Preclinical Abuse Liability Evaluation in Drug Control

Preclinical Abuse Liability 

Evaluation in Drug Control 

Srihari R. Tella, Ph.D. 

Pharmacologist 

Drug and Chemical Evaluation Section 

Office of Diversion Control 

Drug Enforcement Administration, Washington DC 

Tel: 202-307-7183; Fax: 202-353-1263 

email: Srihari.R.Tella@usdoj.gov

Drug and Chemical 

Evaluation Section (ODE) 

Drug Scheduling (Domestic and 

International) 

Quotas for Schedule I and II Substances 

Exempt Products 

Review Schedule I Researcher license 

applications 

United Nations Treaty Activities

Designer Drugs 

Background 

Applicable current laws 

Recently controlled drugs 

Currently encountered drugs 

Data used

Designer Drugs - 

Background 

Popular name for Controlled Substance 

Analogs 

Origin – Clandestine laboratories 

“Drug Culture” in early 1960s was led by 

LSD made in Clandestine laboratories. 

Mescaline analogs (“alphabet soup”) – 

MDA, MMDA, DOM, TMA, PMA & DMA. 

Analogs of methaqualone, PCP and 

amphetamines in 1970s

Advent of Designer Drugs 

Potent fentanyl analogues from 1979 

Alpha-methylfentanyl – Controlled in 1981 

Many other fentanyls soon appeared 

Over 100 deaths due to fentanyls 

In 1982 – MPPP (meperidine analog) under 

the street name “new heroin” – Neurotoxicity 

(Parkinson’s”) due to by-product MPTP 

In 1980s – MDMA was another popular drug

Amendments to the 

Controlled Substances Act 

(CSA 1970) 

Comprehensive Crime Control 

Act of 1984 (Temporary 

Scheduling) 

Anti-Drug Abuse Act of 1986 

(Analogue Statute)

Temporary Scheduling 

(Comprehensive Crime Control Act of 1984) 

Actual abuse and imminent hazard to 

public health/safety risks 

As set forth under 21 U.S.C 811(h), 

following three factors under the CSA (21 

U.S.C. 811(c)) are to be considered in the 

evaluation 

4.Its history and current pattern of abuse 

5.The scope, duration, and significance of 

abuse 

6.What, if any risk to the public health

Temporary Scheduling 

(Comprehensive Crime Control Act of 1984) 

Lawfully marketed and IND drugs 

excluded 

DHHS notified but approval not required 

Schedule I (CI) status - 1 year + 6 months 

extension 

Initiation of full review including 

preclinical abuse liability assessment

Temporary scheduled 

drugs (1985-2005) 

Number of Drugs 

Scheduled 

14 

12 

10 

8 

6 

4 

2 

12 

1 

3 

1 

Total drugs = 26 

2 1 1 

3 2 

0 

1985 

1987 

1989 

1991 

1993 

1995 

Year 

1997 

1999 

2001 

2003

Analogue Enforcement Act 

Anti-Drug Abuse of Act of 1986 

As set forth under 21 U.S.C 802 (32 (A)), 

Controlled Substance Analogue means a 

substance with 

1. Chemical structure substantially similar 

to that of a CI or CII substance; 

2. Pharmacological effects substantially 

similar to that of a CI or CII substance; or 

3. Represented or intended to produce a 

similar effect as a CI or CII substance



Analogues are treated as CI substances 

only if they are intended for human use 

Analogues need not be clandestinely 

produced nor derived from a CI or CII 

substance 

Criminal, not regulatory controls of CI 

substances 

Prosecution on case by case basis 

Prosecution require expert testimony



Analogue does not include 

A controlled substance 

Any lawfully marketed substance 

With respect only to an investigational 

new drug (IND) holder, any substance 

with a currently active IND status

Recent Temporary 

Scheduling Actions 

Tryptamines (in 2003) 

Alpha-methyltryptamine (AMT) 

5-Methoxy-N,N-diisopropyltryptamine (5-MeO- 

DIPT) 

Piperazines (in 2002) 

Benzylpiperazine (BZP) 

1-[3-(trifluro-methyl)phenyl]piperazine (TFMPP) 

Phenethylamines (in 2002) 

2,5-Dimethoxy-4(n)-propylthiolphenylethylamine 

(2C-T-7)

Currently Encountered 

Tryptamines 

CH 3 O 

H 

N 

NH 2 

CH 3 

5-Methoxy-alphamethyltryptamine (5-MeO 

MeO-AMT)*# 

CH 3 O 

5 

H 

N 

H 3 C H CH 3 

H 

N H 

H 

5-Methoxy-N-methyl 

H 

N 

H 3 C 

N 

CH 3 O 

CH 3 

CH 3 

CH 3 

N,N-Diisopropyltryptamine (DIPT)* 

5 

CH 3 O 

5-Methoxy-N,N-diethyltryptamine (5-MeO 

MeO-DET) DET)* 

methyl-N-isopropyltryptamine (5-MeO 

MeO-MIPT) MIPT)* 

* These are positively identified by the Lab analysis. 

#One death associated with its abuse 

H 

N 

H 3 C 

H 

N 

N CH 3 

5-Methoxy-N,N-dimethyltryptamine (5-MeO 

MeO-DMT) DMT)*# 

CH 3 

N 

CH 3



H 

N 

H 

N 

CH 3 

H 

C 

H 

C CH 3 

H 

4 

O 

H 

N 

H 3 C H CH 3 

H 

N H 

H 

CH 3 

N,N-Dipropyltryptamine (DPT)* 

4-Methoxy-N-methyl-N-isopropyltryptamine (4-MeO 

MeO-MIPT) MIPT)* 

H 

H 

H 

H 

N 

H H C 

H 

H 

CH 

N 3 

C 

C 

C H 

CH 

H 3 

N 

H 

H 

N 

CH3 

H H 

H 

H 

N-Methyltryptamine (NMT)* 

N-methyl-N-isopropyltryptamine (MIPT)* 

4-Hydroxy-N,N-diisopropyltryptamine (4-OH 

OH-DIPT) 

* 

* These are positively identified by the Lab analysis. 

#One death associated with its abuse 

4 

OH 

H 

N 

CH 3 

H 3 C H CH 3 

N H 

CH 3



Cases (#) 

60 

50 

40 

30 

20 

10 

0 

54 52 

25 

6 4 3 1 1 1 1 

5-MeO-DMT 

5-MeO-AMT 

DPT 

5-MeO-MIPT 

NMT 

DIPT 

MIPT 

4-OH-DIPT 

4-MeO-MIPT 

5-MeO-DET


Phenethylamines 

O C H 3 

OCH 3 

N H 2 

NH 2 

I 

Cl 

O C H 3 

2,5-Dimethoxy 

Dimethoxy-4-iodophenethylamine iodophenethylamine (2C-I) 

I)*# 

CH 3 CH 2 

H 

CH 3 O 

OCH 3 

C 

H 

C 

H 

NH 2 

2,5-Dimethoxy 

Dimethoxy-4-ethylphenethylamine ethylphenethylamine (2C-E) 

E)* 

H 

H 

H 

H 3 

C 

C H 3 

O 

S 

OCH 3 

2,5-Dimethoxy 

Dimethoxy-4-chloro- 

phenethylamine (2C-C) 

C) * 

O C H 3 

2,5-Dimethoxy 

Dimethoxy-4-ethylthioethylthio 

phenethylamine (2C-T-2) 

2)* 

•These are positively identified by the Lab analysis. 

•## One death associated with its abuse. 

N H 2



CH 3 O 

NH 2 

H3C 

CH 3 O 

NH 2 

FH 2 C S 

OCH 3 

2,5-Dimethoxy 

Dimethoxy-4-(2-fluoroethylthio) 


21)@ 

H 3 C 

S 

OCH 3 

2,5-Dimethoxy 

Dimethoxy-4-(i) (i)-propylthio 


4)* 

H 3 CO 

NH 2 

Cl 

NH 2 

H 3 CO 

3,4-Dimethoxy 

Dimethoxy-phenethylamine (3,4-DMPEA) 

H 3 CO 

OCH 3 

4,5-Dimethoxy 

Dimethoxy-2-chlorophenethylamine* 

•These are positively identified by the Lab analysis. 

•@Possibly one death



30 

25 

29 

2C-I 

2C-T-2 

20 

15 

10 

5 

0 

8 

3 3 3 

1 1 1 

2C-C 

2C-E 

3,4-DMPEA 

2C-T-21 

2C-T-4 

2Cl-4,5-DMPEA


Designer Drugs 

Scope and magnitude of the problem – 

Internet; thousands of customers 

July 2004 - DEA shut down five websites 

under “Operation Web Tryp” 

Some purchases (Over 1 year 3 months 

period) found in a seized computer used by 

an website operator 

 

 

 

5-MeO-DMT 

– 679 orders for 824 gms 

5-MeO-DIPT 

– 536 orders for 642 gms 

5-MeO-AMT 

– 347 orders for 414 gms etc..

Administrative Scheduling 

- Designer Drugs 

Time window of 18 months following 

temporary scheduling 

Need for pharmacology evaluation 

NIDA/CPDD support - Chemical synthesis 

and preclinical abuse liability assessment 

Pharmacology tests - 5-MeO-AMT, DIPT, 

5-MeO-DET, 4-OH4 

OH-DIPT, 5-MeO5 

MeO-MIPTMIPT 

Chemical synthesis - 2C-I I and 2C-T-2

Administrative Scheduling 

- Designer Drugs 

Preclinical studies 

Receptor binding and functional assays (e.g. 5-5 

HT2A, 5-HT1A, 5 

DAT, NET, 5-HTT, 5 

monoamine uptake inhibition) 

Locomotor activity in mice 

Drug discrimination in rats (Training drugs: 

LSD, DOM, MDMA, DMT, methamphetamine, 

or cocaine) 

Self-administration

Contact Information 

Srihari R. Tella, Ph.D. 

Pharmacologist 

Drug and Chemical Evaluation Section 

Office of Diversion Control 

Drug Enforcement Administration 

Washington DC 

Tel: 202-307-7183 

Fax: 202-353-1263 

email: Srihari.R.Tella@usdoj.gov

Preclinical Abuse Liability Evaluation in Drug Control

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