8 post-operative adults.

T1/2: 2 h, 1‒3 h, 5h・Glutethimide is piperidinedione derivative used as sedative, pharmacological actions of which are similar to barbiturate group.
・In therapeutic use, adult oral doses are 250‒500 mg at once.
・A 500 mg oral administration gave mean peak plasma concentration at 4.3 μg/mL after 2.2, in 6 adults.

T1/2: 5‒22 h

・Flunitrazepam is one of aminobenzodiazepine derivatives, which is used for treatment of insomnia andanesthesia.
・In therapeutic use, adult oral or injection doses are 1‒2 mg at once, for insomnia or pretreatment ofanesthesia.
・A 2 mg oral administration gave peak plasma concentration averaging 0.008 μg/mL after 2 h, in 7 adults.
・In investigations, metabolite 7-aminoﬂunitrazepam can be detected as predominant target, as substituteof ﬂunitrazepam.

T1/2: 10‒20 h, 9‒25 h・Cyclobarbital belongs to a barbiturate group, which have binding aﬃnity to GABA receptors.
・In Russia, cyclobarbital was distributed as combination with other drugs (10 mg diazepam and 100 mg
cyclobarbital); now, not available.
・Cyclobarbital was frequently used in suicidal cases, and thus withdrawn at 1973 in Japan.

T1/2: 8‒17 h

Table 3. Continued

[68]
[81]

[67‒69][80][67‒69][79][67‒69][67, 68]
[78]

[68]

Ref.

June 2022
Medical Mass Spectrometry Vol. 6 No. 1

10

Stimulant

Benzphetamine(benzfetamine)

Bromazepam

3-6

3-7

Sedative

Sedative

Stimulant

Aminorex(aminoxaphen)

3-4

Barbital

Stimulant

Amfepramone(diethylpropion)

3-3

3-5

Sedative

Type ofeﬃcacyAlprazolam

Name (synonym)

3-2

No.

Category-

0.05‒0.2

0.025‒0.5

2‒20

n/a

0.007‒0.02

0.005‒0.05,
0.025‒0.1

Therapeuticlevels0.3‒0.4

0.5

20‒50, 60‒80n/a2

0.1‒0.4

Toxic levels

1‒2, 0.8‒5.0

1450, 90n/a(at least 34
fatalities
reported)

5.4

0.1‒2.1

Fatal levels

〇

〇

〇

Available
in JapanSupplemental information

・Bromazepam is benzodiazepine derivative having binding aﬃnity to GABA receptors, and acts as agonist.
・In therapeutic use, adult oral doses are 6‒30 mg in 2 portions a day.
・A 6 mg oral administration gave peak plasma concentration averaging 0.088 μg/mL after 1.5 h, in adults.

T1/2: 20 h・Benzphetamine is used as appetite suppressant agent. Methamphetamine is one of metabolites of benzphetamine.
・In treatment for obesity, adult oral doses are 25‒50 mg, in 1‒3 portions a day.

T1/2: n/a・Barbital is long used sedative-hypnotic agent. It was withdrawn in United States, but is still available inJapan.
・In treatment for insomnia, adult oral doses are 30‒200 mg at once before bedtime.
・A 1500 mg oral administration gave peak serum concentration averaging 26 μg/mL after 12 h, in 4 adults.

T1/2: 2 days

・Aminorex is an oxazoline derivative used as appetite suppressant agent, ﬁrstly used at 1965.
・After used as appetite suppressant, it was withdrawn in 1972 because primary pulmonary hypertension
and cardiovascular disorder were observed in users. However, it could be contained in illegal products.

T1/2: 1‒3 h (intravenous in animal)

・Amfepramone is phenethylamine derivative used as appetite suppressant agent. It is widely known as
diethylpropion than as amfepramone.
・As appetite suppressant, adult oral doses are 75 mg per day.
・A 25 mg oral administration gave peak plasma concentration averaging 0.01 μg/mL after 2 h in 6
adults.

T1/2: 2 h・Alprazolam is triazolobenzodiazepine derivatives, which is used as short acting antidepressant andanxiolytic agent.
・In therapeutic use, adult oral doses are 0.25‒2 mg at once, not exceeding to 6 mg, a day.
・A 1 mg oral administration gave peak plasma concentration averaging 0.019 μg/mL after 1.3 hours, in 6
adults.

T1/2: 6‒27h

Table 3. Continued[67, 68][86][67, 68][85][67, 68]

[67]
[84]

[67, 68][83][67‒69]
[81]
[82]

Ref.

June 2022
Medical Mass Spectrometry Vol. 6 No. 1

11

Chlordiazepoxide

Clobazam

Clonazepam

Clonazolam

3-12

3-13

3-14

Camazepam

3-10

3-11

Sedative

Butobarbital(butethal)

3-9

0.02‒0.07

Sedative,
Anticonvulsant

n/a0.03‒0.3

Sedative,
Anticonvulsant

Sedative0.4‒3

0.1‒0.6

2.9‒4.1

0.001‒0.02

TherapeuticlevelsSedative

Sedative

Sedative

Type ofeﬃcacyBrotizolam

Name (synonym)

3-8

No.

Category-

n/a

0.1

0.5

3.5‒15, 20

2

118

0.02

Toxic levels

〇

〇

1.5
(with diazepam
1.1),
3.9

median 0.3(with multiple
drug overdoses,
in 51 persons)

n/a

〇

〇

Available
in Japan20, 26n/a

166

0.01‒0.03

Fatal levels
Supplemental information

・Clonazolam is triazolo benzodiazepine analog, which was detected as designer benzodiazepine, andbeing sold through internet.
・Clonazolam was ﬁrst reported in 1971 to be highly potent as sedative agent, which can lead to abuseeasily.

T1/2: n/a・Clonazepam is one of benzodiazepine derivatives. As other benzodiazepines, it is used as sedative andanti-convulsant agent.
・In therapeutic use, adult oral doses are 2‒6 mg, in 1‒3 portions a day.
・A 2 mg oral administration gave peak plasma concentration averaging 0.011 μg/mL after 3.1 h, in 12
adults.

T1/2: 19‒60 h・Clobazam belongs to benzodiazepine derivatives, thus act as agonist for GABA receptors.
・In therapeutic use, adult oral doses are 10 mg at once, up to 30 mg a day.
・A 10 mg oral administration gave peak plasma concentration averaging 0.173 μg/mL after 1.4 h, in 14
adults.

T1/2: 10‒50 h・Chlordiazepoxide can produce other benzodiazepines, as their prodrug. As metabolites, nordiazepam
and oxazepam would be produced in vivo.
・In therapeutic use, adult oral or intermuscular doses are 5‒100 mg, not to exceed 300 mg a day.
・A 30 mg oral administration gave peak plasma concentration averaging 1.6 μg/mL after 4 h, in 2 adults.

T1/2: 6‒27 h・Camazepam is benzodiazepine derivative, and is metabolized to temazepam as its prodrug in vivo.
・In therapeutic use, adult oral doses are 15‒30 mg at once a day.
・A 20 mg oral administration gave peak plasma concentration 0.06 μg/mL after 7 h, in adult.

T1/2: 20‒24 h, 6‒10 h (i.v. in animal)

・Butobarbital (butethal) is barbiturate derivative used as sedative-hypnotic agent. It was withdrawn inUnited States, but is still available in Europe.
・In therapeutic use, adult oral doses are 50‒200 mg at once for insomnia.
・A 200 mg oral administration gave peak serum concentration 2.9‒4.1 μg/mL after 0.6‒2 h, in 5 adults.

T1/2: 34‒42 h・Brotizolam is triazolobenzodiazepine derivative having binding aﬃnity to GABA receptors, and acts asagonist.
・In therapeutic use, adult oral doses are 0.25‒0.5 mg at once before bed time.
・A 0.25 mg oral administration gave peak plasma concentration averaging 0.0049 μg/mL after 0.9 h, in
8 adults.

T1/2: 7 h, 3.6‒7.9 h

Table 3. Continued[91][67, 68][81][90][67, 68][89][67‒69][88][67, 68][67][67, 68]
[87]

Ref.

June 2022
Medical Mass Spectrometry Vol. 6 No. 1

12

0.1‒2.5

Sedative

Diazepam

Diclazepam(Chlorodiazepam)

Estazolam

3-20

3-21

Sedative

Sedative,anti-convulsant

0.055‒0.2

n/asee
cloxazolam

seecloxazolam

Sedative

1, 1.25

n/a

3‒5

n/a

0.016
(4 mg for 24
persons)

Sedative

3-19

Cloxazolam

3-17

1.5‒2
(as
nordiazepam)

0.02‒0.8(asnordiazepam)

n/a

Toxic levels

Therapeuticlevels0.1‒0.7

Sedative

Delorazepam

Clotiazepam

3-16

Sedative

Type ofeﬃcacy3-18

Clorazepate(Clorazepric acid)

Name (synonym)

3-15

No.

Category-

0.48

n/a

4.8‒30see cloxazolam

n/a

n/a

5.5‒15(asnordiazepam)

Fatal levels

〇

〇

〇

〇

〇

Available
in JapanSupplemental information

・Estazolam is benzodiazepine derivative, which have aﬃnity to GABA receptor as its agonist.
・In therapeutic use, adult oral doses are 1‒4 mg at once before bedtime.
・A 1 mg oral administration gave peak plasma concentration averaging 0.055 μg/mL within 2 h, in 17
adults.

T1/2: 10‒24 h, 10‒30 h・Diclazepam is benzodiazepine derivative, which has not been used as prescription medicine. In animalmodels, pharmacological eﬀect like other benzodiazepines were observed.
・Self-administration study of 1 mg diclazepam gave peak plasma concentration averaging 0.0034 μg/mL
after 3 hours in an adult.

T1/2: 42 h・Diazepam is benzodiazepine derivative, which used as sedative-hypnotic and anticonvulsant agent by
oral, intramuscular and intravenous administration.
・In therapeutic use, adult oral doses are 2‒5 mg at once, in 2‒4 times. For intravenous or intramuscular
injection, 10 mg would be administrated at once.
・A 5 mg oral administration gave peak plasma concentration averaging 0.179 μg/mL after 0.5 h, in 6
adults.

T1/2: 21‒37 h, 24‒48 h

Delorazepam is predominant metabolite of cloxazolam.

・Cloxazolam is prodrug for delorazepam; they have aﬃnity to GABA receptors, which used as sedative-hypnotic agent.
・In therapeutic use, adult oral doses are 3‒12 mg, in 3 portions a day.
・A 2 mg oral administration gave peak plasma concentration averaging 0.0074 μg/mL after 2.8 h, in 7
adults.

T1/2: 50‒200 h (as delorazepam), 2‒4 h (animal)・Clotiazepam is benzodiazepine derivative, which used as sedative-hypnotic agent.
・In therapeutic use, adult oral doses are 15‒30 mg, in 1‒3 portions a day.
・A 5 mg oral administration gave peak plasma concentration averaging 0.179 μg/mL after 0.5 h, in 6 adults.

T1/2: 3‒12 h・Clorazepate is prodrug for nordiazepam and oxazepam.
・In therapeutic use, adult oral doses are 9‒30 mg, in 2‒4 portions a day.
・A 15 mg oral administration gave peak plasma concentration averaging 0.16 μg/mL after 2 h, in 2 adults.

T1/2: 1‒2 h

Table 3. Continued[67, 68]
[97]

[96]

[67, 68]
[95]

[67]

[67]
[94]

[67, 68][93][67, 68]
[92]

Ref.

June 2022
Medical Mass Spectrometry Vol. 6 No. 1

Etizolam

Fencamfamine

Fenproporex

3-26

3-27

3-28

Ethyl loﬂazepate

3-24

3-25

Ethinamate

3-23

Ethyl amphetamine(Etilamfetamine)

Ethchlorvynol

Name (synonym)

3-22

No.

Category-

13

Stimulant

Stimulant

Sedative

Stimulant

Sedative

Sedative

Sedative

Type ofeﬃcacyn/adose case)0.03 (probably therapeutic level,
found in fatal
multiple over-0.008‒0.02

n/a

n/a

1.5‒100.5‒8Therapeuticlevels

n/a

n/a

0.03

0.5
(with 0.221
amphetamine)n/a50‒10020

Toxic levels

tyrate)0.9(in a suicide
case by gamma-hydroxybu-

n/a

n/a

n/a

200

50

Fatal levels〇〇

Available
in JapanSupplemental information

・Fenproporex is a phenethylamine analog, used as appetite suppressant in some countries.
・In therapeutic use, adult oral doses are 10‒20 mg a day.

T1/2: 2 h・Fencamfamine is an amphetamine analog, used as appetite suppressant and psychostimulant.
・In therapeutic use, adult oral doses are 10‒60 mg a day.

T1/2: 12‒16 h・Etizolam is benzodiazepine derivative, having aﬃnity to GABA receptor. Its prolonged use can lead todependency easily.
・In therapeutic use, adult oral dose is 3 mg, in 3 portions a day.
・A 0.5 mg oral administration gave peak plasma concentration averaging 0.008 μg/mL after 0.9 h, in 6
adults.

T1/2: 7‒15 h・Ethyl amphetamine is an amphetamine analog, used as appetite suppressant.
・In therapeutic use, adult oral doses are 10‒30 mg a day.

T1/2: n/a・Ethyl loﬂazepate is benzodiazepine derivative. They have aﬃnity to GABA receptors as its agonist,showing anxiolytic, sedative and muscle relaxant properties.
・In therapeutic use, adult oral dose is 2 mg, in 1‒2 portions a day.
・A 2 mg oral administration gave peak plasma concentration averaging 0.034 μg/mL after 2.1 h, in 4 adults.

T1/2: 51‒103 h (loﬂazepate)・Ethinamate is carbamate derivative. It is used for treatment of insomnia.
・In therapeutic use, adult oral doses are 500‒1000 mg before bedtime.
・A 1000 mg oral administration gave peak plasma concentration averaging 5.9 μg/mL after 1 h, in 8 adults.

T1/2: 2 h, 1‒3 h・Ethchlorvynol have aﬃnity to GABA receptors, acting as its agonist. It is used as sedative and hypnotic
agent.
・In therapeutic use, adult oral doses are 100‒500 mg at once, up to 1000 mg.
・A 200 mg oral administration gave peak plasma concentration averaging 1.2 μg/mL after 1 h, in 6 adults.

T1/2: 10‒25 h, 19‒32 h

Table 3. Continued

[67]

[67]

[67, 68]
[99]

[67]

[67]
[98]

[67, 68][67, 68]

Ref.

June 2022
Medical Mass Spectrometry Vol. 6 No. 1

14Halazepam

Haloxazolam

3-33

3-34

Fludiazepam

3-31

Flurazepam

Flubromazolam

3-30

3-32

Flualprazolam

Name (synonym)

3-29

No.

Category-

Sedative

Sedative

Sedative

Sedative

Sedative

Sedative

Type ofeﬃcacyn/a0.03‒0.1

0.02‒01

n/a

n/a

n/a

Therapeuticlevelsn/asee
nordazepam

see
nordazepam

n/a

0.5‒5.5, 0.8‒24

n/a

n/a

n/a

Fatal levels

0.2‒0.5

n/a

n/a

n/a

Toxic levels

〇

〇

〇

Available
in JapanSupplemental information

・Haloxazolam is benzodiazepine derivative, having aﬃnity to GABA receptor; its pharmacologicalpotency is similar to nitrazepam. They are used for treatment of insomnia.
・In therapeutic use, adult oral dose is 5‒10 mg at once, before bedtime.
・In oral administration for animals, peak organ concentrations were observed after 1 hour. Almost no
haloxazolam could not be detected 24‒72 h after administration.

T1/2: n/a・Halazepam is benzodiazepine derivative. After administration, they are metabolized to active metabolite, nordazepam.

T1/2: 30‒40 h・Flurazepam is benzodiazepine derivative, used for preoperative sedation and treatment of insomnia.
・In therapeutic use, adult oral doses are 10‒30 mg, in 1‒2 portions prior to bedtime.
・A 30 mg oral administration gave peak plasma concentration averaging 0.002 μg/mL after 1 h, in 9
adults. After administration, ﬂurazepam is metabolized to active metabolite desalkylﬂurazepam inshort interval.

T1/2: 1‒3 h, 2.3‒12 h・Fludiazepam is benzodiazepine derivative, having aﬃnity to GABA receptor and acting as agonist. Its
use can lead to dependency.
・In therapeutic use, adult oral dose is 0.75 mg, in 3 portion a day.
・A 0.25 mg oral administration gave peak plasma concentration averaging 0.0058 μg/mL after 1 h, in
adults.

T1/2: 23 h・Flubromazolam is triazolo benzodiazepine analog, which was detected as designer benzodiazepine, andbeing sold through internet.
・Flubromazolam was estimated to have higher potency than that of its analog ﬂubromazepam, although
no detailed data on ﬂubromazolam is available.

T1/2: n/a・Flualprazolam is one of benzodiazepine derivative which was synthesized as late as 1970s, although
was never marketed throughout the world. In 2018, however, ﬂualprazolam was found in drug abusecase in Sweden.

T1/2: n/a

Table 3. Continued

[103]

[68]

[67]
[102]

[101]

[91]

[100]

Ref.

June 2022
Medical Mass Spectrometry Vol. 6 No. 1

15MazindolMedazepam

3-41

3-38

3-40

Lorazepam

3-37

Lormetazepam

Loprazolam

3-36

3-39

Analgesic

Lefetamine(Lephetamine)

Sedative

0.1‒1

n/a

Stimulant,
Appetite-suppressant

Sedative0.02‒0.25

0.003‒0.01

n/a

0.001‒0.02

Therapeuticlevels

0.002‒0.025

Sedative

Sedative

Sedative

Type ofeﬃcacyKetazolam

Name (synonym)

3-35

No.

Category-

0.6

n/a

0.1

0.3‒0.5

n/a

n/a

n/a

Toxic levels

n/a

n/a

n/a

0.52, 2.8

n/a

n/a

n/a

Fatal levels

〇

〇

〇

〇

Available
in JapanSupplemental information

・Medazepam is benzodiazepine derivative. Diazepam, temazepam and oxazepam are produced in metabolism of medazepam.
・In therapeutic use, adult oral doses are 10‒30 mg a day.
・A 20 mg oral administration gave peak plasma concentration averaging 0.52 μg/mL after 1 h, in 9 adults.

T1/2: 1‒2 h, 2‒5 h・Mazindol is amphetamine analog. As monoamine retake inhibitors, it is used for treatment of obesity
as appetite suppressant.
・In therapeutic use, adult oral doses are 0.5 mg in 1 portion a day.
・A 2 mg oral administration gave peak plasma concentration averaging 0.0025 μg/mL after 2 h, in 2 adults.

T1/2: 6‒16 h・Lormetazepam is benzodiazepine derivative, having aﬃnity to GABA receptor. Lormetazepam is used
for treatment of insomnia.
・In therapeutic use, adult oral dose is 1‒2 mg at once before bedtime. Potency of lormetazepam wasstronger than that of diazepam in animals.
・A 1 mg oral administration gave peak plasma concentration averaging 0.0056‒0.0070 μg/mL after2‒2.2 h, in 6 adults.

T1/2: 7‒17 h, 10‒45 h・Lorazepam is benzodiazepine derivative, having aﬃnity to GABA receptor. Lorazepam is used fortreatment of depression and anxiety.
・In therapeutic use, adult oral dose is 1‒3 mg, in 2‒3 portions a day.
・A 2 mg oral administration gave peak plasma concentration averaging 0.018 μg/mL after 2 h, in 8 adults.

T1/2: 9‒16 h, 10‒40 h・Loprazolam is benzodiazepine derivative, having aﬃnity to GABA receptor.
・In therapeutic use, adult oral dose is 1‒2 mg for insomnia.
・A 1 mg oral administration gave peak plasma concentration averaging 0.004 μg/mL after 2 h, in elderly.

T1/2: 5 h・Lefetamine is opioid analgesic and antitussive agent, being developed by Santen pharmaceuticals inJapan in 1940s, as Santenol . They were abused in Japan in 1950s.

T1/2: n/a

・Ketazolam is benzodiazepine derivative, having aﬃnity to GABA receptor. As metabolite, diazepam
can be produced from ketazolam in vivo.

T1/2: 1‒3 h

Table 3. Continued

[67]
[109]

[67]
[108]

[67, 68][107][67, 68]
[106]

[68]
[105]

[104]

[68]

Ref.

June 2022
Medical Mass Spectrometry Vol. 6 No. 1

16

Methyprylon(e)Midazolam

3-46

3-47

Mesocarb

3-44

Methylphenobarbital(mephobarbital)

Meprobamate

3-43

3-45

Mefenorex

Name (synonym)

3-42

No.

Category-

Sedative

Sedative

Sedative

Stimulant

Sedative

suppressantStimulant,
Appetite-Type ofeﬃcacy0.04‒0.25

10‒20

0.5‒1.5

n/a

5‒10

n/a

Therapeuticlevels

1‒1.5

25‒75

40‒

n/a

10‒25

n/a

Toxic levels

0.05‒2.4

50‒100

n/a

30

n/a

Fatal levels〇

Available
in JapanSupplemental information

・Midazolam is benzodiazepine derivative used for pre-operative sedation by intravenous or intramuscular administration. As GABA agonist, they produce muscle relaxant, sedative and hypnotic eﬀects.
・In preanesthetic use, 0.03 mg/kg dose is administrated intravenously over 1 minute, not exceeding to
0.3 mg/kg.
・A 7.5 mg intramuscular administration gave peak plasma concentration averaging 0.09 μg/mL after 0.5
h, in adults.

T1/2: 1.5‒6.4 h

・Methyprylon is piperidinedione derivatives, used for treatment of insomnia. Its use can lead to dependency.
・After being withdrawn from major markets, methyprylon is not used commonly nowadays.

T1/2: 3‒6 h, 9‒11 h

・Methylphenobarbital, also known as mephobarbital, belongs to a barbiturate group. Phenobarbital is
produced as metabolite of methylphenobarbital.
・In therapeutic use, adult oral maintenance doses are 200‒600 mg a day.
・A 800 mg oral administration gave peak plasma concentration averaging 2.5‒3.5 μg/mL after 2‒8 h, in
2 adults.

T1/2: 48‒52 h・Mesocarb is phenethylamine analog. It is used for treatment of attention-deﬁcit/hyperactivity disorder(ADHD) as stimulant.
・In therapeutic use, adult oral doses are 5‒10 mg once a day.
・A 10 mg oral administration gave peak plasma concentration averaging 0.065 μg/mL after 1.6 h, in 4
adults.

T1/2: 2‒4 h・Meprobamate is carbamate derivative, intended to be used as tranquilizer. Meprobamate is produced as
metabolite of carisoprodol (muscle relaxant); meprobamate can be biomarker of exposure to carisoprodol.
・In therapeutic use, adult oral doses are 200‒600 mg at once, for 3‒4 times a day.
・A 800 mg oral administration gave peak plasma concentration averaging 12‒19 μg/mL after 2 h, in 6
adults.

T1/2: 6‒17 h・Mefenorex is amphetamine analog; amphetamine is produced as metabolite of mefenorex.
・It is used as appetite suppressant.
・In therapeutic use, adult oral doses are 40‒80 mg in 1 portion a day.

T1/2: 2.5‒4 h (excretion in urine)

Table 3. Continued[67, 68]
[111]

[68]

[67, 68]

[67]
[110]

[67, 68]

[67]

Ref.

June 2022
Medical Mass Spectrometry Vol. 6 No. 1

17

OxazepamOxazolam

Pemoline

Phenazepam

3-52

3-53

3-54

Sedative

Stimulant

Sedative

Sedative

Sedative

Nordazepam(nordiazepam,
desmethyldiazepam)

3-50

3-51

Sedative

Nitrazepam

3-49

Sedative

Type ofeﬃcacyNimetazepam

Name (synonym)

3-48

No.

Category-

0.02‒0.04

5

0.386(with morphineand codeine),
0.97‒1.64

0.208‒0.632(average),
0.04‒3.2(range)see nordazepam

3‒5, 4.4‒6.1

5.5‒155, 1.2‒9n/aFatal levels

n/a

see
nordazepam

see
nordazepam

1‒7

2

1.5‒2

0.2‒3

n/a

Toxic levels

0.2‒1.5

0.02‒0.8

0.03‒0.1

n/aTherapeuticlevels〇〇〇Available
in JapanSupplemental information

・Phenazepam is benzodiazepine derivative, developed in Russia. It is use for treatment of anxiety.
・In therapeutic use, adult oral dose is 0.5 mg for 2‒3 times a day.
・A 3‒5 mg oral administration gave peak plasma concentration 0.024‒0.038 μg/mL after 4 h, in 2 adults.

T1/2: 60 h, 40‒300 h

・Pemoline is used for treatment of depression and sleep disorder, as dopamine retake inhibitor.
・In therapeutic use, adult oral doses are 10‒30 mg once a day for depression, 20‒200 mg in 2 portions a
day for sleep disorder.
・A 37.5‒50 mg oral administration gave peak plasma concentration averaging 0.98 μg/mL after 2.7 h, in
4 adults.

T1/2: 7‒13 h・Oxazolam is one of prodrugs of nordazepam, which is active metabolite of oxazolam.

・Oxazepam is benzodiazepine derivative as an active metabolite of clorazepate and nordazepam; temazepam and diazepam are also prodrug of oxazepam.
・In therapeutic use, adult oral doses are 30‒60 mg in 3‒4 portions a day.
・A 15 mg oral administration gave peak serum concentration averaging 0.31 μg/mL after 1.5 h, in 7 adults.

T1/2: 4‒16 h, 6‒20 h・Nordazepam is one of major metabolites of clorazepate, oxazolam, pinazepam and of diazepam;
ketazolam and medazepam can also produce nordazepam. Oxazepam is produced as an active metabolite of nordazepam.
・In therapeutic use, adult oral doses are 7.5‒15 mg in one or more portions a day.
・A 5‒10 mg oral administration gave peak plasma concentration ranging 0.118‒0.228 μg/mL after 2 h,
in 8 adults.

T1/2: 40‒80 h, 31‒97 h・Nitrazepam is benzodiazepine derivative. It is use as anticonvulsant agent, and for treatment of insomnia.
・In therapeutic use for insomnia, adult oral doses are 5‒10 mg once before bedtime.
・A 10 mg oral administration gave peak plasma concentration averaging 0.084 μg/mL after 2 h, in adults.

T1/2: 20‒30 h, 17‒48 h・Nimetazepam is benzodiazepine derivative. It is potent muscle relaxant, sedative and hypnotic agent,and can lead to dependency easily. Although nimetazepam was manufactured only in Japan until 2015,
it is withdrawn from the market nowadays.
・In therapeutic use, adult oral doses are 3‒5 mg once before bedtime.
・A 5 mg oral administration gave peak plasma concentration averaging 0.013 μg/mL after 2‒4 h, in adults.

T1/2: 10‒30 h

Table 3. Continued[67, 68][67, 68]
[115]

[114]

[67]

[67, 68]
[113]

[68]
[112]

[67]

Ref.

June 2022
Medical Mass Spectrometry Vol. 6 No. 1

18

Pipradrol

Prazepam

Propylhexedrine

3-59

3-60

3-61

Phentermine

3-57

Pinazepam

Phenobarbital

3-56

3-58

Phendimetrazine

Name (synonym)

3-55

No.

Category-

Stimulant

0.01

0.2‒0.7

n/aStimulant,
Appetitesuppressant

Sedativesee
nordazepam

0.03‒0.1

Stimulant,
Appetitesuppressant

Sedative

10‒30

0.02‒0.1

TherapeuticlevelsSedative

Stimulant

Type ofeﬃcacy

0.5

1

n/a

see
nordazepam

0.9

30‒40

n/a

Toxic levels

2‒3

0.8‒5

n/a

see nordazepam

1

50‒60

0.3‒0.7

Fatal levels〇

Available
in JapanSupplemental information

・Propylhexedrine is methamphetamine analog. It is used as appetite suppressant, and nasal decongestantagent for rhinitis.
・In therapeutic use, adult inhalation dose is 0.25 mg/inhalation.

T1/2: n/a・Prazepam is benzodiazepine derivative; nordazepam is its predominant active metabolite. Prazepam
has been withdrawn in Japan.
・In therapeutic use, adult oral dose is 20‒60 mg a day.
・After administration, almost all prazepam is estimated to be metabolized to nordazepam.

T1/2: 1‒3 h・Pipradrol is piperidine analog stimulant which used for treatment of attention-deﬁcit/hyperactivity
disorder (ADHD), and obesity. Pipradrol was withdrawn in Japan, but is still used in some countries
nowadays.

T1/2: n/a・Pinazepam is metabolized to nordazepam (desmethyldiazepam), as its prodrugs.

T1/2: 12‒20 h・Phentermine is amphetamine analog. It is used as appetite suppressant for treatment of obesity.
・In therapeutic use, adult oral doses are 15‒30 mg a day.
・A 0.375 mg/kg oral administration gave peak blood concentration averaging 0.09 μg/mL after 4 h, in 6
adults.

T1/2: 19‒24h

・Phenobarbital is a barbiturate derivative, which is used as sedative and anticonvulsant agent by oral or
intramuscular/subcutaneous administration.
・In therapeutic use, adult oral doses are 30‒200 mg in 1‒4 portions a day as anticonvulsant. For intramuscular or subcutaneous injection, 50‒200 mg of doses are administrated in 1‒2 portions a day.
・A 120 mg (powder) oral administration gave peak blood concentration averaging 4.6 μg/mL after 2.4 h,
in 5 adults.

T1/2: 48‒144 h・Phendimetrazine is phenethylamine analog. It is used as appetite suppressant.
・In therapeutic use, adult oral doses are 70‒210 mg a day.
・A 35 mg oral administration gave peak serum concentration averaging 0.09 μg/mL after 1 h, in 5 adults.

T1/2: 2‒4 h, 16‒31 h

Table 3. Continued[67, 68][67, 68][67][67, 68][67, 68]
[116]

[67]
[69]

Ref.

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Medical Mass Spectrometry Vol. 6 No. 1

19

Temazepam

Tetrazepam

3-66

3-67

Remimazolam

3-64

Secbutabarbital(butabarbital)

Quazepam

3-63

3-65

Pyrovalerone

Name (synonym)

3-62

No.

Category-

0.02‒0.9

0.05‒1

Sedative,musclerelaxant

5‒15

n/a

0.01‒0.15

TherapeuticlevelsSedative

Sedative

Sedative

Sedative

Stimulant

Type ofeﬃcacy1

20

n/a

Toxic levels

8.2, 1430

n/a0.042 and 0.059(femoral veinand heart blood)

Fatal levels〇

Available
in JapanSupplemental information

・Tetrazepam is benzodiazepine derivative, used for muscle relaxant, anxiolytic and anticonvulsant
agent.
・In therapeutic use, adult oral doses are 50 mg for 1‒2 times a day.
・A 50 mg oral administration gave peak serum concentration averaging 0.512‒0.558 μg/mL after 2 h, in
12 adults.

T1/2: 16‒44 h・Temazepam is active metabolite of diazepam, and temazepam also produce oxazepam as metabolite.
・In therapeutic use, adult oral doses are 15‒30 mg before bedtime.
・A 20 mg oral administration gave peak blood concentration averaging 0.363‒0.856 μg/mL after
0.25‒1.25 h, in 6 adults.

T1/2: 3‒13 h, 6‒25 h・Secbutabarbital is a barbiturate derivative, which is used as sedative and hypnotic agent.
・In therapeutic use, adult oral doses are 15‒30 mg for 3‒4 times a day for sedation.
・A 600 mg (unusual large amount) oral administration gave peak blood concentration averaging 12 μg/
mL after 0.5 h, in 5 adults.

T1/2: 34‒42h

thesia 1 mg/kg/h dose should be used.
・A 0.5 mg/kg/1 min intravenous administration gave peak plasma concentration 7.0 μg/mL just afteradministration, in 5 adults.

・Remimazolam is very-short acting benzodiazepine derivative, which can lead to dependency easily.
Remimazolam was approved as medicine around 2020, and being used for introducing anesthesia andpreoperative sedation.
・For introducing anesthesia, 12 mg/kg/h dose is used by intravenous administration; for maintaing anes-

T1/2: 0.6‒0.9 h・Quazepam is benzodiazepine derivative, having aﬃnity to GABA receptors. It is used for treatment of
insomnia and for preoperative sedation.
・In therapeutic use, adult oral dose is 20 mg before bed time, not exceeding to 30 mg.
・A 25 mg oral administration gave peak plasma concentration 0.148 μg/mL after 1.5 h, in 6 adults.

T1/2: 39‒53 h・Pyrovalerone is synthetic cathinone, used as appetite suppressant. In 2010s, its various analogs havebeen abused as bath salt .
・In therapeutic use, adult oral doses are 20‒40 mg once.
・Pharmacodynamic data of pyrovalerone in human has not been reported,

T1/2: 1.5 h (rat)Table 3. Continued[67, 68]

[68]
[113]

[67, 68]

[118]

[67]
[81]
[117]

[67]

Ref.

June 2022
Medical Mass Spectrometry Vol. 6 No. 1

Zolpidem

3-70

20

Sedative

Sedative

Sedative

Sedative

Type ofeﬃcacy0.01‒0.05

0.08‒0.2

1‒3

0.002‒0.02

Therapeuticlevels

0.15

0.5

5

0.04

Toxic levels

0.6‒1.8

2‒4, 9.6(intravenous
injection case)

80.022‒0.078

Fatal levels

〇

〇

〇

Available
in JapanSupplemental information

・Zopiclone is cyclopyrrolone derivative, used as short-time acting hypnotic agent. Zopiclone is known
as one of Z-drugs with zolpidem; their pharmacological properties are similar to that of benzodiazepines, though structures are quite diﬀerent.
・In therapeutic use, adult oral doses are 7.5‒10 mg before bed time.
・A 5 mg oral administration gave peak blood concentration averaging 0.029 μg/mL after 1‒2 h, in 8
adults.

T1/2: 3.5‒8 h・Zolpidem is imidazopyridine derivative, have diﬀerent structure from that of benzodiazepine derivatives. Zolpidem is used as short-time acting hypnotic agent.
・In therapeutic use, adult oral doses are 5‒10 mg before bed time.
・A 3.5 mg oral administration gave peak serum concentration averaging 0.032 μg/mL after 3 h, in 33
adults.

T1/2: 2‒3 h・Vinylbital is a barbiturate derivative, which is used as sedative and hypnotic agent. Its pharmacologicalproﬁle is said to be similar to pentobarbital.

T1/2: 18‒33 h

・Triazolam is wide used benzodiazepine derivative tranquilizer, being well known as halcion . Triazolam is frequently abused in drug facilitated crimes
・In therapeutic use, adult oral doses are 0.125‒0.25 mg a day.
・A 0.25 mg oral administration gave peak serum concentration averaging 0.003 μg/mL after 0.75‒1.5 h,
in 6 adults.

T1/2: 1.8‒3.9 h, 2‒5 h

Table 3. Continued

Cmax: maximum serum/plasma concentration, T1/2: biological half life time, GABA: γ - Aminobutyric acid, n/a: not available

Zopiclone

Vinylbital

3-69

3-71

Triazolam

Name (synonym)

3-68

No.

Category-[67, 68][122][67, 68]
[121]

[68]

[67, 68]
[119]
[120]

Ref.

June 2022
Medical Mass Spectrometry Vol. 6 No. 1

June 2022

Medical Mass Spectrometry Vol. 6 No. 1

Toxicological Analysis on Forensic Investigations in Determining Cause of Deathpared and, if needed, investigated again later. These details
on toxicological analysis can bring about chain of cus-

As mentioned before, the distribution/concentration of

tody of the whole investigations.

substances may be changed dynamically due to condition

Acknowledgmentsof forensic samples, where various factors can vary
6,65,123,124)

widely. Therefore, in drug related cases, it can beoften diﬃcult for examiners to determine the degree of con-This work was supported by research grant from Japan
Society for the Promotion of Science KAKENHI Grant-in-

tribution of concerned substances to the manner of death,

Aid for Scientiﬁc Research(C), Grant Number 21K10519.

by comparing the lethal and poisoning levels of the drugs insamples with those reported in previous literature or data-

Conﬂict of Interest
There are no ﬁnancial or other relations that could lead tobases, and the administrated amount of the compounds
61)

prior to the death ; regarding some drugs, there may be noa conﬂict of interest.

data to refer to. In such cases, it is necessary to evaluate theEthical Approval

pharmacological eﬀects of drugs and the cause of death,

This article does not contain any studies with humanalong with considering autopsy ﬁndings and other test
results, which are also quite important information in foren-

participants or animals performed by any of the authors.

sic examinations and judgement of cause of the death.
When investigating the cause of death in drug related cases,

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