Some science behind the scenes

Salvinorin

Salvinorin A is found in Salvia Divinorum.  Salvinorin A is a potent and selective κ-Opioid (kappa-Opioid) receptor agonist.   However, it is an even more potent D2 receptor partial agonist, and it is likely this action plays a significant role in its effects as well.

The kappa activity

Opioid receptors and legal highs: Salvia divinorum and Kratom - Babu KM, McCurdy CR, Boyer EW;  Division of Medical Toxicology, Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
Salvia divinorum and Mitragyna speciosa ("Kratom"), two unscheduled dietary supplements whose active agents are opioid receptor agonists, have discrete psychoactive effects that have contributed to their increasing popularity.
Salvia divinorum contains the highly selective kappa- opioid receptor agonist salvinorin A; this compound produces visual hallucinations and synesthesia. …... Despite their widespread Internet availability, use of Salvia divinorum and Kratom represents an emerging trend that escapes traditional methods of toxicologic monitoring.

and

Salvinorin A: the "magic mint" hallucinogen finds a molecular target in the kappa opioid receptor - Sheffler DJ, Roth BL;  Department of Biochemistry, Case Western Reserve University Medical School, , Cleveland, OH, USA.
Salvinorin A, a neoclerodane diterpene, is the most potent naturally occurring hallucinogen known and rivals the synthetic hallucinogen lysergic acid diethylamide in potency.
Recently, the molecular target of salvinorin A was identified as the kappa opioid receptor (KOR). Salvinorin A represents the only known non-nitrogenous KOR selective agonist..  PMID: 12628350

The dopamine activity

To understand the following paper, you need to know that Conditioned place preference (also known as environmental place conditioning) is a technique commonly used in animal testing to evaluate preferences for environmental stimuli that have been associated with a positive or negative reward.

The technique is often used to determine the addiction potential of drugs.  If the little animal likes what it has been given in one environment ‘preference’, it will return,  once it is back in its normal state to see if it can find the same thing again – much like we do if we find a nice restaurant or a pub.  If the experience was none too pleasant ‘aversion’, the animal will avoid the place, like we do with dentists.

Effects of the plant-derived hallucinogen salvinorin A on basal dopamine levels in the caudate putamen and in a conditioned place aversion assay in mice: agonist actions at kappa opioid receptors - Zhang Y, Butelman ER, Schlussman SD, Ho A, Kreek MJ; The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY, USA

 OBJECTIVES:  To study the effects of salvinorin A on basal dopamine levels in the caudate putamen and nucleus accumbens, and to determine whether salvinorin A induces conditioned place preference or aversion and changes in locomotor activity in the mouse.

METHODS:  In the first experiment, changes in dopamine levels in these brain regions after administration of salvinorin A were measured with in vivo microdialysis. In the second experiment, we examined whether salvinorin A led to conditioned place preference or aversion, and changes in locomotor activity during conditioning sessions.

RESULTS:  The higher doses of salvinorin A studied (1.0 mg/kg and 3.2 mg/kg, i.p.) significantly decreased dopamine levels in the caudate putamen, but not in the nucleus accumbens, and this effect was completely blocked by pre-injection with 10 mg/kg of the kappa opioid receptor antagonist nor-binaltorphimine. The same doses of salvinorin A caused conditioned place aversion and decreased locomotor activity.    PMID:  15682306

and

Depressive-like effects of the kappa-opioid receptor agonist salvinorin A on behavior and neurochemistry in rats - Carlezon WA Jr et al  Department of Psychiatry, McLean Hospital, Belmont, MA 02478.
Endogenous opioids seem to play a critical role in the regulation of mood states. For example, there is accumulating evidence that stimulation of kappa-opioid receptors, upon which the endogenous opioid dynorphin acts, can produce depressive-like behaviors in laboratory animals. Here we examined whether systemic administration of salvinorin A (SalvA), a potent and highly selective kappa-opioid agonist, would produce depressive-like effects …………
. At a dose that caused the depressive-like effects……, SalvA decreased extracellular concentrations of dopamine (DA) within the nucleus accumbens (NAc), a critical component of brain reward circuitry, without affecting extracellular concentrations of serotonin (5-HT). These data provide additional support for the hypothesis that stimulation of brain kappa-opioid receptors triggers depressive-like signs in rats and raise the possibility that decreases in extracellular concentrations of DA within the NAc contribute to these effects.

The nucleus accumbens is thought to play an important role in reward, pleasure, laughter, addiction, aggression, fear, and the placebo effect.

Overall effect

Salvinorin A is a D2 agonist and a potent one.  But is it one directly or one indirectly?  I think it is one indirectly.  The kappa activity that we have seen in the section on neurotransmitters is partly achieved via the dopamine receptor and thus the D2 activity is a by-product of the overall kappa activity.  If we summarise the effects of the D2 agonistic actions, we see that they are

Normal dose

High or over dose

Vasodilation

 

 

 

Increased renal perfusion

Nothing

Orthostatic hypotension leading to hypoxia

 - Unusual tiredness or weakness

-        Dizziness, drowsiness, lightheadedness, or fainting

Incontinence and urinary urgency

Nausea

 

 The kappa effects

These receptors are found in the brain, the spinal cord and ‘pain neurons’ in the skin.   The functions are fairly complex, acting both directly and indirectly:

  • Dysphoria - The anti-rewarding properties of κ-opioid agonists are well known and seem to work a number of ways.  These receptors  produce dysphoria (the opposite of euphoria) where the dysphoria differs between sexes.  Effects can include nervousness, depression, restlessness and crying.  In addition, the immediate effect of κ-opioid agonism leads to reduction of dopamine release, although the administration of a κ-opioid agonist as we have seen  produces an increase in dopamine D2 activity and receptors in the brain. 
  • Pain relief - Stimulation of relief from abdominal pain and bloating this may be accompanied at high dose by cramps, dyspepsia, and a bitter taste, this is why the plant salvia is being considered as an aid to help in stomach problems
  • Nausea – and vomiting at higher doses, this may be a knock on effect from the dopamine effects
  • Diuretic - It also causes an increase in urine production this was attributed to the release of vasopressin, but it could also be attributable to the dopamine effects. 
  • “Interoceptive effects” - depersonalising and derealising, psychotomimetic  - psychotomimetic actions mimic the symptoms of psychosis, including ‘delusions, visions and/or hallucinations’.  Because the principal effects are that of dysphoria, these hallucinations may not be pleasant and can include psychological symptoms such as feelings of unease and  paranoia
  • Cardiovascular – hypertension,  increased cardiac load,  or hypotension, bradycardia, tachycardia
  • Respiratory depression -  at higher doses pulmonary edema occurs when the pressure in blood vessels in the lung is raised because of obstruction to remove blood via the pulmonary veins. Pulmonary edema produces shortness of breath. Pleural effusions may occur when fluid also accumulates in the pleural cavity
  • Visual distortions – possibly caused by the increase in blood pressure

One rather odd knock on effect is that kappa opiate receptor agonists increase the pituitary hormone prolactin [Source PMID: 3079599].  Prolactin has all sorts of effects:

  • Sexual depressant - It decreases the normal levels of sex hormones — estrogen in women and testosterone in men. It is this inhibition of sex steroids that is responsible for loss of the menstrual cycle in lactating women as well as lactation-associated osteoporosis.
  • Hair thinning - It seems to delay hair regrowth leading to balding
  • Brain neuron increase -  It “promotes neurogenesis”, neurogenesis is responsible for populating the growing brain with neurons.  This is why drugs in this class have sometimes been used to counteract the effects of drugs that cause permanent memory impairment.
  • It also stimulates growth hormones, whilst inhibiting the thyroid-stimulating hormones (TSHs).