J. COCHIN 
705 
abstinence illness. It is now possible to make a 
preliminary estimate based on work in primates 
that has relevance to the risk of abuse of and 
addiction to that drug in man. 
It is obvious that subjective changes pro- 
duced by drugs can only be measured in man, 
although one gets a fairly reliable idea of some 
of the subjective phenomena in animals by sim- 
ply observing them carefully. Anyone who has 
worked with mescaline in the dog or monkey 
knows that these animals are hallucinating, but, 
since there is no way of proving it, most of us 
rion't have the courage of our convictions and 
would never put such statements in a scientific 
paper. Despite this limitation, it is still possible 
to qualitatively describe and quantitate the ab- 
stinence syndrome in animals, especially the 
monkey, using objective criteria very similar to 
those devised for the assessment of this syn- 
drome in man. 
Table I shows the large number of signs that 
are used in a weighted fashion in order to ar- 
rive at a score that gives one an idea of the in- 
tensity of the syndrome in the monkey. It is a 
close approximation of the Himmelsbach point 
system devised in Lexington,-" the most impor- 
tant difference being that subjective signs such 
as nausea, muscular discomfort and pain, burn- 
ing sensations, abdominal cramps, dizziness, 
headache and so on are omitted. In the monkey, 
it is possible to chart the temporal course of 
withdrawal and to measure the intensity, the 
Table I. — Signs of Abstinence in the Monkey 
Gastro-Intestinal 
Behavior (cont. ) 
Retching 
Fighting 
Vomiting 
Masturbation 
Dianhea 
Lying on Side 
Anorexia 
Peculiar Postures 
Insomnia 
Central Kervous System 
Holding Abdomen 
Muscle Rigidity 
Calling and Crying 
Muscle Twitches 
Docility 
Body Tremors 
Prostration 
Convulsions 
Autonomic Nervous System 
Metabolism 
Yawning 
Peak Respirations/Minute 
Lacrimation 
Lowest Temperature 
Rhinorrhea 
Weight Loss (Kg) 
Sweating Face 
Dyspnea 
Piloerection 
Miosis 
Behavior 
Pallor 
Apprehension 
Conjunctivitis 
Restlessness 
Vascular Collapse 
Chattering 
Quarreling 
Death 
peak and the duration of the syndrome with 
precision and great reliability. The overall point 
scores are compiled for each drug and some es- 
timate can be made of its addiction potential in 
man. Of course, there are some differences be- 
tween monkey and man in this respect but for 
the most part there is a striking parallelism. 
Once the criteria for the measurement of de- 
pendence were worked out for the monkey, they 
were used in two general procedures developed 
by Irwin-^ and by Deneau and Seevers.^^ The 
first, the single-dose suppression test, ascertains 
whether the test drug is capable of complete 
suppression of all abstinence signs in the mor- 
phine-dependent monkey. A large colony of 
monkeys is maintained in a state of morphine 
dependence and when a drug under study is to 
be tested, the morphine injections are discontin- 
ued until abstinence signs appear. The test drug 
is then substituted for morphine and the sup- 
pression or lack of suppression of abstinence is 
noted. The second procedure is a direct addic- 
tion test, in which the monkeys are chronically 
treated with the test drugs for a period of sev- 
eral weeks, the drug then withdrawn and the 
severity of abstinence compared with that of 
morphine-dependent animals. 
Although studies in primates have proven to 
be extremely valuable, there are obvious draw- 
backs. Because of the cost of maintaining a pri- 
mate colony, the difficulty of working with large 
and often extremely aggressive animals, and 
the expertise needed to evaluate the signs of ab- 
stinence, a number of smaller and/or less 
expensive species have been evaluated with ref- 
erence to their usefulness in the assessment of 
addiction potential. 
The mouse has been used by a number of in- 
vestigators but, in general, proves to be less 
satisfactory than other species. Tolerance is diffi- 
cult to induce and the precipitation of abstinence 
by the antagonists is subject to variability 
due to strain, age and method of drug ad- 
ministration. Recently two Chilean investiga- 
tors^^ developed a method of pellet implan- 
tation of morphine in mice and have been 
able to induce both tolerance and physical de- 
pendence in the implanted animals. Way and his 
associates have devised a test for dependence in 
which antagonist-treated mice are allowed to 
