in this topic is both professional and personal. I was first introduced to ayahuasca

back in 1987, during a trip to Ecuador. We were working with shamans, and

I met my future wife just before an ayahuasca session and changed my life in some

very significant ways, including my two children, who are now here, my two youngest children.

Also, about three years ago, I think it was, I traveled to Ecuador with my oldest son

who is now 22, who was experiencing substance abuse problems with alcohol and marijuana

and was getting into a lot of trouble. Fortunately we have a friend who's a shaman from Ecuador,

who now lives in Santa Fe, New Mexico, and he had said that [if] we traveled to Ecuador

to drink ayahuasca, that it would help him with his substance abuse problem. So, trusting

this gentleman very much, we traveled to Ecuador and drank ayahuasca under the tutelage of

an older shaman, friend of his, who had been drinking ayahuasca daily for over 50 years

in the Rio Napo region of Ecuador. Since my son has...it was not an instant cure, but he is

doing much better and not abusing substances any longer. So I have both a personal and

professional interest in this topic. Along with my friend James we decided to investigate

how [it is] possible that this foul-tasting liquid from the Amazon could help people with addictions.

So we began studying different mechanisms to see if we could come up with some hypotheses

that might be tested, to better understand how this medicine might work.

In looking at this we have come up with four different hypotheses, which we believe are interrelated,

that may explain how ayahuasca works. These are not independent hypotheses, but interrelated.

We looked at how ayahuasca may work at biochemical, physiological, psychological and

transcendent levels. That's what we'd like to present today. I'll turn [this] over to James,

for the hard parts of the talk.

[James:] So, to set the stage for our first and second hypotheses, I'm going to talk a little bit

about the basic biochemistry of ayahuasca and addiction. I'll start with the biochemistry

of ayahuasca. I suspect at this point in the conference many of you have been exposed to this material,

so I'll move through this first section relatively quickly.

Ayahuasca is most commonly a[n] admixture of two plants, Banisteriopsis caapi, from the

family malpighiaceae, which is a lot of fun to say, and Psychotria viridis, from the family rubiaceae.

Banisteriopsis caapi contains beta-carboline alkaloids. There's the structure of beta-carboline

there. It's an indole group, connected to a pyridine ring.

Banisteriopsis contains multiple beta-carbolines, primarily harmine and harmaline,

and to a lesser degree tetrahydroharmine. You can see how closely these resemble beta-carboline.

They differ only among themselves by the location and number of double bonds on the pyridine ring,

which is on the right.

So what makes beta-carbolines so important? They are important because they are

potent monoamine oxidase inhibitors, otherwise known as MAOIs. MAOIs prevent

the breakdown of monoamines by inhibiting the enzyme that breaks them down.

Some examples of monoamines (you've probably heard of many of these):

the catecholamines, like dopamine, norepinephrine, epinephrine, the tryptamines:

serotonin, melatonin, dimethyltryptamine, and there are many other amines:

trace amines, tyramine, histamine, thyronamine. The ones in red are going to be important for

our talk today. So the other plant, Psychotria viridis, contains N,N-dimethyltryptamine.

See the chemical structure there? It's an indole-alkylamine.

DMT is pretty much ubiquitous in nature, and it's even been found in human cerebro-spinal fluid.

You can tell by the name, dimethyltryptamine is similar to 5-hydroxy-tryptamine,

otherwise known as serotonin. They both have the indole group on the left [and a] tryptamine base.

Because of that similarity between dimethyltryptamine and serotonin, dimethyltryptamine works

on basically all of the serotonin receptors. In particular, it has agonist action at

subreceptor types 1C, 2A and 2C. Unfortunately for us researchers, [eerie cackling from audience]

DMT is a Schedule 1 drug under the Controlled Substances Act of 1970, and thus

has no approved medical use in the US. When smoked or snorted, DMT is a very potent,

very short acting medicine which causes a rapid altered state of consciousness.

However, when orally ingested, it's not active because it's broken down by monoamine oxidase

enzymes in the GI tract. It is active when orally ingested in the presence of an MAOI.

So when dimethyltryptamine in Psychotria viridis is combined with the monoamine oxidase

inhibitors in Banisteriopsis caapi, orally active ayahuasca is formed.

So on to the biochemistry of addiction. It is an incredibly complex phenomenon.

We don't really understand much about it. The brain is the most complex thing in the universe,

and addiction uses a lot of parts of the brain, so we're just now starting to figure this out.

We're going to be using a pretty broad definition of addiction today that is

inclusive of dependence, a complex set of behaviors that includes withdrawal, tolerance,

loss of control, compulsivity, preoccupation, and continued use despite adverse consequences.

Dopamine is one of the monoamines that we talked about earlier, a catecholamine,

it's a neurotransmitter and it's very strongly implicated in both the etiology and the

maintenance of addictive behavior. It is associated with things like desire, motivation,

salience, novelty, all surrounding pleasurable experiences, like Facebook. [laughter]

Natural pleasures, like food, sex, and for me recently, Girl Scout mango creme cookies,

[laughter] all increase dopamine levels. Delicious.

Drugs of abuse, however, increase dopamine much more than natural responses, 2-10 times

more, in fact, than non-drug experiences.

There is a mountain of research that supports the idea that elevations in dopamine

in a particular brain circuit called the mesolimbic pathway [contribute] to the reinforcing

effects of drug abuse and other addictive stimuli/behaviors.

The five major types of addictive substances, including alcohol, nicotine, stimulants, opiates,

and marijuana, are all known to increase dopamine in this pathway.

So what is the mesolimbic pathway? [It] has often been referred to as the pleasure center or

reward pathway of the brain. As basic as it gets, it's primarily three brain areas:

the ventral tegmental area, the nucleus accumbens, and the prefrontal cortex.

The ventral tegmental area is a group of neurons in the midbrain that release dopamine when

exposed to addictive drugs or even cues associated with addictive behavior.

That dopamine is communicated to the nucleus accumbens, which communicates with the

prefrontal cortex.

The prefrontal cortex is one of the evolutionarily newest parts of the brain.

It's associated with higher-level cortical processes like personality, executive functioning,

motivation...It completes the reward circuit by communicating back to the ventral tegmental

area both directly and indirectly through another limbic structure called the amygdala.

So we've been talking about elevations in dopamine in this particular brain circuit.

That's associated with reinforcement. However, acute withdrawal after chronic use

of substances is, in contrast, associated with low dopamine levels.

Doctors Michael Baumann and Richard Rothman at NIDA have proposed a very provocative

model for addictions called the dual deficit model. The premise of this model is that

repeated use of drugs of abuse result[s] in decreased levels of both dopamine and serotonin.

These deficits in these neurotransmitters are thought to contribute to withdrawal symptoms,

drug craving, and the potential for relapse.

The low dopamine is thought to play a role in anhedonia, psychomotor slowing, and craving

associated with withdrawal. The low serotonin is thought to basically underlie

symptoms consistent with major depression: depressed mood, obsessive thoughts,

suicidal ideation, impulsivity, etc. So craving may be a subjective manifestation of the brain's

homeostatic drive to normalize dopamine in withdrawal.

Researchers have found genetic polymorphisms for the dopamine D2 receptor.

There's 2 major alleles, DRD2 A1 and DRD2 A2. About a third of the US population is hypothesized to

have the [DRD2] A1 allele. People with this allele have a genetically predisposed lower level

of dopamine receptors and overall dopaminergic functioning, and as a result of this,

they're predisposed to addictive behavior because they always want to normalize that dopamine

level, that deficit, based on this principle.

So in review, high dopamine in the mesolimbic dopamine pathway is associated with

conditioning and reinforcement of addictive behavior. Low dopamine and low serotonin

are associated with withdrawal. So therefore, an ideal biochemical treatment would be something

that increases serotonin, and balances or normalizes dopamine between withdrawal and reinforcement.

Balance is not only the key to life, it is also the key to dopaminergic functioning.

High dopamine results in reinforcement of addictive behavior, low dopamine: withdrawal.

So our biochemical hypothesis is that ayahuasca's anti-addictive properties result from

its ability to raise global serotonin levels in addition to acting as an agonist at particular

serotonin receptors, and normalize and stabilize dopamine by what we're calling

tug-of-war mechanisms. So how does it act on serotonin? The monoamine oxidase inhibitors

in Banisteriopsis that we talked about inhibit the enzyme that breaks down serotonin,

which is a tryptamine, therefore raising global serotonin levels. DMT, as we talked about,

is an agonist at multiple serotonin receptors. Ayahuasca and dopamine is a little bit

more complex. This is the tug-of-war mechanism that I was talking about. So again, monamine oxidase

inhibitors are going to block the degradation of catecholamines like dopamine

just as they block the tryptamines like serotonin, resulting in elevated global levels.

In addition to that, 5-HT(1C) agonism is known to raise dopamine in the mesolimbic pathway.

In contrast to those two mechanisms, 5-HT(2A) and -C agonism is known to lower dopamine

in the mesolimbic pathway. So what we're hypothesizing is that these tug-of-war

mechanisms result in the net effect of normalization or stabilization of dopamine

above withdrawal but below reinforcement. So on to the physiology of addiciton.

The elevations in dopamine that we've been talking about in the mesolimbic pathway

are associated with a phenomenon called synaptic plasticity. This is a process by which

the communication and connections between nerve cells are altered or changed.

Synaptic plasticity has been associated with the development and maintenance

of addictive behavior. So releasing dopamine in two parts of the mesolimbic pathway that

we talked about, the ventral tegmental area and the nucleus accumbens, has been hypothesized

to reorganize neuronal circuits leading to or reinforcing addictive behavior.

We know drugs of abuse acutely raise dopamine in both those areas. This results in a

change in neural architecture, and that's associated with conditioned and learned processes.

This process has been referred to as "diabolical learning."

These neuroplastic changes result in the activation of reward circuitry even when exposed to

objectively neutral cues associated with addictive behavior. When I walk down the street,

I don't get a dopamine push when I see a street corner. However, the heroin addict who

walks by that same street and buys his heroin will get a little bit of a rush just walking by the corner.

That's the diabolical learning that we're talking about.

According to Stahl, the reward pathway has been "hijacked" by the addiction process.

Our physiological hypothesis is that ayahuasca facilitates adaptive synaptic plasticity by

regulating dopamine levels and a bunch of other associated cascades in the mesolimbic

pathway: things like glutamate, GABA, metabitropic second messengers, transcription factors.

There's a lot that goes on behind synaptic plasticity, but dopamine does play a large role,

we know. So again, balance is important. High dopamine: reward circuit hijacking.

Low dopamine: diminished impetus for neural plasticity. This adaptive plasticity

that we're talking about would allow the learning of new behaviors and associations without

hijacking the circuit. It would also, interestingly, supporting the unlearning of addictive

associations and cues, by allowing the person who is under the influence of ayahuasca to experience

these cues in the visionary state while being protected from the dopaminergic surge

that would lead to reinforcement or pathological learning (diabolical learning).

On to the psychology of ayahuasca and [I'll] pass it over to Mitch.

[Mitch:] So we've covered our first two hypotheses and we're running out of time,

so we're going to cover the psychological and transcendent hypotheses next.

one of the ways that it's believed that ayahuasca may work is to allow access to unconscious

emotional memories and issues which allows an opportunity to heal those.