Date: Sat, 21 Jan 1995
From: Alexander T. Shulgin
To: Carl Olsen
Subject: old letters
Hi:
I think these are the two files that you wanted. It is awful
to lose stuff from the hard disk, when there is no one else to
blame.
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olsen-01.ats
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Hello Carl:
Thanks for the letter. Let me see if I can answer your questions
without waiving my hands around.
(1) How many isomers are there of the THC molecule?
There is delta-1 THC (using a different numbering system, this is
also known as delta-9 THC). It has two asymmetric centers, and
so it can exist in a trans- or as a cis-form (known as
stereoisomers) and each of these forms is resolvable into a
dextro- and a levo-component (known as optical isomers). Putting
this into a box form, you have:
trans-pair (stereo) cis-pair (stereo)
dextro- d-(trans)-delta-1 d-(cis)-delta-1
(optical) THC ** THC
levo- l-(trans)-delta-1 l-(cis)-delta-1
(optical) THC * THC
which adds up to four isomers.
There is also delta-6 THC (same as delta-1(6) THC or, with a
different numbering systems delta-8 THC). Using the same square
as with the delta-1 isomer, we have:
trans-pair (stereo) cis-pair (stereo)
dextro- d-(trans)-delta-6 d-(cis)-delta-6
(optical) THC THC
levo- l-(trans)-delta-6 l-(cis)-delta-6
(optical) THC THC
which totals another four isomers.
There is a third isomer explicitly named in the law, not a
natural material, but a laboratory product that had been studied
in the early days of the chemistry of these compounds. This is
called delta-3,4 THC (or delta-6a,10a THC with the other
numbering system). Here the two optically active carbon atoms
that allowed the cis-trans argument now carry the double bond
(the meaning of the term delta) but a new optically active site
has been opened up at the 1- (9-) position. So there can be a
dextro-form and a levo-form (optical isomers) but no cis- or
trans-pairs. This totals to another two isomers. Thus the
answer to your first question, there are ten possible isomers of
THC to be considered in the halls of law enforcement.
(2) What is an isomer?
That depends upon who you ask, and in what context. Literally,
iso- means the "same", and -mer is from meros, meaning "part."
In common chemical usage, it is generally taken to mean that the
same atoms are there (in terms of which elements and how many of
them), but they are just hooked up differently. And when there
are describing (or limiting) prefixes, they emphasize just how
these different hookups are most readily recognized.
Stereoisomers are distinguished by the differences in shape.
Think of a hand in a five-fingered rubber glove, making all kinds
of different forms, but always with the same amount of hand
inside the glove. A fist shape and a splayed finger shape would
be stereoisomers.
Optical isomers are distinguished by their mirror-image
relationships. Two molecules not superimposable but are in every
other way identical. Put a rubber glove on your right hand, and
another on your left. They are identical, except that cannot be
superimposed. One is the mirror reflection of the other.
Positional isomers are defined as have certain groups as being
over there rather than over here. Consider a conventional rubber
glove (the thumb-shaped covering at position one) and then
another with the thumb position where the third finger usually
is, and the third finger position at the thumb's location. These
are positional isomers, with the finger positions being the
rearranged factor.
The authors of the law, and thus the DEA, are quite inconsistent
in the use of this term. Since you have the Controlled
Substances Manual, check out the first full paragraph on page 226
for some insight into this confusion (page 212 if you have the
first edition).
(3) Is delta-9 THC an isomer, or does it have isomers of its
own?
Look up at the first box. All for named items are isomers of
delta-9 THC (the trans- and cis-pairs, and the optical isomers of
each pair). Thus delta-9 THC can exist in any of four isomeric
forms. This is pretty close to saying that delta-9 THC has its
own isomers.
But, in common parlance, the term delta-9 THC is very often used
for the natural component of cannabis, the active component, and
this is explicitly the trans, levo-isomer of delta-9 THC. This
is the lower left isomer in that box, the one marked with a "*".
If this is the sense in which the term delta-9 THC is used (and
it is so used frequently and casually) then it is an isomer, the
natural isomer, the one with the * above.
The answer to this question depends exactly on what the asker has
in mind when he uses the term delta-9 (or, delta-1) THC.
Remember, that the two names are synonymous.
One final caveat. The delta-9 THC that is the material used in
the Schedule II drug known as Dronabinol is something yet
different than any of these. It is a synthetic material, and is
isolated as the trans- material, but I do not believe that it is
resolved into its optical isomers. Thus, in this context, delta-
9 THC is a 50:50 mixture of l-(trans)-delta-9 THC and d-(trans)-
delta-9 THC. This is a 50:50 mixture of the one * and the two **
things in the first box above.
To summarize:
When the term delta-1 (delta-9) THC is used to represent the
active factor of cannabis, it is the isomer with the one *.
When the term delta-1 (delta-9) THC is used to represent the
active component in the Schedule II drug, it is a 50:50 mixture
of the one * and two ** isomers.
When the term delta-1 (delta-9) THC is used to represent the
chemical concept without stereo- or optical-designations, then
the term embraces all four isomers in that first box.
Hope this helps. It is a one hour lecture distilled down into a
ten minute note.
Sasha
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olsen-02.ats
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Hi Carl:
I have just now been looking with more care at the package insert
that accompanies the commercial Marinol, Dronabinol, and also the
PDR, and both of them give the chemical name as:
(6a-R-trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-
dibenzo[b,d]pyran-1-ol
and the Merck index refers to these commercial drugs as
(-)-delta1-3,4-trans-form
I had assumed, without checking, that the synthetic material was
the racemate (the two trans isomers in the first of the diagrams
I sent you. But the letter "R" in the first name, and the minus
sign "-" in the second name, both attest to the fact that the
synthetic drug (the component of the schedule II item) is indeed
a single isomer. Thus the term delta-1 THC (delta-9 THC) means
not three things, but only two. As a general term, it can be all
four of those isomers, individually or collectively. As a
botanical term, it is the one specific isomer in that collection,
the l-trans delta-1 isomer (the first "l" is the letter ell, as
the first letter of levo, or rotating to the left and the second
is the number "1"). And so is the synthetic.
And, as to your other question, no, the two isomers cannot be
isolated from the plant, as only one is there.
To summarize:
l-trans- (the letter ell)
levo-trans
6a-R-trans
all refer to the natural (as well as the synthetic) delta-1 THC,
that is apparently prepared from optically active starting
materials.
dl-trans
racemic trans
6a without the R but with the trans
all refer to an optically inactive form of delta-1 THC, still
trans, but containing an isomer that is not found in nature, and
that is not in the drug Marinol.
delta-1 THC can refer to any or all of the four isomers,
both trans and cis, both levo and dextro.
Sorry about the wrong assumption above. Hope this makes
everything clearer.
Sasha